Robinson Research Institute Annual Report 2014 Our vision is to achieve life-time health for all children and families, through research excellence

Our mission is to deliver world-class advances in knowledge of human reproduction, pregnancy and child health, and to inform clinical care, policy and practice that will improve health across generations and global communities.

Contents

Who we are 1 Community and Sector Engagement 24 RRI at a glance 2 Science Stories 27 Message from the Deputy Media Impact 28 Vice-Chancellor Research 3 Research Groups 29 Message from the Chair 3 Advisory Board 4 Fertility and Conception 31 Pregnancy and Birth 40 Message from the Director 5 Early Origins of Health 45 Executive Committee 6 Child and Adolescent Health 50 Research Highlights 9 Fostering Research Excellence 58 2014 Discovery Highlights 10 Core Facilities 58 Funding Highlights 12 Investing in People and Building Capacity 59 Fellowships and Awards 13 Financials 14 Robinson Research Foundation 63 Key Collaborations 16 Robinson Research Institute Member List 64 International Visitor Spotlight 18 Publications 66 Support us 79 Clinical translation 19 Commercial Development 22 Who we are

The Robinson Research Institute is a collective of internationally renowned researchers in human reproduction, pregnancy and child health at the University of Adelaide.

We focus on the early stages of life to improve the health and well-being of children and families over the life course and across generations, in Australia and around the world. We seek to enable a healthy start through fertility choices and mindful conception, nurturing the baby during pregnancy and birth, strengthening the brain and body in early life, and advancing child and adolescent health to treat and prevent disease.

The Robinson Research Institute Structure

University of Adelaide Vice-Chancellor & President

Deputy Vice-Chancellor (Research)

Advisory Board

Director

Deputy Director

Executive Committee

Professional Research Themes Core Facilities Research Support

> Fertility & > Adelaide Research > Management / Conception Assay Facility (ARAF) Finance > Pr egnancy & Birth > Bioinformatics > Reputation & > Early Origins > Biostatistics Communication Robinson of Health > Resear ch Funding Foundation > Cohort & Committee > Child & Adolescent Intergenerational & Support Health Studies (CIS) > Executive > Gene Silencing & Assistance & Expression (GSEx) Administration > SA Genome Editing (SAGE)

Annual Report 2014 1 RRI at a glance

$16.5m+ 4 370+ funding in 2014 Research Themes publications

$34,000+ 10 Embedded in raised for the Robinson Research Priorities SA hospitals Research Foundation 5

48 100+ Affiliations the School of Paediatrics Research Leaders PhD students and Reproductive Health

400+ 20+ Collaborations multiple national and Members Honours students international

2 Robinson Research Institute Message from the Deputy Vice-Chancellor Research

The University of Adelaide is committed to expanding and further investing into strategic research.

Our goal is to deliver world-class research and and bridging the gap between research discoveries to translate our research findings to bring about and clinical practice. improvements in people’s lives. Our five research As you read through the stories within this report you institutes are set-up to address national, state and will appreciate the great breadth and depth of the global priorities, focussing on the key challenges of research being undertaken at The Institute. critical value to society. One of those challenges is I would personally like to commend the members of securing a healthier future for our children. This is the Institute for their commitment and drive to solving closely aligned with one of the highest-level objectives major health burdens that impact upon society across of the South Australian State Government in the globe. I am confident they will continue to bring to recognising that ‘good health is everything’ and that light new discoveries, and make major contributions we are ‘giving our children every chance to achieve toward the transformation of clinical care and policy their potential in life’. for the health of all children and families. The Robinson Research Institute aims to uncover the factors that influence health across our lifetime and Professor Mike Brooks across generations. With over 400 talented scientists Deputy Vice-Chancellor and and clinicians, the Institute is advancing knowledge Vice-President Research

Message from the Chair

2014 was a year of consolidation, enhanced collaboration and preparation for the future.

As members embrace the model of collaboration, I government and the community on the importance am witnessing a renewed vitality and an emerging of investing in and raising funds for health, medical appetite to challenge the boundaries of research, tackle research and infrastructure. new areas and to develop diverse partnerships to I wish to acknowledge and thank each of the enable this. following: The Institute continues to lead the way and build >> RRI Board Members for their commitment, on past strengths. It remains proactive in reviewing considered contributions and general ‘value-add’ and adapting to the dynamic environment in which to the Institute it operates. This year has seen investments in >> RRI Members who have again made many great research funding programs re-focused and refined strides in their research work to deliver increased value to the research efforts and competitive standing of members. >> RRI Director – Professor Sarah Robertson, she has shown great leadership, tenacity and insight Financial support for medical research continues in progressing and implementing fundamental to be a significant challenge. In 2014, the Federal initiatives that are serving the interests of the Government announced it would establish a Medical Institute well, both now and into the future Research Future Fund valued at $20 billion by 2020. The deregulation of University fee structures The Institute has much to celebrate and much to look is another key policy on the drawing board. At the forward to in 2015. It will be exciting. It will be challenging. time of writing this message the government reforms remain unresolved. We must keep the conversation Professor Jock Findlay alive and build broad understanding across Chair

Annual Report 2014 3 Advisory Board

Prof Jock Findlay AO (Chair) Prof Mike Brooks Prof Alastair Burt

A/Prof Naomi Dwyer Prof Julie Owens Prof Sarah Robertson

Prof Paul Rolan Prof Andrew Zannettino

4 Robinson Research Institute Message from the Director

My first year as Director of the Robinson Research Institute has been a remarkable one. The breadth and talent of science and research we deliver, and the dedication and talent of our wonderful people – the Research Leaders and their staff and students - is extraordinary.

Its been inspiring to get to better know many In 2014 we were committed to refining our In 2015 we will work towards establishing of our 400 people, and to devise concrete Institute goals and to develop mechanisms our new home in the Adelaide Nursing ways the Institute can support and enable and programs to support delivery and Medical Schools building in the West their important work. of the best possible outcomes. We now have End precinct. We look forward to reaping To discover, to understand, and to direct a defined series of initiatives that assist the benefits of new facilities, improved the benefit of new knowledge to improving researchers to develop large scale funding infrastructure and equipment, and greater the health and quality of life for children and applications, to increase project competitiveness opportunity to interact with other medical families is our shared ambition. We have some for national funding support, to provide researchers in Adelaide’s consolidated of the most innovative and skilled researchers seed funding and mentoring schemes to medical research precinct. The synergies in the country. Our capacity to bring our encourage our early career researchers, as and efficiencies to be realised will assist us collective abilities to bear on major questions well as a wide range of opportunities to help in dealing with a difficult economic climate, spanning reproduction, pregnancy and researchers communicate their research and a contracting medical research funding childhood is unparalleled. The Institute affords outcomes, publish in the best journals, and base. With new partnerships there will be us the vehicle to work collaboratively to tackle better engage with media. even better opportunities to strengthen our the important and difficult research questions These programs build on the Institute’s team-based approach to issues that have that are beyond our scope as individual research investment in core facilities to underpin the global significance. groups, but tractable if we pull together. research effort across all of the four Research The Institute is proud to foster and develop Tackling the earliest phase of life is the Themes. We are now delivering advanced Adelaide’s historic leadership in reproductive key to solving many of the major health capability in gene manipulation through the science and medicine. I am grateful to the conditions affecting Australians and people GSEx Facility, in large-scale data analysis in University leadership for their investment in across the globe. Focussing our efforts the Bioinformatics Facility, in measuring a our research and confidence in our research on conception, pregnancy, and the infant wide range of analytes through the Research excellence. We are supported by the and child will deliver great dividends in Assay Service and in delivering coordinated fantastic work of the Institute office staff, not community and population health. We are epidemiological and mechanistic analyses least the efforts of Institute Manager Ms Kate committed to ensuring that all intending through the Cohort and Intergenerational Irving. I also thank the Advisory Board, and parents plan good pregnancy health from Studies Facility. New in 2014 were the particularly Chair Professor Jock Findlay, for before conception; to reduce the toll of SA Genome Editing Service, to fast-track encouragement and guidance. preterm birth on conditions like preeclampsia development of genetic mouse models, and I hope you enjoy this report, which and gestational diabetes that have life-long services to deliver Biostatistics support. highlights the diversity and impact of our consequences; to alleviate the pregnancy In 2014 we secured several new NHMRC research programs over the last 12 months. disorders and early life events that contribute and ARC project grants and fellowships, and Our contributions continue to push the to non-communicable conditions including were especially pleased with the award of boundaries of human knowledge, and show obesity, diabetes, allergy and neurological two NHMRC Centres of Research Excellence the many ways we translate our discoveries impairment; and to develop new interventions in the Protection of Pancreatic Beta Cells to make a real difference in people’s lives. that protect children from infection, disability and in Polycystic Ovary Syndrome. Professor Sarah Robertson and neuro-developmental disorders.

Annual Report 2014 5 Executive Committee

Prof Sarah Robertson (Chair) A/Prof Simon Barry Prof Jenny Couper

Prof Jodie Dodd Kate Irving A/Prof Helen Marshall

Prof Julie Owens Prof Claire Roberts Prof Ray Rodgers

A/Prof Darryl Russell A/Prof Michael Stark

6 Robinson Research Institute Associate Professor Helen Marshall Preterm infants are at risk of severe whooping cough

While most countries have a vaccine In Australia a program has recently been introduced program against whooping cough (pertussis), to protect infants by immunising pregnant mothers in epidemics still occur every 3 – 4 years. the third trimester of their pregnancy. Helen’s research findings strengthen the evidence for the value of this Currently there is no effective treatment for whooping new approach. cough. Those who present to hospital with symptoms receive supportive treatment – which may include “By immunising pregnant mothers against whooping antibiotics, oxygen and intravenous fluid – and wait cough, the mother transfers protective antibodies to for the infection to pass. However, those with severe the fetus which protect the infant during the few few infection may need to be managed in the intensive months of life, when they are most at risk, prior to care unit, and may be sick for up to 3-6 months. For developing their own active protection through infant some, the infection can lead to death. Ten Australian immunisation,” said Helen. babies died in the last whooping cough epidemic. For those mothers who do not receive the vaccine in Research led by Associate Professor Helen Marshall, pregnancy or who deliver preterm infants, their babies who leads the Vaccines and Infectious Diseases are at highest risk of severe infection. Group, studied 120 children with whooping cough This also raises questions about alternative strategies who were admitted to hospitals across Australia. They such as whether the immunisation could be given earlier set out to find whether they could predict earlier the - at birth. Helen’s group recently investigated this as children who are more likely to become severely unwell part of a large national study, the largest study of its from whooping cough. kind in the world. Further research is required to better “We found the most severe cases of whooping cough understand the immunisation strategies that will provide were in infants less than two months of age and those the best overall protection for our most vulnerable babies. born prematurely, who had almost five times the risk The last whooping cough epidemic occurred in of severe disease compared to older infants and those Australia in 2010, where more than 34,000 cases were born at term.” notified nationally. “The dilemma is that those at highest risk of severe “Australia has not experienced a whooping cough disease are too young to be protected by immunisation, epidemic of that size since, but we are well overdue as childhood vaccines in current national programs for another one.” start at six to eight weeks of age,” said Helen. “I am also interested in looking at strategies for improving uptake in pregnant women so our most vulnerable are protected when the next epidemic hits,” said Helen.

Annual Report 2014 7 Associate Professor Rebecca Robker Passing on obesity – can we reverse the damage?

There is a growing body of evidence “Understanding the type of stress involved, suggesting that one’s susceptibility we were able to utilise compounds known A/Prof Rebecca Robker and Dr Linda Wu to becoming overweight or obese is to alleviate endoplasmic reticulum stress in established very early in life. Associate cells.” Professor Rebecca Robker leads the “These compounds were highly successful Ovarian Cell Biology group and has in preventing the stress response – they 60% of Australian studied the ovary for many years. Her restored egg quality, embryo development understanding of the ovary’s importance for and mitochondrial DNA levels to those women are overweight women’s health led her to look at the effect equivalent of a healthy mother,” said Linda. of maternal obesity on egg development. Rebecca and Linda’s research has been or obese. This is a “When examining the oocytes of obese undertaken largely in mice, however, they mice we noticed there was a reduced level believe similar mechanisms are at play in major concern as type of mitochondrial activity. This was an humans. Through restoring egg quality, important discovery as all of the mitochondria offspring from obese women will be less 2 diabetes is projected in the subsequent offspring must be generated susceptible to obesity later in life. from those in the egg,” said Rebecca. to be the leading cause “Although this research offers relief for Mitochondria are energy-producing obese women struggling to conceive and of disease burden in ‘organelles’ within living cells. They are who are concerned for their children’s long- essential for the normal functioning of our term health, we believe it highlights that a Australia by 2023. body tissues, and Rebecca has shown that woman’s nutritional state prior to getting obesity leads to an endoplasmic reticulum pregnant matters greatly.” stress response in ovarian cells that causes “Women are urged to eat healthy diets damage to the mitochondria. to optimise their chances for a healthy “The reduced levels would affect an conception and to prevent multi-generational offspring’s metabolism, potentially pre- disease risk passing onto their children.” disposing them to obesity later in life. In While this research sends an important support of this, we found that the offspring message to would-be mothers, it is important conceived from the eggs of obese mothers to note that nutritional cues are also passed were heavier,” explained Rebecca. on through sperm from the father. Once Rebecca and Postdoctoral Researcher “The next piece of the puzzle is Dr Linda Wu uncovered the type of stress understanding how the male and female involved, they were the first to test whether cues interact in programing the offspring - candidate drugs could protect the eggs and not just for obesity, but a range of metabolic improve embryo development. conditions,” said Rebecca.

8 Robinson Research Institute Research Highlights

2 cell embryo Dr Melanie McDowall

Annual Report 2014 9 2014 Discovery highlights

Excellence in Research >> A potential intervention to reverse the >> Demonstration that dietary sodium impact of obesity in pregnancy on the affects vascular health in children with for Australia offspring. Rebecca Robker and Linda type 1 diabetes. Jennifer Couper, Chad Excellence in Research for Australia (ERA) Wu demonstrated that mitochondrial Andersen and Alexia Pena’s discovery is an initiative of the Federal Government. loss in offspring results from obesity in has implications for diet management in ERA is a research quality and evaluation pregnancy, and they were able to reverse affected children. system developed by the Australian these changes during the final stages of >> Finding that gastric emptying is more Research Council (ARC) in conjunction with oocyte development. rapid in children with type 1 diabetes. the Department of Innovation, Industry, >> Mapping of more than 1,000 genes Shiree Perano and Jennifer Couper found Science and Research (DIISR). that are differentially expressed in the gastric emptying affects these childrens’ The ERA initiative aims to provide a oviduct and regulated by the steroid ability to control blood glucose levels transparent system to assess research hormone progesterone. Lisa Akison and after meals. quality, utilising a combination of metrics Rebecca Robker’s research is important >> Demonstration that patterns of focused on publications and other research in understanding how progesterone cytokines in the mammary gland vary outputs, research income, esteem and establishes an optimal environment for over different stages of the menstrual applied measures. The information is early embryo development. cycle. Pallave Dasari and Wendy Ingman’s reviewed at the national level by evaluation >> Discovery that hemoglobin is present finding of inflammatory cytokines at committees comprising experienced, in the ovary, particularly granulosa and ovulation advances understanding of how internationally-recognised experts. cumulus cells, as well as the oocyte. the biology underpinning breast cancer risk, The most recent ERA results were released Hannah Brown and Jeremy Thompson are and may lead to new preventative strategies. in 2012. The Robinson Research Institute, investigating why this gas-binding protein >> New data showing that oxygen through the School of Paediatrics and appears in these cells, and how this utilisation accurately identifies those Reproductive Health, performed in the contributes to healthy ovarian function. preterm infants at increased risk of highest level in both the 2012 and the earlier >> Evidence revealing that pregnant significant brain injury. Michael Stark 2010 rounds, ranking 5 – well above world women who eat a diet high in fat and believes this novel approach will lead to standard. This cements the University of sugar are 50% more likely to deliver improved neuro-protection through early Adelaide’s leading position in paediatrics and preterm. Jessica Grieger and Vicki identification of infants requiring interventions. reproductive medicine – we are the only Clifton believe that dietary changes prior >> Discovery that male factors present University in Australia to achieve this discipline to pregnancy and during pregnancy will in seminal fluid have a major impact ranking for the second time running. prevent many preterm deliveries. on the phenotype of offspring – >> Discovery of 12 isoforms of the programming obesity and metabolic Discovery Highlights: glucocorticoid receptor in the human dysfunction in males when disrupted. placenta. Zarqa Saif and Vicki Clifton are John Bromfield, John Schjenken and Research in 2014 resulted in: now exploring how these isoforms enable Sarah Robertson discovered that male >> Understanding that the contribution of placental cells to refine their response to seminal fluid effects are mediated in part genetic mutations to cerebral palsy is environmental stressors. through the regulation of cytokines in the higher than previously believed. Alastair >> Utilising x-rays to measure the depth female reproductive tract. MacLennan and colleagues advanced of the airway surface liquid to assess >> An invitation to Sarah Robertson, the field by finding common mutations the state of hydration on the airway Rebecca Robker and Michelle Lane amongst cases of cerebral palsy. surfaces of cystic fibrosis patients. from Science to explain how information >> Identification of a novel gene implicated David Parsons, Martin Donnelley and transmitted through female and male in intellectual disability with epilepsy. collaborators at the Japanese Spring-8 gametes at the time of conception can Lachlan Jolly and Jozef Gecz discovered x-ray synchrotron developed this non- have life-long effects on offspring health. a link with the USP9X gene, coding for invasive technique. >> Finding that healthy female embryos ubiquitin specific protease. >> Pioneering the use of genome editing at mid-gestation display hallmarks >> Identification of the role for a receptor (CRISPR/CAS9) technology to rapidly of intrauterine growth restriction called CRIg implicated in diabetes, generate genetically modified mouse consistent with differences in fetal arthritis and inflammatory bowel strains for biomedical research. Paul biometry at birth. Stefan Hiendleder disease. Tony Ferrante and colleagues Thomas and colleagues have produced believes this could explain sex-specific found CRIg to be a key gateway through over 15 mutant strains that are providing differences in postnatal health outcomes. which inflammatory mediators work to new insight into diseases such as epilepsy promote or resolve inflammation and and intellectual disability. tissue damage.

10 Robinson Research Institute Oocytes stained with markers that detect anti-oxidants Dr Melanie McDowall

>> Demonstration of the interface between >> Discovery of a method of engaging the >> Evidence proving that healthy eating the maternal endocrine system and tumour necrosis factor (TNF) receptor and increased physical activity during the developing oocyte. Darryl Russell to give a more selective signal to cells pregnancy improves outcomes uncovered a specific family of proteins and reduce the side effects of potential for babies at birth. Jodie Dodd and regulated by maternal hormones, which therapies. Tony Ferrante and colleagues colleagues’ LIMIT trial (the world’s biggest control the development and ovulation of believe these findings may mediate the study of its kind) resulted in fewer babies the oocyte. effects of therapeutics that result in lung born over 4kg, decreased chance of >> Discovery that follicular cells of women damage in children. respiratory distress syndrome and reduced with diminished ovarian reserve have >> Demonstration that a six-month length of stay in hospital. altered metabolic function, deacteylation structured lifestyle intervention >> Improved understanding of risk factors and desuccinylation. Michelle Lane, program in subfertile women with a BMI leading to severe whooping cough. Leanne Pacella and Deidre Zander-Fox ≥ 29kg/m2 is successful. Ben Mol and Helen Marshall showed that infants who demonstrated the molecular nature of Meike Mutsaers’ multicenter randomised were less than 2 months of age, presented the ovulated oocyte is different in these controlled trial showed that 45% of with a fever, were born preterm and had women and it appears to have a reduction ongoing pregnancies were achieved a concurrent infection were more likely to in mitochondrial function. spontaneously in the intervention group, develop severe whooping cough. >> New studies showing how the versus 28% in the control group. >> Interventions to prevent or ameliorate hyaluronan (HA) inhibiter, >> Improvements in IVF success through risks of pregnancy complications. Claire 4-methylubelliferone (4-MU) more effective quality embryo selection. Roberts and Gus Dekker have developed significantly inhibits the growth of Melanie McDowall is researching how a test that uses a combination of genetic ovarian cancer cells. Martin Oehler autofluorescence signals of metabolism biomarkers and clinical and lifestyle factors and Carmela Ricciardelli believe reducing can be used as a diagnostic for embryo to predict risks in early pregnancy for HA production is a promising strategy to health, without damaging the embryo. future complications including preeclampsia, improve ovarian cancer survival. >> Discovery that the trace element preterm birth, growth restriction and >> Identification of new genetic pathways selenium protects the egg from oxygen gestational diabetes. in follicular development. Ray Rodgers radicals in the late stages of follicular and colleagues discovered that granulosa development. This advance by Ray cells change dramatically and thecal cells Rodgers and colleagues is pertinent barely change during follicle development, information for people living in areas with and small follicles vary considerably in low levels of selenium in the soil and food. their gene expression profiles, but large or atretic follicles are much less variable.

Annual Report 2014 11 Funding highlights

In 2014 the Robinson Research Institute attracted funding from major bodies to support our research. Highlights are listed below.

NHMRC $2.5 million to Professor Helena Teede Cerebral Palsy Alliance Professor Helena Teede (Monash University Research Foundation Project Grants commencing in 2014: CIA) together with RRI members Professors Professor Caroline Crowther and colleagues Robert Norman, Michael Davies and Ray were awarded $250,000 for their project $763,953 to Professor Jozef Gecz Rodgers and Drs Lisa Moran and Alice commencing in 2014: Working to improve The role of UPF3B and nonsense mediated Rumbold awarded a CRE for evaluation, the survival and good health for babies born mRNA decay surveillance in the pathology management and health care needs of preterm: The Wish project follow up study. of intellectual disability Polycystic Ovary Syndrome and related $755,660 to Associate Professor health implications. Channel 7 Children’s Michael Ridding Research Foundation Characterising post stroke neuroplasticity Project grants awarded in 2014: RRI members were awarded 16 project in humans? Identifying a critical window grants commencing in 2014/2015 totaling $585,276 to Professor Sarah Robertson for rehabilitation more than $965,000 from the Channel Infl ammatory cytokines as causal agents 7 Children’s Research Foundation. This $755,934 to Professor Jodie Dodd in peri-conception programming of includes $58,600 to Dr Nicolette Hodyl Causal pathways from maternal obesity offspring health for: Regulating infl ammation in the preterm to pregnancy, perinatal and childhood $397,077 to Dr Michelle Lane neonate: the contribution of microRNAs. health outcomes Metabolic and molecular basis of embryo $576,174 to Associate Professor signaling Juvenile Diabetes Cheryl Shoubridge Research Foundation Investigating the role of mutations in the ARC Professor Jennifer Couper was awarded ARX homeobox transcription factor Associate Professor Jeremy Thompson $7.8 million for the Environmental contributing to intellectual disability is a Chief Investigator on an application Determinants of Islet Autoimmunity study. led by Professor Tanya Monro; Director of $548,748 to Associate Professor the Institute for Photonics and Advanced Ovarian Cancer Darryl Russell Sensing. They were awarded $23,000,000 Research Foundation Manipulating ovarian follicle–oocyte by the ARC to establish a Centre of Professor Martin Oehler was awarded communication to control reproductive Excellence for Nanoscale BioPhotonics – $338,000 for two projects: Autoantibody outcomes commencing in 2014. biomarkers for ovarian cancer detection and $534,021 to Professor Claire Roberts The ARC awarded Professor Paul Thomas Biospecimen collection and processing, Fetal sex: an important determinant of the $390,000 for the project commencing in maintenance of databases, and provision of placental transcriptome 2014: Genetic control of spermatogenesis - samples for the OCRF tissue bank. defi ning the role of SOX3 in spermatogonial $511,226 to Dr Julia Pitcher Women’s and Children’s progenitor cells. Mechanisms underlying impaired Hospital Foundation neuroplasticity in adolescents born preterm Alzheimer’s Australia RRI members were awarded 9 project $499,169 to Associate Professor Dr Mitchell Goldsworthy was awarded grants commencing in 2014/2015 totaling Rebecca Robker $50,000 for his project: Combined TMS-EEG $599,157. This included $75,000 to The obesity prone oocyte-causes, for early diagnosis of Alzheimer’s disease. Professor Tony Ferrante for: Vitamin D and consequences, treatments innate immunity in the neonate. Australian Pork Limited Centres for Research Excellence Associate Professor Mark Nottle was awarded in 2014: awarded $191,000 for his project: $2.5 million to Professor Jennifer Couper Development of thyroid biomarker for Professor Jennifer Couper (CIA), Professor use in pre-pubertal gifts to select for Jodie Dodd and Dr Lynne Giles awarded a embryo survival. CRE for the Protection of Pancreatic Beta Cells.

12 Robinson Research Institute CRE for the Protection of Pancreatic Beta Cells

Professor Jennifer Couper

In October, the Hon Tony Abbott announced the creation of the $2.5 million Centre of Research Excellence in the Protection of Pancreatic Beta Cells.

Led by Professor Jennifer Couper, this CRE brings together an expert team of clinicians and researchers from across Australia to investigate: >> What causes the immune system to attack pancreatic beta cells? >> Why do certain genes put some people at greater risk of developing type 1 diabetes? >> Where could we possibly intervene to prevent or reduce beta cell destruction? >> How can we preserve beta cell function in people already diagnosed with type 1 diabetes?

Fellowships and Awards

ARC Other Fellowships (awarded 2014) Endocrine Society of Australia Dr Lisa Moran awarded the Ken Wynne ARC Future Fellow Barbara Kidman Women’s Fellowship Post-Doctoral Research Award Dr Adriana Parrella Associate Professor Megan Warin Healthy Development Adelaide (HDA) (awarded 2014) Cerebral Palsy Foundation Fellow Ms Bing Wang awarded the HDA PhD Dr Clare van Eyck Scholarship and Dr John Schjenken awarded NHMRC Lloyd Cox Fellowship a HDA Travel Grant Professor David Kennaway, Dr Julia Pitcher, International Conference of Spermatology Commencing in 2014 Associate Professor Michael Ridding and Dr Nicole McPherson awarded the Best Associate Professor Darryl Russell Early Career Fellowship Scientific Talk Dr Rosalie Grivell and Dr Luke Grzeskowiak Robinson Research Institute Fellowship International Society for Animal Genetics Dr Hannah Brown Mr Ruidong Xiang awarded a Travel Grant Awarded in 2014 Women’s and Children’s Hospital National Public Health Senior Research Fellowship Friend’s Fellowship Association of Australia Associate Professor Jeremy Thompson Ms Jane Tuckerman Ms Bing Wang awarded the Early Career Senior Practitioner Fellowship Public Health Award in Immunisation Awards and Prizes Professor Jodie Dodd and Professor Ben Mol Perinatal Society of Australia Australian Society for Medical Career Development Fellowship and New Zealand Research (ASMR) Associate Professor Helen Marshall Dr Kathryn Martinello awarded the Ms Chantelle McIntyre awarded the Early Career Researcher Travel Award Early Career Fellowship Best Presentation at the ASMR Annual Ms Philippa Middleton Scientific Meeting Safework SA Ms Renae Fernandez awarded the CJ Martin Biomedical Australian Society for Clinical Augusta Zadow Scholarship Early Career Research Fellowship Immunology and Allergy Dr Alison Care Dr Jovanka King awarded the Best Clinical Skeptic Society Round Presentation Emeritus Professor Alastair MacLennan Peter Doherty Biomedical awarded Co-Skeptic of the Year Early Career Research Fellowship Australian Society for Immunology Dr Prabha Andraweera, Dr Nicole Mr Hanan Wahid awarded the Graham McPherson and Dr Ann-Maree Vallence Jackson Memorial Mucosal Immunology Prize

Annual Report 2014 13 Society for Reproductive Biology Supervisor of the Year Mr Victor Chen, Ms Shanshan Han and Professor Robert Norman awarded Dr Lynne Giles awarded an Academic Ms Noor Lokman awarded the Deans Life Membership Leadership Award Commendations for Doctoral Thesis Excellence Dr Melanie McDowall awarded the Meat and Professor Jozef Gecz and Dr Lachlan Jolly Livestock Australia New Scientist Award jointly awarded the Most Outstanding Paper Ms Siew Wong awarded DR Stranks in the School Postgraduate Travelling Fellowship Society for the Study of Reproduction Ms Macarena Gonzalez awarded the Ms Harshavardini Padmanabhan awarded Dr John Schjenken awarded the International Outstanding Postgraduate Student Award the 3 Minute Thesis Award Best Abstract Award and the Larry Ewing Ms Ella Green awarded the Derrick Rowley Memorial Trainee Travel Grant Professor Claire Roberts awarded the Excellence in Higher Degree by Research Prize for Honours in Microbiology and Society of Obstetric Medicine Supervision Immunology of Australia and New Zealand Dr Adrian Kaczmarek awarded the Florey Women’s and Children’s Health Network Dr Luke Grzeskowiak awarded the Postgraduate Research Poster Prize Dr Amy Keir awarded the Young Investigator Andrew Phippard Memorial Award for Best of the Year and the New Investigator Award Oral Scientific Presentation and Research, and a Travel Grant Dr Jovanka King awarded the Registrar as Trainer of the Year Award Texas A&M University World Congress for Reproductive Biology Professor Sarah Robertson awarded the Dr Hannah Brown awarded a Travel Grant Raymond O. Berry Award The University of Adelaide Professor Vivienne Moore awarded HDR

Financials $128,925

NHMRC ARC

Government and public sector

Industry

Donations and philanthropic foundations $10,003,982 $57,682

$5,645,106

The financial information presented is for funds $1,117,547 administered through the University of Adelaide, and may exclude funds earned directly by members.

14 Robinson Research Institute Dr Melanie McDowall A new approach to improve IVF success

At least 1 in 6 Australian couples experience “When we culture embryos we try to provide conditions infertility and now 4% of children are similar to those occurring naturally in the body. Through conceived by IVF. However, only 17% of IVF autofluroescence techniques, we found significantly cycles are successful and result in a live birth. fewer differences between blastomeres in embryos cultured at 7% oxygen than we did in stressed embryos To select the best embryos for transfer following IVF, cultured at 20% oxygen.” morphology is thought to be the best indicator – that is, quality is judged by appearance. However, differences between blastomeres within embryos are not always seen using morphology, which partially explains why the “You simply cannot pick best quality embryos can be hard to identify. Dr Melanie McDowall, a Senior Post-Doctoral up these differences using Scientist in the Early Development Research Group is taking a new approach to embryo selection. Using traditional morphology autofluorescence, a technique that utilises a cell’s natural emission of fluorescent light under UV illumination, techniques,” said Melanie. embryos can be examined under a microscope, imaged and returned to the culture undisturbed. The resulting images highlight differences in blastomeres, and poor quality embryos are easily identified. Melanie is currently collaborating with researchers at Macquarie University and the ARC Centre of Excellence “The exciting thing about autofluorescence is that it is for Nanoscale BioPhotonics using a technique known non-invasive, takes five minutes, uses technology which as non-labeling hyperspectral analysis. This technique currently exists in most labs, and embryos continue to also uses autofluroescence to examine the embryo but grow with no negative effects on development.” it is more powerful and can measure at least 8 different “Using this simple technique would limit the number of molecules, showing patterns of increased heterogeneity poor quality embryos used in IVF – leading to an increase in stressed embryos. in the number of successful pregnancies,” said Melanie. Melanie’s work has significant implications for the IVF Using autofluroescence, Melanie compared embryos industry. IVF is currently very expensive and with such exposed to two different concentration levels of oxygen. low rates of successful pregnancies, techniques that Once an egg is fertilised and enters the oviduct the select high quality embryos cost effectively will be oxygen concentration decreases to 7%. She found beneficial for both clinics and patients. that culturing embryos at 7% led to more successfully “In the future I believe this technique will be widely used developed embryos than culturing at the atmospheric in human reproduction and may also provide the ability oxygen level of 20%, and this was reflected in a change to identify an incorrect number of chromosomes in in autofluorescence. an embryo - this currently cannot be tested without embryo biopsy.”

Annual Report 2014 15 Key collaborations

Hospitals The Robinson Research Institute is firmly embedded within South Australia’s public health system. Institute members occupy a physical presence and conduct collaborative research projects in the state’s key hospitals, including the Women’s and Children’s, the Lyell McEwin, The Queen Elizabeth, Modbury and the Royal Adelaide. The unique and diverse affiliations we enjoy in these hospitals ensure our scientists and clinicians are integrated within South Australia’s medical practice, play a role in shaping effective health policy and have access to clinical material as appropriate.

Jean Hailes The Institute collaborates with Jean Hailes through the National Alliance on Polycystic Ovarian Syndrome (PCOS). This unique initiative brings together multidisciplinary clinicians, women with PCOS, researchers and government representatives, and has developed a vision to improve the lives Women’s and Children’s understanding of healthy development, and of Australian women with PCOS through the physical, psychological and social health education, research and evidence-based Health Research Alliance of infants, children and adolescents. health care. Through the WACHRA Alliance, the Established in 2004 as an initiative of the Institute builds allegiance with the Women’s University of Adelaide, HDA plays a key role Institute for Photonics and and Children’s Hospital, Women’s and in South Australia linking research, service Children’s Hospital Foundation, Women’s delivery and policy development, and is Advanced Sensing and Children’s Health Research Institute, currently led by Institute research leaders The Institute for Photonics and Advanced Women’s and Children’s Health Network, Professor Claire Roberts and Professor Sensing (IPAS) were successful in receiving SA Pathology, The South Australian Health Michael Sawyer. a $23,000,000 ARC Centre of Excellence and Medical Research Institute and other In 2014, HDA was supported by a for Nanoscale BioPhotonics grant, research groups at the Women’s and partnership of South Australian organisations, headquartered at the University of Adelaide. Children’s Hospital site. This alliance seeks including the Robinson Research Institute, Institute research leader Associate Professor to foster research excellence in the area Channel 7 Children’s Research Foundation, Jeremy Thompson is a group leader on of women’s and children’s health in South University of South Australia, Flinders thisproject and collaborates with IPAS to Australia, translate research findings into University, Department for Education and develop new technologies to advance policy, practice and delivery, establish a Child Development, Fertility SA, Repromed, reproductive health research and practice. highly visible focus for funding, ensure Women’s and Children’s Health Research sufficient research infrastructure needs are Institute, and the University of Adelaide. met, and communicate the benefits of health Fertility clinics investment to the wider community. HDA runs a suite of events each year to Robinson Research Institute members create opportunities for communication, have a key presence in clinical practice and networking and multidisciplinary research research development at two leading fertility Healthy Development collaborations, and ran 9 events in 2014. clinics in Adelaide: Fertility SA and Repromed. Adelaide Additionally HDA supports the next generation of researchers and offered 5 top-up PhD The Institute is a major founding partner scholarships funded by the Channel 7 Children’s of Healthy Development Adelaide (HDA). Research Foundation and 8 travel grants to HDA promotes, facilitates and enables outstanding PhD Candidates in 2014. multidisciplinary research that advances the

16 Robinson Research Institute Your Fertility Fertility Week 2014 (1-7 September) VARTA’s annual Louis Waller lecture, which will take place in 2015 during Fertility Week. Your Fertility works to address the gap in Fertility Week is a national campaign community knowledge and understanding promoting fertility awareness, and is a major about modifiable factors that affect fertility. focus of the Your Fertility program. Fertility South Australian Health and By sharing the latest scientific and medical Week 2014 focused on raising awareness of the fertile window of the menstrual cycle Medical Research Institute information, Your Fertility aims to empower (SAHMRI) people to make informed and timely and how to time sex to achieve pregnancy. decisions regarding their reproductive health. The theme sought to address poor public The Robinson Research Institute connects understanding of this issue as many women with SAHMRI to develop collaborative Delivered by the Fertility Coalition consisting are not aware of the best time for conception partnerships in research relevant to the Healthy of the Robinson Research Institute, the or may over-estimate their knowledge. Mothers, Babies and Children research theme. Victorian Assisted Reproductive Treatment Authority (VARTA), Jean Hailes for Women’s Annual Meeting Health and Andrology Australia, Your Fertility Researchers from the Institute met with Presentations and targets its messages to Australian women VARTA representatives to explore potential speaker invitations and men aged 25-35 years old. As a partner, collaboration to promote and translate the Robinson Research Institute made In 2014 Robinson Research Institute emerging research into public education important contributions to the program and members were invited to deliver more than resources and web content for Your Fertility. its major activities, including: 140 presentations. Of these more than 55 Professor Sarah Robertson accepted an were international invitations. invitation to be the guest presenter for

University and Institute Collaborations The Robinson Research Institute collaborates with national and international universities and research institutes including but not limited to:

Institution Country Institution Country ANZAC Research Institute Australia Prince Henrys Institute for Medical Research Australia Baylor College of Medicine USA Royal Children’s Hospital Melbourne Australia Benaroya Research Institute USA Shanghai Jiao Tong University China Birmingham Women’s Hospital UK Telethon Institute for Child’s Health Research Australia Bristol University UK The University of Auckland New Zealand Charles Darwin Institute Australia The University of Edinburgh UK CSIRO Australia The University of Newcastle Australia ETH Zurich Switzerland The University of Nottingham UK Flinders University Australia The University of South Australia Australia Garvan Institute of Medical Research Australia The University of Western Australia Australia Goethe University Germany QIMR Berghofer Medical Research Institute Australia Harvard Pilgrim Health Care USA University of California, San Francisco USA Howard Florey Institute Australia University of Cambridge UK Hudson Institute of Medical Research Australia University College Cork Ireland Indiana University USA University College London UK Japan Synchrotron Radiation Research Institute Japan University of Lausanne Switzerland King’s College London UK University of North Carolina at Chapel Hill USA LIMES Bonn Germany University of Pennsylvania USA March of Dimes USA University of Reading UK McGill University Canada University of Sassari Italy Medical Research Council UK University of Southampton UK Monash University Australia University of Westminster UK MRC National Institute for Medical Research UK Utrecht University Netherlands Mount Sinai Hospital Canada Victoria University Australia National Institutes of Health USA Vanderbilt University USA Oregon National Primate Research Center USA Vrjie Universiteit Brussell Belgium Oxford University UK Walter and Eliza Hall Institute of Medical Research Australia Peking University China

Annual Report 2014 17 International Visitor Spotlight

Professor Richard Dr Min Jin Professor A Anderson China Neil Johnson United Kingdom New Zealand Dr Min Jin is Chief Professor Richard A of the Center for Professor Neil Anderson is the Elsie Reproductive Johnson is the Inglis Professor of Medicine at the 2nd President Elect of the Clinical Reproductive Affiliated Hospital, World Endometriosis Science, and Head Zhejiang University. Society, Medical of Section, Obstetrics and Gynaecology at Min is an expert in assisted reproductive Director of Fertility Plus in Auckland, and the MRC Centre for Reproductive Health technology, polycystic ovary syndrome and Honorary Academic with the University of at Queen’s Medical Research Institute, reproductive immunology research – with Auckland and the University of Adelaide. University of Edinburgh. overlapping research interests with Professors Around 1 in 10 women suffer from Richard and Professor Ray Rodgers Sarah Robertson and Rob Norman. Min learnt endometriosis and currently the only began collaborating on ovarian development about the Institute’s research when Rob visited accurate way to diagnose this painful and in 2009 – with Richard focusing on germline China in 2012. She then read about our crippling condition is through an invasive cells in humans and Ray on the hormone- work in reproductive immunology publications laparoscopy procedure. Neil’s mission is to producing cells and other areas in a online, and made contact to arrange a 12 change this and is collaborating with RRI bovine model. month visit to the Institute. During Min’s members Drs Louise Hull and Vicki Nisenblat At the time of meeting, Ray had been time in Adelaide she achieved a substantial who are conducting systematic reviews to unsuccessfully looking for expression of amount, developing new flow cytometry develop low invasive diagnostic techniques for gene linked to polycystic ovary syndrome protocols for the assessment of immune endometriosis including imaging and biomarkers in the adult ovary. Ray turned his attention cells in reproductive disorders. of urine, blood and endometrium samples. to perturbed fetal development that During Min’s latest trip to the Institute, she In addition, Neil is collaborating with could lead to PCOS in later life and first commenced a new clinical study to evaluate Professors Ben Mol and Rob Norman and investigated this in the bovine model and how the oral contraceptive pill affects the Dr Paul Duggan, with a goal of establishing then in humans with Richard. With Richard’s phenotype of T regs in women’s peripheral multi-centre research in endometriosis. parallel studies in humans, they found a blood. Following this study, Sarah visited Dr Large scale collaborative trials across gene that was expressed at a critical stage Jin in China to advance the collaboration, Australia and internationally will be the most of ovary development. As a result, Richard and together they are now evaluating immune reliable way to unearth new information and contributed with Ray’s leadership, to a major cells in Asian women to establish a new study develop effective interventions. review in leading journal, Endocrine Reviews. in China. This productive visit has resulted in a Richard visited the Institute in 2014 to new ongoing collaboration between the RRI continue this research collaboration. and Zhejiang University, and both partners look forward to working together in the future.

18 Robinson Research Institute Clinical translation

The Robinson Research Institute’s research changes policy and practice, leading to improved patient treatments and better community health.

Global Obstetrics Network GONet has been invited to present its Professor Ben Mol is a member of PREBIC, philosophy for collaborative research at and has played an instrumental role in the (GONet) the annual general meeting of the Global scientific meetings and workshops. These In 2010, Professor Ben Mol co-initiated the Coalition to Advance Preterm Birth workshops provide an opportunity for members Global Obstetric Network, which he leads as Research, a coalition of the main funders for to meet and discuss the latest developments Chair. The primary goal of this network is to preterm birth research around the world. in preterm birth research, identify knowledge facilitate a worldwide collaborative approach to gaps, and plan future projects. clinical trials and observational studies in the field of maternal-fetal medicine and obstetrics. Preterm Birth International World Health During the last five years GONet has Collaborative (PREBIC) developed or completed 10 individual patient The Preterm Birth International Collaborative Organisation Taskforce data meta-analyses from merged large is a multinational collaboration of clinicians Associate Professor Helen Marshall was data sets of randomised studies, defined and research scientists. The collaboration appointed to the World Health Organisation uniform and relevant endpoints for clinical aims to improve pregnancy and birth Taskforce to: Evaluate influenza to inform trials in preterm birth, and facilitated the outcomes, thereby optimising infant health vaccine impact and economic modeling, development of clinical guidelines. and long-term development. particularly in relation to maternal influenza immunisation.

Professor Ben Mol

Annual Report 2014 19 While this taskforce seeks to inform maternal The Committee meets every three months to health care within hospitals and the wider influenza vaccination programs globally, discuss research proposals in the areas of perinatal community. it has a particular focus on low resource embryonic stem cell research, human embryo Her research findings have improved clinical settings, and evaluates the evidence of culture and training for procedures such as practice in South Australia with several states the burden of influenza, and the safety pre-implantation genetic diagnosis biopsies. developing subsequent guidelines based on and effectiveness of influenza vaccines in Additionally the committee is heavily involved the South Australian model. Additionally her pregnant women. in discussion regarding mitochondrial transfer, findings have been incorporated into the Additionally, the taskforce will review the development of embryonic stem cell lines for United Kingdom’s guidelines relating to the evidence of the impact of influenza on the particular diseases and research into their management of women with twin pregnancies. developing fetus, including the potential origins and treatment, and authorisation of for congenital abnormalities from influenza the use of embryos for development of new infection in early pregnancy. The taskforce culture techniques and equipment. Expert Panel to the NHMRC will develop guidelines to inform decision- The Australian Research Centre for Health of making for the introduction of influenza Women and Babies (ARCH) led by Philippa vaccine programs in low resource countries. Perinatal Practice Middleton, was re-appointed to the NHMRC and Guidelines panel of providers with expertise relevant to the development and presentation of NHMRC Embryo Research Professor Jodie Dodd is actively involved in translating research findings into evidence based health advice. ARCH Licensing Committee improved clinical practice and health policy. continued to develop the national evidence- Professor Robert Norman AO has been a Through her role as Chair of the South based antenatal care guidelines - which have member of the NHMRC Embryo Research Australian Maternal and Neonatal Clinical now been released. Licensing Committee for the past six years. Network and Chair of the SA Maternal and This committee is involved in regulating Perinatal Mortality Committee, she regularly human embryo research and embryonic contributes to the development of statewide stem cell development from laboratories perinatal practice guidelines and policy throughout Australia. documents, which promote evidence-based

20 Robinson Research Institute Professor Stefan Hiendleder Males and females follow different growth strategies in utero

Over several years, Professor Stefan adolescent boys have higher systolic blood Hiendleder has investigated the epigenetic pressure than girls, more males die from and non-mendelian genetic factors in cardiovascular disease before the age of bovine fetuses at mid-gestation. While fifty than females, while the risk for fatal discussing his findings with colleague Dr coronary heart disease associated with type Karen Kind, they realised that since males 2 diabetes is higher in females than in males.” and females have very different body “There is increasing evidence that sex-specific proportions, different growth trajectories differences for these diseases stem from must occur in utero. factors and exposures in early life, and what Once he classified his data by sex, new we’ve discovered provides new insight and a insights were revealed. Stefan showed that new way to consider this research,” said Stefan. A corridor discussion female fetuses display Intrauterine Growth Stefan then approached Professor Restriction (IUGR)-like features, even when Claire Roberts who leads the Placental between colleagues offspring go on to be delivered within the Development Group, to work together with normal birth weight range. PhD candidate Consuelo Estrella to explore led to a deeper “We found that females had lower fetal more deeply the significance of his findings. understanding of sex and placental weights, smaller umbilical “We know that the placenta and umbilical cord vessel diameters and a lower fetus cord display strong sexual dimorphism in differences in utero. to placenta weight ratio than males at normal pregnancies. This may affect nutrient mid gestation. Commonly used clinical and oxygen supply through the feto- indicators of IUGR such as weight ratios of placental circulation and contribute to the brain to liver, brain to fetus and heart to sex-specific growth and development,” fetus were significantly higher in females.” explained Stefan. “Additionally, lower amounts of insulin-like While Stefan’s research utilised bovine growth factor 2 (IGF2) gene transcript in fetuses, he believes similar principles would the female brain and heart, and lower levels operate in humans. of circulating IGF2 and total IGF binding “We used the bovine as the best fit model proteins are consistent with the hypothesis as it is outbred and carries a single fetus, of sex-specific restriction of nutrient supply,” with gestation length, relative fetal growth explained Stefan. curve and maturity at birth similar to humans. Stefan who leads the Epigenetics and Genetics As such we would expect similarities between Group, believes these findings help to this model and humans,” said Stefan. explain the sex-specific differences observed The next steps for Stefan’s research will include in major non-communicable diseases. detailed genome-wide molecular profiling “There are many examples of diseases of key tissues to identify mechanisms and affecting males and females differently – drivers of this sex-specific fetal growth.

Annual Report 2014 21 Commercial development

Advancement in fertility, pregnancy and child health is enabled by successful partnerships with the private sector to develop and deliver new technologies, treatments and therapies. Innovative research discoveries made by Robinson Research Institute members are being developed with commercial partners to transform medical practice and the health of our community.

22 Robinson Research Institute In 2014 the Institute worked with a IVF Vet Solutions Cell Therapy variety of industry partners to generate over $1 million in contract research, The IVF Vet Solutions business unit, led by Manufacturing consulting income and royalty income. Associate Professor Jeremy Thompson, In 2014 a new $63 million CRC for provides services to the human and The Institute is also actively engaged in Cell Therapy Manufacturing was jointly veterinary IVF market. This includes the established with the University of South research translation to improve clinical Mouse Embryo Assay, a quality assurance practice through non-commercial Australia, with Associate Professor test for media and other products used in Simon Barry leading the T cell therapy pathways. Several Research Leaders IVF. A variety of national and international are involved in setting policy and programme. This CRC aims to develop companies and reproductive medicine novel cell manufacturing devices and changing clinical practise through various clinics utilise this service. translational activities. protocols aimed at increasing the The unit has also developed a suite of availability and reducing the cost of cell bovine IVF media, with significant sales therapy. EmbryoGen® of media to Australian Reproductive In April 2013 the first baby was born in Technologies PTY LTD and OVASEM PTY Collaboration with Australia using EmbryoGen®, a treatment LTD. The media is being exported to a product for miscarriage containing number of countries including Canada, Cook Medical cytokine Granulocyte-Macrophage Colony South Africa and USA. Several Institute Research Leaders enjoy Stimulating Factor (GM-CSF). a strong relationship with Cook Medical Developed in collaboration with Origio Production and supply LLC - a privately owned medical device A/S, EmbryoGen® offers a novel of antibodies company based in Bloomington Indiana, treatment option for women undergoing in USA. Cook produce more than 30,000 vitro fertilisation (IVF) after a history of one Professor David Kennaway partners with medical and surgical products, and their or more miscarriages. Professor Sarah Buhlmann Laboratories, to supply and use Women’s Health Division is a global Robertson, who spent more than 20 years antibodies that form the active agents in producer of IVF products. working on cytokine regulation of embryo assays to detect the hormone melatonin. For the past 10+ years, Cook have development, leads the science behind The antibodies are incorporated into kits partnered on grants, engaged Associate the technology. The key to its success is sold by Buhlmann to measure melatonin Professor Jeremy Thompson as a the technology’s ability to closely mimic for laboratory and clinical applications in consultant, and supported several the natural environment of the uterus and Australia and around the world. research projects which focus on the support early embryo growth and firm development of assisted reproductive implantation. Biomarker translation technologies, especially in collaboration The work has entered a new phase with The University of New South Wales As part of a biomarker discovery program and Vrije Universiteit Brussel (Belgium). with new trials to evaluate a second- jointly funded by the CRC for Biomarker Cook have supported patent filings generation formulation. A blastocyst translation and the NHMRC, a novel related to these technologies, and also culture medium containing GM-CSF, biomarker of immune cell subsets PI16, resourced the Robinson Research Institute marketed as BlastGen® is currently in trial also named CD364, has been developed to fund the China Exchange Grant. Cook in partnership with Fertility SA and other by Associate Professor Simon Barry. international partners. BlastGen® is due is a commercial partner in the Premiers Beckton Dickenson now licenses this to be released to the international market Science Research Fund and Australian biomarker for sale on the international in 2015. Research Council Linkage Grants related market. The antibody is being tested for to the Sensing Technologies and Advanced diagnostic utility in a number of diseases Reproduction Research lab, which is including type1 diabetes IBD and infertility, a joint project between the Robinson and is a new tool to advance research into Research Institute and the Institute for regulatory T lymphocytes in laboratories Photonics and Advanced Sensing. around the world. New patents Continuing a strong culture of translation, Robinson Research Institute members filed several new patent applications and are progressing commercialisation in the areas of IVF, mastitis technology, swallowing disorders and plasma biomarkers for ovarian cancer.

Annual Report 2014 23 Community and Sector Engagement

Mr Tony Zappia MP Visits the Robinson Research Institute In April, the Institute welcomed Mr Tony Zappia, MP for the Labor Party, to the Medical School precinct to showcase and share information about the Institute’s key areas of research. The Institute’s research agenda and the importance and advantages of investing in the early stages of life and development was discussed. This highlighted the imperative to invest in research that improves not only the long-term intergenerational health of families, but also the economic impact to the community. Mr Zappia toured the Medical School facilities and laboratories. He met with key Research Leaders and Clinicians and learned L to R: Dr Suzette Coat, Dr Luke Grzeskowiak, Prof Claire Roberts, Sam Buckberry and Prof about the Institute’s leading research in Jodie Dodd at the RRI Symposium reproduction, pregnancy and child health.

New Frontiers for a Healthy Start The conference covered diabetes care from Work Experience Students to Life workshop all angles including prevention, diagnosis, The Institute supported two year-10 work In May the Institute initiated The New management, follow-up and fetal impact, experience student placements in June. Frontiers for a Healthy Start to Life and was attended by more than 40 people Each student spent time with multiple workshop, to encourage collaborations from a range of disciplines and locations research teams at the Medical School and between established and emerging (local, interstate and international). Norwich sites to get a taste of the scope researchers, within the Institute and with of work being undertaken across the Introduction to writing a Cochrane interstate colleagues. Institute. These students participated in Review workshop This two-day conference focusing on fertility, basic laboratory work under the supervision In May the Institute hosted the Australasian pregnancy and child health was held at of post-docs and senior researchers, and Cochrane Centre’s annual Introduction Serafino McLaren Vale and attended by 20 gained an understanding of the extensive to writing a Cochrane Review workshop, researchers from Monash University, The work that happens behind-the-scenes with facilitated by Miranda Cumpston and Kelly University of Melbourne, Prince Henry’s medical and clinical research. Allen from the Australasian Cochrane Centre Institute, The University of Newcastle and in Melbourne. the Robinson Research Institute. Due to the Research Tuesdays: events success and positive feedback, this Over 30 local and interstate review authors Less gain, less pain? workshop is scheduled to again run in 2015. who are commencing Cochrane systematic In its ninth year, the Research Tuesdays reviews attended the three-day workshop. lecture series shares the breadth and depth Current Controversies in A mixture of presentations and hands-on of the University of Adelaide’s research with Gestational Diabetes conference sessions provided authors an overview of the community. In May the Institute hosted the Current the methods required to write protocols and Professor Jodie Dodd, Head of the Institute’s Controversies in Gestational Diabetes provided them with the tools to begin. Health of Pregnant Mothers and Babies Group, conference, and was pleased to welcome The Cochrane Collaboration is a global, was selected to present in July on the topic: Professor Chittaranjan Yajink (Director of the independent network of health professionals, Less gain, less pain? How limiting gestational Diabetes Unit, KEM Hospital Pune, India) as researchers, patient advocates and others, weight gain is affecting pregnancy outcomes the main discussant during the day. responding to the challenge of making the for obese mothers and their babies. vast amounts of evidence generated through research useful for informing decisions about health.

24 Robinson Research Institute 1 2

3 4

Held in the University’s Bragg’s Lecture >> Does the food pregnant women eat play a 1. Attendees from the Current Controversies Theatre and attended by more than 100 role in allergy development? in Gestational Diabetes conference people, Jodie discussed the implications of >> Will my child outgrow his/her food allergy? 2. E/Prof Alastair MacLennan AO, Prof Bob being overweight or obese during pregnancy Seamark, Prof Rob Norman AO, E/Prof >> What is the difference between food and the results of her recent clinical trial. Brian Setchell, Prof Grant Sutherland AC, allergy and intolerance? A/Prof Ossie Petrucco and E/Prof Jeffrey Robinson CBE at the INSPIRE series Inaugural INSPIRE Series luncheon Lloyd Cox Memorial Lecture luncheon Initiated in 2014, the INSPIRE Series provides In October, the Institute hosted the 3. Laura Spencer, Shanshan Han, Prof Jane E the opportunity for the Institute’s early career Harding, Emily Bain and Mairead Hooper at inaugural Lloyd Cox Memorial Lecture. researchers and PhD students to hear from and the Lloyd Cox Memorial Lecture This new lecture series to be held annually, engage with the Institute’s Emeritus Faculty. 4. A/Prof Peter Richmond, A/Prof Helen features international research and policy Held in August, this luncheon was hosted Marshall, Dr Tom Snelling, Maureen leaders, tackling grand health challenges in Watson, Prof Maria Makrides and A/Prof by Professor Robert Norman AO and guest pregnancy and child health. Ann Koehler at the SA Vaccinology update speaker Emeritus Professor Jeffrey Robinson The Institute was delighted to welcome CBE. E/Prof Robinson shared insights and Professor Jane E Harding, Deputy Vice provided advice from his impressive and Chancellor, University of Auckland to present comprehensive research career. SA Vaccinology Update the inaugural lecture on the topic: Health for The Institute teamed up with SA Health, The luncheon was successful and highly now or for life? Dilemmas and trade-offs in the Women’s and Children’s Hospital valued by all who attended. The Institute caring for mothers and babies. and SAHMRI, to host the inaugural SA plans to host a similar event in 2015 for a This lecture series plays tribute to Professor Vaccinology conference in October. The new group of members. Lloyd Cox who was appointed as the sold out event was opened by the Hon Jack Food Allergies in Early Life foundation professor of The University of Snelling MP, Minister for Health and featured Adelaide’s Obstetrics and Gynaecology a range of local, interstate and internationally In September, the Institute co-hosted the Department in 1958. He strongly believed recognised speakers on maternal and Food Allergies in Early Life seminar with in close collaboration between scientists childhood immunisation. SAHRMI, FOODplus, Women’s and and clinical practitioners and this culture Children’s Health Research Institute and This forum provided the opportunity for GPs, continues today within the Robinson Healthy Development Adelaide. practice nurses, midwives, obstetricians and Research Institute. Professor Cox established other health practitioners to come together This event provided the opportunity for obstetrics and gynaecology as a science- to progress the research agenda for vaccine the public to hear from some of Australia’s based department and was instrumental in research and practice in South Australia. finest practitioners and researchers in food bringing infertility as a medical issue to the Feedback received from the 100+ guests allergy development, and answered the attention of mainstream medicine. was very positive and a similar event is following questions: scheduled for 2015.

Annual Report 2014 25 L to R: Nerissa Lakhan, Shamika Moore, Dr John Schjenken, Kerrilyn Diener, Dexter Chan, Dr David Sharkey, Ella Green, Dr Lachlan Moldenhauer, Prof Sarah Robertson and Peck Chin at the RRI Research Symposium

Research Symposium Sponsorship ASMR Annual Scientific Meeting The 2014 annual Robinson Research To support our members and to increase For the first time, the Institute sponsored Institute Symposium was held at the brand awareness, the Robinson Research the ASMR Annual Scientific Meeting by National Wine Centre in November. The full Institute sponsored three events in 2014. providing the prize for the Best Presentation day program provided the opportunity for in the Field of Reproduction, Pregnancy or members to network and learn more about Society for Reproductive Biology Child Health, awarded to Institute member the great research being undertaken across The Institute was proud to again support Dr Prabha Andraweera. the Institute’s four themes. the Society for Reproductive Biology (SRB) Held in June at the Adelaide Convention This event saw a record number of attendees by sponsoring the SRB Robinson Research Centre, this event provides the opportunity and poster submissions, and included a full Institute Mid-Career Award, awarded after for early-career researchers and higher program with 16 research presentations, 51 national competition to Institute member degree by research students to network, poster presentations and a Q&A with key Associate Professor Rebecca Robker in practice their presentation skills and share research leaders facilitated by Dr Paul Willis 2014. their research with their peers. (Director of RiAus). The award was presented at the Annual The Australian Society for Medical Research The day concluded with an awards Scientific Meeting of the Endocrine Society (ASMR) is the peak professional society presentation, and networking over wine and of Australia and the Society for Reproductive representing Australian health and medical canapés. Congratulations to A/Prof Jeremy Biology at the Melbourne Convention Centre research. Thompson, who received the 2014 Director’s in August. This is a prestigious award valued Young Investigator Award Award. Other award recipients included: at $3,000 and recognises sustained and substantial research achievement in the In 2014, the Institute was proud to be a major >> Dr Noor Alia Lokman – Best Early Career field of reproductive biology for a researcher sponsor of the Young Investigator Award, Researcher Poster who is less than 15 years post-receipt of awarded to Institute member Dr Amy Keir. >> Harshavardini Padmanabhan – Joint Best their Doctorate. Run by the Women’s and Children’s Hospital Student Poster The Society for Reproductive Biology is the Foundation, these awards recognise and >> Daniel Pederick – Joint Best Student Poster premier scientific society for reproductive promote outstanding research undertaken >> Consuelo Amor S. Estrella – People’s biology in the Asia-Pacific region. The by South Australia’s young researchers in Choice Poster Institute has a long-standing relationship the area of women’s and children’s health. >> Dexter Chan – 2014 Jeffrey Robinson with SRB and 2014 was the 9th year of our The prize is judged on the basis of quality Honours Scholarship partnership. The Institute will again sponsor of science, and ability to communicate using this award in 2015 and 2016. language that is readily understood by >> Ella Green – 2014 Robinson Research the public. Institute Honours Scholarship

26 Robinson Research Institute Science Stories

Science Stories profiles the Institute’s early career researchers and PhD students, and provides a behind-the-scences look at their research. To read the full stories visit the Institute’s website.

Is chronic pain a symptom A new approach to improve of the brain? IVF success. Dr Ann-Maree Vallence Dr Melanie McDowall Two people experience the same At least 1 in 6 Australian couples injury. Both receive identical experience infertility and now 4% of treatment and rehabilitation children are conceived by IVF – and programs – so naturally, we would this number is on the rise. Age is expect to see similar results. the largest cause of infertility and Unfortunately this is not always the increasingly women are having case. Six months later one patient has fully recovered, while children later in life, and turning to IVF. However, IVF is not the other develops a chronic pain condition. What caused the a magic solution that works for all women. Only 17% of IVF transition to chronic pain and why did it happen to one patient cycles are successful and result in a live birth. Why is the and not the other? Dr Ann-Maree Vallence, a Postdoctoral success rate so low? This is a complicated question and Fellow in the Neuromotor Plasticity and Development Group, the full answer is not clear. However, Dr Melanie McDowall, is undertaking studies to understand how changes in the a Senior Postdoctoral Fellow in the Early Development brain may be contributing to the development of chronic pain. Research Group has focused her research on increasing IVF success and hopes to gain clinical acceptance for her new and uncomplicated approach.

Fit for a gene – how sex- biased gene expression contributes to fetal growth. Is shift work harming Sam Buckberry your baby? It is well known that there are sex Dr Tamara Varcoe differences in fetal growth in utero. Approximately 16% of the working Males on average are larger than population in Australia are shift females at birth – demonstrating that workers, with females accounting males grow faster in utero. However, for almost half – 48%. Shift workers this difference in fetal growth has other consequences. Several are at greater risk of developing a studies have shown that the sex of the fetus can also influence range of health problems including the risk of pregnancy complications such as preeclampsia and increased weight gain, diabetes, cardiovascular disease and growth restriction. So how does the male development strategy even breast cancer. However, working shifts during pregnancy differ from females, what role does the placenta play and why may also negatively affect the developing baby. Dr Tamara are males at greater risk? Sam Buckberry, a PhD candidate in Varcoe, an Early Career Fellow in the Sleep Disorders Group, the Placental Development Group, has conducted extensive is focusing her research on understanding the effects of genetic analyses to understand how sex-biased gene prenatal shift work exposure on not only the mother during her expression may contribute to sex-specific fetal development pregnancy, but also on the fetus in utero, and whether there strategies in utero and what that could mean for predicting are consequences for those babies as they grow and develop the risk of developing a pregnancy complication. into adults.

Annual Report 2014 27 Media Impact

The Robinson Research Institute continues to make a strong impact in the media. In 2014, the Institute Media Circulation disseminated 22 media releases, reaching more than 4.5 billion people, with online, press and television Internet 4,538,765,300 increasing substantially from 2013. The Institute actively publicises its research outcomes in the media to better inform the Television 11,010,000 community about fertility, pregnancy and child health issues. The Institute will continue to engage the media in 2015 to share its discoveries, and increasingly it will utilise social media Radio 1,825,300 for communication and conversations between researchers and the community.

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28 Robinson Research Institute Annual Report 2014 29 Professor Jodie Dodd and Dr Rosalie Grivell World’s largest pregnancy study in overweight mums

Approximately 50% of women have a BMI The intervention group were 18% less likely to give of 25+ in early pregnancy, which can lead to birth to a large baby weighing 4kg or more, had a 53% a host of pregnancy complications for both reduction of moderate to severe respiratory distress themselves and their baby. syndrome in their babies, and length of hospital stay was reduced, compared with infants born to women Results of the world’s largest pregnancy study of its kind receiving standard antenatal care. have shown that a lifestyle intervention to improve diet quality and increase physical activity is associated “We were surprised to see that there wasn’t a significant with significant improvements in outcomes for babies. difference in weight gain between the two groups.” Pregnant women with a BMI of 25+ were invited to participate in the LIMIT trial during their first antenatal visit to the Women’s and Children’s Hospital, “The differences in outcomes Lyell McEwin Hospital or Flinders Medical Centre. Women were randomly allocated to receive either for babies was significant – a comprehensive lifestyle intervention or standard antenatal care. resulting from simple, practical Women allocated to the intervention group were provided with healthy eating recommendations – to and achievable lifestyle reduce intake of processed foods and saturated fat, and increase consumption of fruits and vegetables. changes,” said Rosalie. Additionally, they were encouraged to increase walking and incidental activity and to set simple and realistic goals such as swapping white bread to wholemeal bread, or getting off the bus one stop earlier. In parallel to their LIMIT trial, Jodie and Rosalie ran an economic evaluation to analyse the cost of the Study leaders Professor Jodie Dodd and Dr Rosalie intervention. They found the additional cost of $320 per Grivell designed the intervention to be achievable within woman to receive the lifestyle intervention was offset by the current antenatal care model so recommendations the reduction in hospital costs. could be implemented. “We hope that our comprehensive lifestyle intervention “We understand how difficult it can be for women will be rolled out across hospitals in Australia and enhance to change their diet and increase movement during current antenatal care provided to pregnant women.” pregnancy – particularly if they led a sedentary life prior to their participation in the trial.” “This easy-to-implement program not only improves outcomes for babies, but is cost-neutral – it’s a no “We provided women with advice that encouraged brainer,” said Jodie. modest changes and we were surprised to see such significant health outcomes for their babies,” said Jodie.

30 Robinson Research Institute Professor Bill Breed Comparative Biology Reproduction of Mammals

Comparative morphology and evolution of gamete form and their interaction with Australian mammals

Australia has a unique mammalian fauna that During 2014 we focused on the adverse Group Members includes both southern Gondwanan origin environmental effects of high temperatures Research Leader: Bill Breed - the marsupials, and northern Asian origin - on testis function, quality of sperm production, Senior Lecturer: Eleanor Peirce the native rodents. Our work focuses on the and the pathology of several diseases, PhD Candidates: Liberty Olds, Karleah morphology and evolution of their gametes, especially those in koalas and wombats. Trengove and Harsha Wechalekar sperm and eggs, and their interaction at Our work on gamete interactions at the Research Assistant: Chris Leigh fertilisation. By comparing reproductive time of fertilisation in an old endemic rodent biology of different species, we can find Honours Students: Alison Pullen and Hanna species was published together with a broad Maclennan common strategies and unique differences study on the co-evolution of rodent sperm that provide insight on the evolution and egg coats. Additionally, we published a of reproductive biology more broadly. study on the plasma biochemistry of koalas Our group passionately believes in the with and without oxalate nephrosis, and a conservation of Australia’s native fauna and preliminary investigation of the effects of much of our recent research has focused on sarcoptic mange on hairy-nosed wombats. identifying diseases with the long-term aim of minimising their adverse effects on the populations of these species.

Professor Frank Grützner Comparative Genome Biology

Seeking to understand how genetic and epigenetic mechanisms contribute to human diseases through comparisons with other mammalian species

The comparison of genes, genomes and of genes involved in digestion. Studying Group Members epigenetic mechanisms in different species monotremes provides the opportunity Research Leader: Frank Grützner has provided many fundamental insights to identify the role of key genes involved Visiting Research Fellow: Dan Kortschak into how genes function in humans, how in stomach function and metabolism in Lecturer: Tasman Daish they evolved, and how they contribute humans, and may lead to the identification to diseases. Studying genes in species of new therapeutic targets for metabolic PhD Candidates: Aaron Casey, Reuben Jacob, David Stevens, Deborah Toldo-Flores, Nicole distantly related to humans has also helped diseases such as diabetes. Williams and Megan Wright the development of novel drugs including In 2014 we continued to investigate the role Honours Student: Cyan Sylvester treatment for type 2 diabetes. of genes in the piRNA pathway in the ovary External Collaborators: Peter Donnelly (Oxford The Comparative Genome Biology Group and ovarian cancer. We also began new University), Briony Forbes (Flinders University), studies gene evolution in mammalian research to investigate if the interaction of Henrik Kaessman (University of Lausanne) species distantly related to humans – genes in the nucleus changes in ovarian cancer and James Turner (Medical Research Council monotremes in particular. Monotremes when compared to normal cells. We finished London) (platypus and echidna) have an extraordinary our analysis of the histology of the monotreme sex chromosome system that can reveal pancreas and continued our work on GLP-1 novel genes and pathways involved in mediated Insulin release. Additionally, our sex determination and differentiation in all long-term collaboration with Professor mammals, including humans. Monotremes Kaessmann culminated in two Nature have undergone radical changes to publications, which provided fundamental their stomach anatomy and physiology, insights into the evolution of non-coding accompanied by massive loss or change RNAs and Y-chromosomes in mammals.

Annual Report 2014 31 Associate Professor Leonie Heilbronn Obesity and Metabolism

Understanding and overcoming the metabolic risks of IVF

Globally, the number of children and adults with the process of controlled ovarian Group Members conceived by in vitro fertilisaton (IVF) stimulation used to collect eggs for IVF. Research Leader: Leonie Heilbronn totals more than five million. Accumulating In 2014 the group observed gender specific Postdoctoral Researcher: Amy Ryan evidence suggests that IVF children have consequences of fertility treatments in Research Assistants: Briohny Bartlett and altered health profiles compared to their non- offspring of mice. They showed that male Nicole Isaacs IVF peers, including increased fatness, raised mice conceived by IVF displayed impaired PhD Candidates: Thomas Butler, Miaoxin blood pressure, increased fasting blood glucose tolerance and insulin resistance in Chen and Bo Liu glucose and triglycerides, and lower flow the liver when they were lean and obese. Rob Norman and Rebecca mediated blood vessel dilation. RRI Collaborators: The ovarian stimulated mice did not show a Robker The Obesity and Metabolism Group aims phenotype compared to naturally conceived External Collaborators: Gary Wittert (University to uncover new data on the long-term mice, suggesting it is the process of IVF of Adelaide), Siobhan Banks (University of health consequences of IVF, and drive - not the hormone treatments - that may South Australia), Alison Coates (University of research towards best IVF practice. They increase type 2 diabetes risk. In contrast, IVF South Australia), Michelle Keske (Menzies), Dorit recently showed that adults conceived females displayed no phenotype but both Samocha-Bonet (Garvan Institute), Charmaine Tam (University of Sydney), Manny Noakes by IVF displayed significantly lower insulin IVF and ovarian stimulated mice were more (CSIRO) and Grant Brinkworth (CSIRO) sensitivity compared to matched control susceptible to the metabolic consequences adults. These changes may be associated of obesity, and were at increased risk of with an increased risk of type 2 diabetes in developing type 2 diabetes. This work later life. Currently we are unsure whether emphasises the continued necessity to these differences are due to IVF or the improve the technical practice of IVF, in order result of genetics, socio-economic status, to strive for best possible health outcomes or parenting differences. The group aims to for IVF children. uncover if metabolic changes are associated

Associate Professor Louise Hull Endometriosis

To identify diagnostic tools and therapies for endometriosis and translate them into clinical practice

Endometriosis affects 10% of women Mouse models of endometriosis have Group Members causing pelvic pain and infertility. Surgery is been established to evaluate how different Research Leader: Louise Hull required for diagnosis and medical therapies environmental factors contribute to the Research Fellows: Jonathan McGuane and treat symptoms rather than the cause of the disease. The group have found that seminal Vicki Nisenblat disease. Diagnostic improvements and the plasma may contribute to the endometriotic NHMRC Early Career Fellow: Wang Zhao development of a broader range of therapies disease process, while specific cytokins such PhD Student: Zahied Johan with fewer side effects is vital to help women as TGFβ regulate the progression of lesion with this debilitating condition. growth on endometriotic lesion development. Honours Student: Katherine Watson The Endometriosis Group have identified Additionally, the group established a bio Summer Student: Gabriel Kuo and evaluated microRNAs as a blood based bank of endometriosis tissues and have RRI Collaborators: Wendy Ingman, Rob diagnostic for endometriosis. They have also been engaged in undertaking Phase III and Norman and Sarah Robertson undertaken Cochrane Reviews of diagnostic IV trials for pharmaceutical companies aiming methods for endometriosis. to improve treatment options for women.

32 Robinson Research Institute Associate Professor Wendy Ingman Breast Biology and Cancer

Exploring how the immune system in the breast affects susceptibility to cancer and mastitis

Breast cancer is the most common type of the breast. Low milk supply frequently a significant improvement on the previous cancer in Australian women, affecting 1 in accompanies these symptoms and leads to models, and provides some exciting new 8 before the age of 85. While breast cancer many women ceasing breastfeeding. opportunities to explore inflammation in the treatment has improved, little progress has The Breast Biology and Cancer Group is mammary gland. been made in reducing the incidence of this based at the Basil Hetzel Institute, and Group Members disease. Understanding the unique biology of group members work with breast and plastic Research Leader: Wendy Ingman this tissue will shed light on why the breast is surgeons at The Queen Elizabeth Hospital particularly susceptible to cancer. to understand how hormones affect the Postdoctoral Researchers: Pallave Dasari, Danielle Glynn and Eleanor Need Lactation mastitis is a debilitating biological function of breast tissue. We made inflammatory disease of the breast that substantial progress in the development of Research Nurse: Kathryn Mildren affects 1 in 4 breastfeeding women. The a new tissue bank to support breast cancer Research Officer: Leigh Hodson disease causes localised pain, and is prevention research, and we now have PhD Candidates: Siti Noordin and Sally Sun frequently accompanied by the rapid onset of the laboratory protocols in place to collect Masters Student: Vahid Atashgaran systemic symptoms including fever, muscle and store living breast cells from women Honours Student: Maddison Archer aches, chills and fatigue. In some cases, undergoing surgery. These cells will be used mastitis leads to breast abscess, which must to investigate the biological pathways that Research Assistant: Harshani Pedige be surgically drained, and in severe disease affect cancer risk. Additionally, we developed RRI Collaborator: Sarah Robertson there may be permanent disfiguration of a new mouse model of mastitis, which is

Dr Michelle Lane Gamete and Embryo Biology

Understanding the impact of environmental insults to gametes on the developmental trajectory of the embryo, and how this influences disease development

Obesity in reproductive aged men and The Gamete and Embryo Biology Group is Group Members women has increased exponentially in the focused on uncovering how paternal health Research Leader: Michelle Lane last three decades, with more than 50% of cues are passed to the next generation, and Research Fellow: Tod Fullston women and men now overweight or obese determining the extent to which non-genetic Research Assistants: Wan Xian Kang, Lauren when their children are conceived. Male and transmission is modifiable through lifestyle and Sandemann and Marni Spillane female obesity is associated with impaired diet interventions. We also seek to understand PhD Candidates: Nicole McPherson, Leanne fertility, and an increased risk of metabolic whether the molecular changes in animal Pacella and Helena Shehadeh dysfunction in offspring - both parents models we have observed also exist in humans. Honours Student: Edwina Blue contribute to this. In our animal models, male In 2014 our group demonstrated that diet Affiliate members: Deirdre Zander-Fox obesity impairs sperm function, reduces and exercise interventions in obese males pregnancy rates, increases miscarriage improved metabolic composition, the RRI Collaborators: Julie Owens and Rebecca Robker and impairs the reproductive and metabolic molecular nature of the sperm, and resulted health of two generations, affecting male in improvements to the health of the offspring. External Collaborators: John Aitken (University of Newcastle), Rob McLachlan (PHMRI), Moira and female offspring differently. We have We further determined that oxidative stress shown that obesity results in alterations to O’Bryan (Monash University) and Gary Wittert appears to be a major causative agent (University of Adelaide) the epigenetic composition of sperm, thus in paternal transmission. In our studies identifying a previously underestimated on mitochondria, we demonstrated that contribution of male health at conception on in vitro treatment of aged oocytes with a the health of pregnancy and offspring. mitochondrial stimulant improved embryo quality and increased pregnancy rates.

Annual Report 2014 33 Professor Ben Mol Evidence Based Women’s Health Care

Evaluation of the effectiveness of health care for women and implementation of best practice

Much medical practice around the world is coordination of research agendas for clinical Group Members conducted without evidence that interventions and basic research, and the establishment Research Leader: Ben Mol are beneficial to the patient and will not cause of guidelines is essential. The group aims to Research Fellows: Luke Grzeskowiak, Astrud harm. Many such interventions are common- involve young people, create large datasets Tuck and Tamara Varcoe place and have been conducted for years and initiate international collaboration. RRI Collaborators: Caroline Crowther, Michael (some for many decades) with little to no During 2014 Ben co-initiated the PROMPT Davies, Jodie Dodd, Gus Dekker, Bill Hague, questioning as to the effectiveness of treatments. initiative (prospective meta-analysis in Louise Hull, John Lynch, Michelle Lane, Helen Marshall, Vivienne Moore, Rob Norman, The Evidence Based Women’s Health pessary trials), which brought together 30 Martin Oehler, Julie Owens, Claire Roberts, Care Group is challenging current practice researchers, commencing 15 pessary trials Sarah Robertson, Michael Stark and Jeremy and believes all medical interventions in around the world. Additionally, planning Thompson reproductive health care require an underlying commenced for future meta-analysis and External Collaborators: Siladitya Bhattacharya evidence base demonstrating treatments are international presentations. This study (University of Aberdeen), Arri Coomarasamy expected to do more good than harm. is positioned within the global obstetric (University of Birmingham), Tony Duan network GONet. (Shanghai Tongji University), Bill Grobham The group aims to develop evidence on the (Northwestern University), Justus Hofmeyr effectiveness of all medical interventions Looking ahead Ben aims to grow GONet, (University of Witwatersrand), Rodolfo in this area, preferably through large and is arranging several events to further Pacagnella (University of Campinas), Shakila collaborations in randomised clinical establish international collaboration. These Thangaratinam (Blizard Institute), Homan Tuong (Vietnam National University) and Xiaoke Wu trials, to provide insight on the available include meetings at SMFM and ESHRE, (Heilongjiang University of Chinese Medicine) evidence tailored to the individual patient hosting international researchers in Australia, for both patients and doctors. To achieve and integrating the Australian/New Zealand’s this, international collaboration through perinatal trial network IMPACT in these activities.

Professor Rob Norman AO Reproductive Endocrine and Medicine

Improving outcomes in IVF, Polycystic Ovary Syndrome and related conditions

Approximately 1 in 10 couples will University. The CRE will continue to increase Additionally, we aim to grow the strong experience infertility and more than 1 in our contributions to PCOS, and will place relationships we have established with 10 women suffer from Polycystic Ovary Australia at the forefront of delivery on healthy overseas groups in Europe, USA and Asia, Syndrome (PCOS), which is the most outcomes for patients with this condition. particularly China. common condition of female reproduction. Together with Professor Ben Mol we Group Members Many interventions to improve fertility involve evaluated the outcomes of several hundred Research Leader: Rob Norman manipulating reproductive hormones through patients who received ovulation induction drugs and techniques such as IVF. at the local fertility clinic, Fertility SA. This Clinical Researcher: Helen Alvino The Reproductive Endocrine and Medicine demonstrated that ovulation induction RRI Collaborators: Michael Davies, Leonie Group seeks to understand the mechanisms can be highly successful and IVF is rarely Heilbronn, Louise Hull, Neil Johnson, Ben Mol, Lisa Moran, Rebecca Robker and Ray Rodgers underlying reproductive disorders and the required for these patients. role hormones play. We are increasing our External Collaborators: Bart Fauser In 2015 we intend to grow the CRE to (University of Utrecht), David Handelsman understanding of the impact of various include new diagnostic methods, improved (ANZAC Institute), Roger Hart (University of factors including obesity, stress, lifestyle and ultrasounds, and a better understanding of Western Australia), Nick Maclon (University genetic factors on reproductive outcomes. menstrual cyclicity. We will continue our work of Southampton), Tanya Monro (University of South Australia) and Helena Teede (Monash In 2014 we were successful in obtaining on the effect of obesity on reproduction, University) an NHMRC National Centre for Research particularly the egg, early pregnancy and Excellence (CRE) in PCOS in collaboration long-term consequences, and will continue with Professor Helena Teede from Monash to look at dietary interventions for PCOS.

34 Robinson Research Institute Associate Professor Mark Nottle Reproductive Biotechnology

Development of organ, tissue and cell replacement therapies

There is a global shortage of human The group seeks to develop new Group Members organ, tissue and cell donors to treat life biotechnologies to address the challenge of Research Leader: Mark Nottle threatening childhood and adult conditions. tissue transplantation. In particular, they are Research Fellow: Ivan Vassilev The Reproductive Biotechnology Group is developing the pig as a large animal model Research Manager: Leanne Srpek working alongside a number of interstate and for human stem cell research. In 2014 the overseas collaborators examining methods group demonstrated that porcine embryonic Research Assistants: Emmy Bouwman and Stephen McIlfatrick to overcome what is one of medical sciences stem cells have the ability to differentiate greatest challenges. This multidisciplinary to multiple cell types, including insulin- RRI Collaborators: Toby Coates, Stefan Hiendleder, Michelle Lane, David Parsons and effort is recognised as the leading research producing cells that may have utility as a Paul Thomas of its kind in the world. new therapy for diabetes. The group aims to continue this research to characterise the External Collaborators: Peter Cowan (St Vincents Hospital), Emmanule Cozzie (University of Padau), clinical value of these and other cell types in Wayne Hawthorne (Westmead Millennium Institute), a pig model. Nam Kim (Chungbuk University), Andrew Lew (WEHI), Philip O’Connell (Westmead Millennium Institute), Simon Robson (Harvard Medical School) and John Paul Soulillou (Universite de Nantes)

Professor Martin Oehler and Dr Carmela Ricciardelli Reproductive Cancer

Identification of novel biomarkers and therapeutic targets for ovarian cancer

Ovarian cancer is a devastating disease In 2014 our research focused on further Group Members and the leading cause of death from understanding the role of the sugar molecule, Research Leaders: Martin Oehler and Carmela gynaecological malignancies. It affects hyaluronan (HA) in chemo-resistance. We Ricciardelli approximately 1 in 90 women in Australia characterised the function and expression Research Assistants: Anita Oehler, Carmen and over 70% of patients present with of an enzyme transketolase (TKT) involved Pyragius and Izza Tan advanced disease. Despite improvements in sugar metabolism in ovarian cancer cells. Postdoctoral Researcher: Noor Lokman in surgery and new developments in Additionally, we established an ex vivo tissue Honours Students: Noor Hammodi and chemotherapy, ovarian cancer mortality rates explant model to assess drug responses in Emily Hawkins have not changed dramatically over the last human ovarian cancer tissues. RRI Collaborator: Frank Grutzner, Ray decade. Significant improvement in ovarian In 2015 we will determine whether a protein Rodgers and Darryl Russell cancer survival will require the development regulated by ovarian cancer-peritoneal External Collaborators: David Callen of novel ovarian cancer biomarkers for early interactions can be used as a diagnostic (University of Adelaide), Peter Hoffmann detection and more effective molecularly marker for serous ovarian cancer in (University of Adelaide), Andrew Ruszkiewicz targeted therapeutics. independent cohorts. We will also assess (SA Pathology), Andrew Stephens (Prince Henry’s Institute) and Florian Weiland (University The Reproductive Cancer Group seeks whether hyaluronan inhibitors are effective of Adelaide) to understand the mechanisms involved at reversing chemo-resistance using in ovarian cancer spread, resistance to established ovarian cancer cell lines and chemotherapy and the identification of novel primary cells derived from ovarian cancer biomarkers for detection. patients.

Annual Report 2014 35 Professor Sarah Robertson Reproductive Immunology

Understanding how cells and cytokines of the immune system contribute to regulation of the reproductive process from conception to birth

In pregnancy, the female immune system are crucial for robust placental development Group Members recognises the fetus as foreign and requires and pregnancy success. Research Leader: Sarah Robertson an active state of immunological tolerance In 2014 we made substantial progress in Research Fellow: Kerrilyn Diener to be established to allow implantation understanding how several factors integrate to RRI Research Fellow: Hannah Brown and development of the fetus. Many of the influence the quality of immune adaptation for reproductive and pregnancy disorders - Senior Postdoctoral Researchers: Lachlan pregnancy. The cytokine IL10 was identified as Moldenhauer and David Sharkey including unexplained infertility, recurrent crucial for generating competent Treg cells. miscarriage, preeclampsia and preterm Postdoctoral Researchers: Peck Yin Chin and Importantly, we discovered that the hormone John Schjenken birth - have their origins in immune and progesterone interacts with cytokines to confer inflammatory disturbances that cause the PhD Candidates: Hanan Wahid and functional stability and prevent potentially Bihong Zhang placenta to not develop properly. This leaves destructive Th1 and Th17 cells from Research Officer: Camilla Dorian the placenta vulnerable to immune attack and becoming activated. Seminal fluid initiates inflammatory injury that impairs fetal growth. this process, and our experiments implicate Honours Students: Dexter Chan and Ella Green The Reproductive Immunology Group several microRNAs induced in female tissues Affiliate Member: Maria Makrides explores the mechanisms through which by male sperm signaling to be a key factor RRI Collaborators: Louise Hull, Simon Barry, the female immune system becomes driving Treg cell differentiation at conception. Wendy Ingman, Rebecca Robker and Jeremy activated to confer tolerance before embryo Work in our laboratory showed the crucial Thompson implantation. In particular, we focus on importance of TLR4 signaling in the pathway External Collaborators: Mark Hutchinson events at conception that elicit a sequence through which both infectious and sterile (University of Adelaide), David Olson (University of events to stimulate generation of cells inflammatory insults converge to overcome of Alberta), Kenner Rice (NIH Washington) and Alison Quayle (Louisiana State University) called regulatory T cells (Treg cells). Treg cells tolerance and accelerate the timing of birth. are anti-inflammatory and pro-tolerance and

Associate Professor Rebecca Robker Ovarian Cell Biology

Identifying cellular mechanisms driving ovulation and embryo development

Ovarian function is central to many aspects to form an embryo and how to reverse the progesterone target genes that are likely to of women’s health. In addition to producing detrimental effects. In mice we have shown sustain and transport the embryo during the essential hormones, the ovary nurtures that female obesity leads to mitochondrial first few days of life. oocytes, providing the building blocks they damage in oocytes, which persists into the need to form an embryo. Uncovering the tissues of offspring. Most importantly, we Group Members molecular mechanisms that control ovarian have discovered a class of compounds that Research Leader: Rebecca Robker processes is essential for understanding the when administered to obese mice, prevents Postdoctoral Researcher: Linda Wu very basics of female fertility in all mammalian the mitochondrial changes in oocytes and PhD Candidates: Miaoxin ‘Victor’ Chen, species. offspring tissues. Macarena Gonzalez and Siew Wong The Ovarian Cell Biology Group aims to We are also investigating the basic biology RRI Collaborators: Leonie Heilbronn, Michelle uncover new knowledge of ovarian biology of the oviduct to understand how it nurtures Lane, Robert Norman, Sarah Robertson, Darryl Russell and Jeremy Thompson and how processes go awry in various embryos and influences their healthy infertility disorders. In Australia, obesity rates development. If transport of the fertilised External Collaborators: Michael Barry (Fertility SA), John Carroll (Monash University), Mark are amongst the highest in the world, and oocyte does not progress normally, ectopic Febbraio (Baker IDI Heart & Diabetes Institute) obesity is associated with female subfertility, pregnancy can result. Using microarray Jon Hennebold (Oregon National Primate altered embryo growth and elevated risk of analysis of oviducts from mice lacking the Research Center) and Justin St John (MIMR-PHI) obesity in offspring. We are investigating how progesterone receptor we were able to excess fat within the oocyte impairs its ability identify and characterise the expression of

36 Robinson Research Institute Professor Ray Rodgers Ovarian Developmental Biology

Understanding the role of the ovary in fertility and endocrine function

Reproductive health significantly impacts infertility, polycystic ovary syndrome, Group Members a woman’s wellbeing throughout her life, premature menopause and ovarian cancers. Research Leader: Ray Rodgers irrespective of her choice to have children. In 2014 we undertook transcriptome profiling Postdoctoral Researcher: Katja Hummitzch In addition to producing eggs, the ovary’s (>18,000 genes) of different follicular cells Research Assistants: Wendy Bonner, Nicholas hormones govern cyclical changes regulating during their development both in vivo and in Hatzirodos and Yvonne Miels somatic and psychological health at puberty, vitro. This broad-brush approach identified PhD Candidates: Mel Ceko, Katrina Copping across the menstrual cycle, during the new genetic pathways and hitherto unknown and Monica Hartanti establishment and maintenance of pregnancy, behaviours of cells, which is important Honours Student: Nicole Bastian and in parturition, lactation and menopause. for future research in understanding the RRI Collaborators: Michelle Lane, Sarah The Ovarian Developmental Biology Group development and function of the ovary. Robertson and Darryl Russell studies the basic cellular biology of the ovary Additionally, we examined ovaries at the External Collaborators: Richard Anderson to understand and prevent diseases of the Australian Synchrotron. We are now able to (University of Edinburgh), Ross Bathgate ovary. Throughout life the ovary continually identify which cells in the ovary accumulate (Howard Florey Institute), Hugh Harris changes its cellular structures as follicles trace elements such as selenium, zinc, (University of Adelaide), Phil Knight (University of Reading), Lisa Martin (Monash University), and corpora lutea grow and regress within it. copper and iron. With this understanding, we There are many opportunities for processes Viv Perry (University of Nottingham) Dieter can formulate new hypotheses and identify Reinhardt (McGill University) and Dagmar to go wrong which can lead to common the function of these trace elements in the Wilhelm (Monash University) disorders including hormone imbalances, ovary and for fertility.

Associate Professor Darryl Russell Ovarian and Reproductive Cancer

Defining the molecular mechanisms of hormone control of ovarian folluculogenesis

Ovarian follicles coordinate input from the causes of infertility and endocrine Group Members maternal system and oocyte secreted factors dysfunction Research Leader: Darryl Russell to guide oocyte maturation. This interaction >> Apply our experience in hormone Senior Research Associate: Jill Muhling impacts the endocrine health of women and controlled morphogenic processes to Postdoctoral Researchers: Lisa Akison and ultimately the lifelong health of offspring. understand the mechanisms of reproductive Kylie Dunning The Ovarian and Reproductive Cancer organ cancer incidence and metastasis PhD Candidates: Adrian Kaczmarek and Group is focused on understanding the In 2014, we published a number of studies Izza Tan unified mechanisms by which hormone that characterised novel aspects of the Research Officer: Laura Watson signals and tissue structure determine the molecular control of oocyte development RRI Collaborators: Frank Grutzner, Michelle health and function of ovaries. The group and ovarian function. We demonstrated that Lane, Carmela Ricciardelli, Claire Roberts, seeks to harness this knowledge to improve a range of environment and lifestyle stressors Sarah Robertson, Rebecca Robker, Ray reproductive health and advance treatments influence ovarian somatic cell function and Rodgers and Jeremy Thompson for infertility and cancer. in turn impact oocyte and embryo health. External Collaborators: Robert Gilchrist We aim to: The mechanisms by which stressed oocytes (UNSW), Juan Carlos Rodriguez-Manzaneque (Genyo, University of Granada) and John Sandy signal to somatic cells and the response >> Understand the fundamental mechanisms (Rush University) by which hormones and tissue intended to prevent damage, which can morphogenesis control ovarian function lead to infertility or poor fetal developmental outcomes, continue to be investigated. >> Harness this knowledge to improve These stress response mechanisms are reproductive health and advance important in the initiation and progression of treatments that directly address the cancers of reproductive organs.

Annual Report 2014 37 Professor Paul Thomas Neural Development

Generation and analysis of mouse models for epilepsy and intellectual disability

Neurological disorders are amongst the into the genetic control of brain development Group Members most common condition in children. The and the biological basis of mental retardation Research Leader: Paul Thomas Neural Development Group seeks to and epilepsy. They have also established a Research Fellow: James Hughes uncover the genetic causes of neurological unique mouse model of sex reversal in which Research Assistants: Sandie Piltz and Melissa disorders with a particular interest in epilepsy chromosomally female mice develop as males. White and intellectual disability, which affect These mice are providing exciting new PhD Candidates: Dale McAnich and Ella approximately 3% of the population. insights into the evolution and molecular Thomson mechanism of sex determination in mammals. Using mouse models and stem cells, the Masters Student: Louise Robertson group aims to understand the disease In 2015 the group will continue to expand Honours Students: Daniel Pederick and Ruby mechanisms that underpin these debilitating their expertise in genome editing, and will Moffat conditions. Using CRISPR/CAS9 genome analyse existing mouse models of epilepsy editing, the group has established novel and intellectual disability to investigate disease mouse models for neurological disease mechanisms and explore new therapies. genes, which are providing unique insights

Associate Professor Jeremy Thompson Early Development

Understanding the link between altered metabolic states within oocytes and embryos, and epigenetic mechanisms controlling growth

Accompanying fertilisation are dynamic development, to develop new tools to Group Members molecular and biochemical processes that measure the changes, and to successfully Research Leader: Jeremy Thompson significantly impact subsequent embryonic develop interventions to reduce the impact. Postdoctoral Researchers: Hannah Brown and fetal development, as well as adult Our involvement with the ARC Centre of and Melanie McDowall health. The newly fertilised egg is extremely Excellence for Nanoscale Biophotonics saw Laboratory Manager: Lesley Ritter sensitive to the microenvironment within the development and use of new and Research Assistants: Annie Whitty and the maternal reproductive tract, and this is novel technologies and techniques designed Melissa White reflected in the resetting of its epigenetic to better understand the nano-scale implications PhD Student: Ryan Rose code. If the metabolic microenvironment of perturbed embryo development. With Technical Officer: Anwar Fatohi surrounding the oocyte and embryo is the application of new fluorophores, we altered as a result of IVF, diet or lifestyle are mapping the metabolic heterogeneity Manager, IVF Vet Solutions: Marie Anastasi factors, this will influence the epigenetic between individual blastomeres of embryos, Visiting Researcher: Nelida Rodrigues-Osorio mechanisms that ultimately control the revealing that whole embryo metabolic RRI Collaborators: Michelle Lane, Sarah growth rate and development potential of the analysis often masks the variability between Robertson, Rebecca Robker and Darryl Russell resulting fetus. individual blastomeres. Continued efforts in External Collaborators: Andrew Abell (University The Early Development Group explores the defining histone modifications within oocyte of Adelaide), Michael Barry (Fertility SA), Jose metabolic and epigenetic consequences of and early embryo chromatin has revealed Buratini (Universidade Estadual Paulista), Pablo environmental stress on the earliest stages of major perturbations associated with not Cetica (University of Buenos Aires), Gabriel Davit (University of Buenos Aires), Michel DeVos (Vrije embryo development. Our multi-disciplinary only hyperglycemic conditions but also Universiteit Brussel), David Gardner (University collaborative team utilise multi-disciplinary standard conditions encountered during the of Melbourne), Rob Gilchrist (University of New approaches to answer questions on the IVF process. This raises questions about South Wales), David Mottershead (Mottasis nano-scale. Our major focus is to explain the long term effects of IVF on the health of Review), Ryan Rose (Fertility SA), Johan Smitz (Vrije Universiteit Brussel) and Yvonne Stokes how environmental stress impacts early children that must be addressed. (University of Adelaide)

38 Robinson Research Institute Dr Jessica Grieger Eat well now - your child will thank you

Preterm birth affects around 1 in 10 babies “It is important to note that this dietary change needs and is a leading cause of infant disability to be a wholefood approach. It has been shown that and death – understanding the contributing supplementation is not useful in preventing preterm factors is crucial to prevent early labour. birth,” said Jessica. It is well understood that maternal nutrition during pregnancy can significantly affect fetal growth, development and birth weight. Postdoctoral Research Dietary intervention is often Fellow Dr Jessica Grieger built upon this knowledge, and for the first time evaluated the pre-conception diet difficult pre-pregnancy, as of more than 300 South Australian women to better understand the association between maternal nutrition around 50% of pregnancies and perinatal outcomes. Jessica found that women who eat a poor diet in the are unplanned. year before they become pregnant are around 50% more likely to deliver their baby preterm than those who follow a healthy diet. However, Jessica hopes to continue her research by “In our study, women who ate protein-rich foods developing a dietary intervention study, to look at the including lean meats, fish and chicken, as well as fruit, benefits of switching to a healthy diet for protecting whole grains and vegetables, had significantly lower against preterm birth, low birth weight risk of preterm birth.” and pre-eclampsia. “On the other hand, women who consumed mainly “Unlike other risk factors for preterm delivery such as discretionary foods, such as takeaway, potato chips, genetics and age, diet is a modifiable risk factor. It is cakes, biscuits, and other foods high in saturated never too late to make a positive change. We hope fat and sugar were more likely to have babies born our work will help promote a healthy diet before and preterm,” Jessica explained. during pregnancy. This will help to reduce the number This is an important discovery as diet is a modifiable of neonatal deaths and improve the overall health of factor that can be changed relatively easily and can children,” Jessica says. potentially reduce the risk of preterm birth. If women understand the impact diet has on the health of their baby they may be motivated to change their eating habits prior to conceiving as well as during pregnancy.

Annual Report 2014 39 Associate Professor Vicki Clifton Pregnancy and Development

Improving the health of pregnant women and their babies in socially disadvantaged communities

Pregnancy complications may arise from throughout gestation and post partum to Group Members pre-existing diseases that affect the health determine the events that contribute to the Research Leader: Vicki Clifton of the mother and the development of her health of their child. We look at maternal diet, Emeritus Member: Basil Hetzel baby. Asthma for example, is highly prevalent asthma control, health knowledge, literacy and Research Fellows: Jessica Grieger, Luke in Australian women and associated with communication. In the children we examine Grzeskowiak, Zarqa Saif and Astrud Tuck poor outcomes for babies including preterm cardiovascular health, growth, neuro- Senior Postdoctoral Researcher: delivery, stillbirth and growth restriction. These development and immune development, and Dianne Rodger poor outcomes can be minimised if asthma link outcomes to in-utero events. From these Kate Roberts-Thompson is managed effectively during pregnancy. studies we have demonstrated that poor diet Research Nurse: Research Midwives: Julia Dalton and Karen Rivers The Pregnancy and Development Group take increases the risk of preterm delivery. a multi-layered approach to understanding In 2014 we uncovered 12 isoforms of Honorary Titleholder: Nayana Parange asthma during pregnancy and its impact on the glucocorticoid receptor in the human PhD Candidates: Natalie Aboustate, Maureen mother and baby. We examine clinical issues placenta. This discovery paves the way Busuttil, Isabella Rose-Meredith, Julie Tucker, Amy Wooldridge, Ian Wright, Chow Yan and associated with improving health service, for a greater understanding of how Nurul Zainal health education and communication, glucocorticoids may affect fetal growth and and asthma management, as well as development. Additionally we developed a Administrative Assistant: Kelly Fulton understanding the mechanisms that affect phone app for early pregnancy to determine RRI Collaborators: Gus Dekker, Kathy Gatford, fetal development and long-term health of how to best communicate with women and Stefan Hiendleder, Karen Kind, Julie Owens, Claire Roberts and Cheryl Shoubridge the children of mothers with asthma. provide important health information to them at crucial time points in pregnancy. External Collaborators: Anil Roy (Royal Adelaide Our group recruits pregnant women at Hospital) and Brian Smith (Basil Hetzel Institute) their first antenatal visit and follows them

40 Robinson Research Institute Professor Caroline Crowther and Ms Philippa Middleton Health of Women and Babies

Improving the health of women and babies

To ensure the best health and wellbeing >> IDEAL Investigation of dietary advice for Group Members possible for women and their babies, women with borderline gestational diabetes Research Leaders: Caroline Crowther and Caroline and Philippa lead high quality and >> MAGENTA Magnesium Sulphate at 30 to 40 Philippa Middleton timely maternal and perinatal research. The weeks gestational age: neuroprotection trial Research Fellows: Emily Bain and Shanshan group runs a diverse research program that Han >> PROGRESS Progesterone after previous encompasses care from preconception preterm birth for the prevention of neonatal Research Officers: Melissa Ewens, Daniela through pregnancy and childbirth, infancy Gagliardi, Michaela Jarrett and Ellen Lyrtztis respiratory distress syndrome and later life using systematic review, Senior Clinical Trials Manager: Pat Ashwood individual participant data meta-analyses, >> BAC Birth After Caesarean: Planned Research Manager: Tanya Bubner randomised trial, cohort studies, qualitative vaginal birth or planned elective repeat and quantitative research methodologies. caesarean for women at term with a single Administrative and Data Assistants: Mary previous caesarean section Paleologos, Caroline Holst and Kaye Robinson In 2014 the Health of Women and Babies Group PhD Candidates: Angela Brown, Emer Heatley >> My Baby’s Movements Trial Maternal continued to conduct major NHMRC funded and Zohra Lassi randomised clinical trials that evaluated care awareness of fetal movements to Honours Student: Laura Spencer during pregnancy and childbirth. Amongst prevent stillbirth Data Management Team: Vincent Ball, Sasha these were: We completed the evaluation of the South Zhang, and Tran son Thach >> A*STEROID Australian antenatal study Australian Family Birthing Program and made to evaluate the role of intramuscular strong recommendations for its continuation Dexamethasone versus Betamethasone and further development. prior to preterm birth to increase survival free of childhood neurosensory disability

Annual Report 2014 41 Professor Jodie Dodd Health of Pregnant Mothers and Babies

Improving health outcomes for pregnant women and their babies

Good nutrition and physical activity are improvements to both their diet and physical Research Midwife: Meredith Kelsey important for women of reproductive age, activity patterns. Additionally, their babies Senior Scientist: Anne MacPherson particularly during pregnancy. The risk of were less likely to be born with a birth weight Research Officer: Thach Tran pregnancy complications, including high above 4kg. Ongoing follow-up of the children Data Managers: Vincent Ball and Sasha Zhang blood pressure, preeclampsia, gestational continues. diabetes and caesarean birth increases with PhD Candidate: Tulika Sundernathan maternal BMI, and may be improved through Group Members Masters Students: Rachel Earl and Sarah Cash Research Leader: Jodie Dodd optimal nutrition and exercise. Administrative Assistant: Jacqueline Smith Emeritus Professor: Jeffrey Robinson The Health of Pregnant Mothers and Babies RRI Collaborator: Julie Owens Research Manager: Andrea Deussen Group investigate the effect of diet and External Collaborators: Matt Gillman (Harvard lifestyle interventions during pregnancy on Clinical Researchers: Rosalie Grivell, Andy Pilgrim Health Care), Mark Kilby (Birmingham pregnancy complications and infant health McPhee and Cecelia O’Brien Women’s Hospital), John Kingdom (Mt Sinai outcomes. Optimal nutrition and exercise Statistician: Lisa Yelland Hospital), Debbie Lawlor (Bristol University), during pregnancy may reduce the risk of Lucilla Poston (King’s College London), Greg Postdoctoral Researcher: Lisa Moran Ryan (Mt Sinai Hospital), Shakila Thangaratinam poor infant health including high birth weight, Research Coordinators: Angela Newman and (QMUL) and Rory Windrum (Mt Sinai Hospital) nursery admissions, as well as an increased Courtney Cramp lifetime risk of subsequent obesity and Research Dietitians: Courtney Cramp and cardiovascular disease. Stephanie Zrim In 2014 the findings of the LIMIT randomised Research Assistants: Lauren Cates, Tiffany controlled trial were published, involving Cornish, Ashlee Fairclough, Louise Fraser, 2,212 pregnant women who were Caroline Holst, Lavern Kannieappan, Anita Lo, overweight or obese. Women who received Ellen Lyrtzis, Caroline Sheppard, Gosia Smezja, dietary and lifestyle advice made significant Fleur Spronk and Sui Zhixian

Professor Bill Hague Obstetric Medicine

Improving outcomes for pregnant women with medical complications

Over 10% of pregnant women experience In 2014 our group contributed to a major In 2015 we will establish two trials; to medical complications. Complications may international trial comparing tight with less compare pregnancy and health economic predate pregnancy, or develop during or after tight blood pressure control in pregnant outcomes in women diagnosed with pregnancy, with some cases threatening the women. The trial showed benefit for women gestational diabetes using new World Health lives of both mother and baby. While early in the prevention of severe hypertension Organization criteria, and to treat women identification and appropriate therapy is with no adverse effect on the fetus. with the pregnancy liver disease, obstetric vital, the research base for some therapeutic Additionally, results were published from cholestasis. decisions is limited with insufficient evidence a large international randomised trial of to support interventions. anticoagulant treatment in the prevention of Group Members Research Leader: Bill Hague The Obstetric Medicine Group seek to pregnancy complications in women with a develop and evaluate interventions for two thrombotic tendency – showing no benefit of Clinical Researcher: Suzette Coat major medical disorders of pregnancy; treatment over standard care. PhD Candidate: Mansi Dass Singh gestational diabetes and preeclampsia.

42 Robinson Research Institute Professor Stefan Hiendleder Epigenetics and Genetics

Understanding epigenetic and other non-mendelian genetic mechanisms and programming in prenatal development to optimise birth weight and pregnancy outcomes

Prenatal growth trajectory and birth weight their interactions with environmental factors. war” hypothesis for the evolution of maternal are strongly associated with developmental This allows us to identify risk factors and to and paternal imprinting. Additionally, we capacity and health throughout life. We now develop intervention strategies for optimal demonstrated that abundance of the imprinted know that prenatal growth and weight at outcomes at birth. maternally expressed miRNA harbouring birth are determined not only by nucleotide In 2014, we used an animal model to long non-coding RNA H19 is correlated with sequence of genes, but also by epigenetic determine the effects of parental genomes, placental and fetal phenotype. mechanisms, such as imprinting, which regulate fetal sex, and non-genetic maternal factors on Group Members gene expression and phenotype at a higher placental and fetal phenotype at mid-gestation. Research Leader: Stefan Hiendleder level. Additionally, interactions between We identified for the first time specific classical mendelian genetic, non-mendelian contributions of the maternal and paternal PhD Candidates: Consuelo Estrella, Ali Javadmanesh, Entesar Shuaib and Ruidong Xiang genetic, and epigenetic mechanisms and genome to placental, fetal and umbilical cord factors shape prenatal development and characteristics. Surprisingly, we found that Research Manager: Dana Thomsen phenotype at birth in a sex-specific manner. while placental phenotype (nutrient source) RRI Collaborators: Vicki Clifton, Kathryn Gatford, The Epigenetics and Genetics Group focuses is predominantly controlled by the maternal Karen Kind, Julie Owens and Claire Roberts on dissection of the complex molecular genetic genome, umbilical cord phenotype (nutrient External Collaborators: Axel Janke (Goethe architecture of prenatal growth trajectory and flow) is predominantly controlled by the paternal University), Sergio Ledda (University of Sassari), Eckhard Wolf (LMU and Gene Center Munich) birth weight. We uncover novel epigenetic genome. This provides further evidence for and Susanne Ulbrich (ETH Zurich) and genetic effects on prenatal growth and and refines the conflict of interest or “tug of

Professor Claire Roberts and Professor Gus Dekker Placental Development

Understanding placental development and maternal adaptation to pregnancy, and developing screening tools to identify women at risk for pregnancy complications

More than one quarter of pregnancies in This understanding informs prediction of and genetic markers. Our next step is to Australian women are associated with pregnancy outcome and will enable future validate these algorithms in an independent pathologies of the placenta which result in interventions to prevent or ameliorate cohort. If validated successfully, these miscarriage, preeclampsia, intrauterine growth pregnancy complications. algorithms may be used in antenatal clinics restriction, preterm birth, unexplained stillbirth Ongoing projects include: during the first trimester of pregnancy. and placental abruption. These conditions >> Predicting risk for pregnancy complications are believed to stem from impaired placental Group Members invasion and inadequate physiological >> The role of Vitamin D in the placenta and Research Leaders: Claire Roberts and Gus Dekker transformation of the uterine spiral arteries pregnancy success Research Fellow: Tina Bianco-Miotto to ensure appropriate maternal blood supply >> Epigenetic programming of placental and Postdoctoral Researchers: Prabha to the placenta. Currently no reliable clinical fetal development Andrawera, Amanda Highet and Sean O’Leary assessments are available to determine which >> Placental invasion and the blood supply to Research Assistant: Dylan McCullough women are at risk of these conditions. As a the placenta PhD Candidates: Sam Buckberry, Sultana result, adverse pregnancy outcomes due to >> The Influence of fetal sex on the placental Khoda, Jessica Laurence, Shalem Leemaqz, placental pathologies often cannot be prevented. Dee McCormack and Rebecca Wilson transcriptome The Placental Development Group Honours Students: Ben Mayne and Zimin Zhuang We have developed algorithms that predict conducts cellular and molecular research to a woman’s risk for pregnancy complications External Collaborators: Louise Kenny elucidate mechanisms that govern normal (University College Cork) and Lesley McCowan using a combination of clinical, biochemical and abnormal placental development. (The University of Auckland)

Annual Report 2014 43 Professors Claire Roberts and Gus Dekker World’s first screening test for major Shalem Leemaqz and pregnancy complications Professor Claire Roberts

25% of first pregnancies in Australia Claire and Gus anticipate this screening test would be are affected by one of the four major simple to integrate into practice. Currently women are complications – which can lead to a range of screened for Down syndrome at 12 weeks gestation life-long health issues (or even death) for both with a blood test. At this appointment additional mother and baby. blood could be taken by clinicians and run through the screening test. The four most common pregnancy complications are preeclampsia, preterm birth, intrauterine growth “Down syndrome occurs in 1 in 700 pregnancies, while restriction and gestational diabetes. For first time the four main pregnancy complications occur in 1 in 4 mothers there is no way of knowing the risk of pregnancies – we anticipate there will be great interest developing these potentially life-threatening conditions. in amalgamating this test into current practice from both a health and an economic perspective,” said Claire. Professors Claire Roberts and Gus Dekker who jointly lead the Placental Development Group recognised the The algorithms have been developed in over 3,200 necessity for early screening and prevention. They have pregnant women in Australia and New Zealand to best spent the last 10 years running the ‘SCOPE’ study, predict each woman’s risk of complications. collecting and analysing data and biological samples These complications can lead to a range of health from pregnant women at the Lyell McEwin Hospital. issues for the resulting babies, some which can alter With Shalem Leemaqz, a statistician and PhD scholar their health for life. in the group, the world’s first screening test to predict a “Health issues originating in pregnancy range from woman’s risk for developing one or more of the above childhood obesity, mild learning and behavioural pregnancy complications has been designed. problems, to severe disabilities such as cerebral palsy, “Gus, Shalem and I have developed algorithms that intellectual handicap and blindness or even death.” combine subtle variations in DNA sequences in “Additionally, when the pregnancy is compromised, genes involved in placental development with clinical, both mother and baby are at higher risk of developing socioeconomic, lifestyle and family history data that adult onset diseases, including cardiovascular disease can predict a woman’s risk for having a pregnancy and type 2 diabetes,” said Gus. complication,” said Claire. The next step is to test women right across Australia This new screening test could be administered in and commercialise the algorithms so they can be early pregnancy and would allow clinicians to initiate offered to pregnant women by clinicians all over the world. treatments for women at risk earlier, helping to reduce “Our hope is that this relatively simple screening test will the severity of, or to prevent, the complications. be offered to pregnant women in all countries – resulting “If it is identified in early pregnancy that a woman is in improved pregnancies and healthier babies for all at risk of preeclampsia for example, low dose aspirin women,” said Claire. before 16 weeks gestation could delay the onset or prevent it completely,” explains Claire.

44 Robinson Research Institute Professor Michael Davies and Professor Vivienne Moore Life Course and Intergenerational Health (LIGHT)

Uncovering how inequalities in the health of women and children arise though integrated social and biological pathways, and identifying opportunities for change

Early life is the foundation for future health >> Social determinants of health Group Members and life potential. Growth and development >> The political and gendered implications of Research Leaders: Michael Davies and of the child, both before birth and after, the above findings Vivienne Moore are intimately linked to the health and well In 2014, we published research demonstrating Research Fellow: Alice Rumbold being of the mother. The mother’s health variable poorer perinatal outcomes for babies Senior Postdoctoral Researcher: Wendy reflects her current environment and social conceived through different infertility treatments March, Melissa Whitrow and Tanya Zivkovic circumstances, policies and structures in compared to naturally conceived babies. We Statisticians: Chris Davies, Suzanne Edwards place in society, and her health inheritance continued our investigations into child growth, and Kristyn Willson from previous generations. showing that body size of the mother prior Academics: Lynne Giles and Megan Warin The LIGHT Group aims to understand the to pregnancy is the strongest predictor of CIS Facility Coordinator: Stephanie Champion interplay of social and biological factors that accelerated growth in children before 3.5 years. Research Coordinator: Kendall Smith influence health over the life course. Our We also demonstrated that a mother’s PhD Candidates: Renae Fernandez research aims to uncover: body size before pregnancy is positively and Renae Kirkham >> How chronic diseases are transmitted through associated with insulin resistance in children generations, and effective interventions at 9-10 years, irrespective of whether >> Developmental origins of congenital the mother had gestational diabetes and malformations, reproductive disorders, independent of the current body size type 2 diabetes and cardiovascular disease of the child, suggesting genetic and/or developmental programming origins.

Professor David Kennaway Circadian Physiology

The impact of disruption of circadian rhythms on physiological processes

Shift work increases the risk of developing Additionally, our animal studies have shown of the human trial, our preliminary evidence a range of chronic disorders including heart that disrupting circadian rhythms during indicates that as few as 4 consecutive 12 disease, diabetes and obesity. These effects the prenatal period may program metabolic hour night shifts induces insulin resistance occur independently to confounding factors disease in the subsequent offspring as they even when there is no sleep deprivation. such as socioeconomic status and smoking, grow into adulthood. Group Members and the risk increases with the number of During 2014 the Circadian Physiology Group Research Leader: David Kennaway years of exposure. Approximately 370,000 continued studies on the physiological Australian women of reproductive age (20-44 changes that occur when animals are Research Fellows: Michael Boden and Tamara Varcoe years) work at night either permanently or subjected to simulated shift work. In addition on rotating shift rosters of varying types. young adults living in a specially built Research Officers: Leewen Rattanatray and Mark Salkeld The resulting altered sleep and meal times, apartment were studied before and after 4 together with altered light exposure, disrupts simulated 12-hour night shifts. External Collaborators: Glenn McConell many physiological systems and rhythms. (Victoria University), Amanda Page (University These studies have demonstrated that There is emerging evidence that not only of Adelaide) and Shantha Rajaratnam (Monash mismatching the timing of sleep opportunity do women who work shifts experience University) and food availability adversely affects poorer fertility, but pregnant women working glucose metabolism and insulin sensitivity in shifts are at increased risk of spontaneous both animal and human models. In the case abortion, preterm birth and low birth weight.

Annual Report 2014 45 Emeritus Professor Alastair MacLennan AO Cerebral Palsy

Discovery of the genetic causes of cerebral palsy

Cerebral palsy is a neurodevelopmental plausible causes of cerebral palsy than the Group Members disorder affecting posture and movement 1-2% previously described in the literature. Research Leader: Alastair MacLennan control for 1 in every 400 children. This Results were presented at the American Genetic Scientist: Mark Corbett disability greatly affects quality of life for those Genetics Society Annual congress and has PhD Candidate: Gai McMichael affected and their families. Its prevalence has now been published in Molecular Psychiatry. not changed during the past 50 years and Detailed in silico and animal function studies Statistician: Stephen Bent costs Australia billions of dollars per year. have commenced to explore the underlying Research Officers: Clare Van Eyk and Kelly Harper The Australian Collaborative Cerebral pathways by focussing on high priority Palsy Research Group is investigating the cerebral palsy candidate genes. Project Officer: Jessica Broadbent contribution of genetic variants (mutations) We have a second large cohort of cerebral Research Assistant: Joshua Woenig to cerebral palsy susceptibility and the palsy families ready for exome sequencing Administrative Assistant: Corrine Reynolds possible interaction of environmental triggers and gene function. Further exome RRI Collaborator: Jozef Gecz during pregnancy. sequencing, identification of contributing External Collaborators: Mathew Bainbridge During 2014 our unique cerebral palsy copy number variations and whole exome (Baylor College), Daniel Geschwind (UCSF), family DNA biobank increased substantially sequencing are likely to increase the Richard Gibbs (Baylor College), Eric Hoffman with recruitment in SA, NSW and Qld. discovery of genetic variants contributing (National Institute of Health) and Michael Kruer (Souix Falls) Using exome sequencing we have shown to cerebral palsy which may allow early a much higher rate of mutations that are diagnosis and genetic interventions.

Professor Julie Owens and Dr Kathryn Gatford Early Origins of Health and Disease

Testing interventions to improve long-term outcomes after perinatal exposures

The early environment - before and shortly metabolic, neurological and immunological Group Members after birth - influences an individual’s risk consequences of restricted placental Research Leaders: Julie Owens and of developing major non-communicable function, supply to the infant before birth, Kathryn Gatford diseases, including diabetes, cardiovascular and three intervention strategies. We Emeritus Professor: Jeffrey Robinson disease, impaired neurological function and demonstrated for the first time that restricted PhD Candidates: Vincent Chu, Patricia Grant, allergy. As an example, over 18% of the risk growth before birth protects against Himawan Harryanto, Dane Horton, Damien for Type 2 diabetes can be explained by poor susceptibility to allergy. We aim to identify Hunter, Wee-Ching Kong, Ezani Mohamed growth in early life. Importantly, the effects of the pathways responsible and potential new Jamil, Hong Liu, Saidatul Mohammad, Siti adverse prenatal exposures are not always approaches to protect infants and children Sulaiman, Tulika Sundernathan and Amy Wooldridge permanent or irreversible. against allergy development. Additionally, Honours Student: Manpreet Kaur The Early Origins of Health and Disease Group we developed new ways to characterise seeks to optimise development of the infant learning outcomes in our experimental RRI Collaborators: Vicki Clifton, Jodie Dodd, models of pregnancy complications, and Stefan Hiendleder, Karen Kind, Julia Pitcher and through improving maternal health during Claire Roberts pregnancy, or reversing adverse consequences are developing a new focus on exercise as an intervention for progeny who grew poorly External collaborators: Robert Bischof of problems during pregnancy. This includes (Monash University), Jane Black (Monash mechanistic studies to understand how before birth. In collaboration, we contributed University), Debbie Lawlor (Bristol University), exposures affect long-term outcomes, with to the assessment of effects of antenatal Glenn McConell (Victoria University), Margaret the aim of developing new interventions and lifestyle advice in overweight and obese Morris (University of New South Wales), Tim Moss (Hudson Institute of Medical Research), improving current practices. women, and improved understanding of how an overweight father impairs the metabolic Beverly Muhlhausler (University of Adelaide), In 2014, we examined the outcomes Caroline Relton (Newcastle University), and and reproductive health of his child. from experimental models testing Rebecca Simmons (University of Pennsylvania)

46 Robinson Research Institute Professor Lyle Palmer Genetic Epidemiology

Investigating the epidemiology and genetic epidemiology of the origins of health and disease

The burden of disease in pregnancy, birth lung function and blood pressure trajectory). and a successful stakeholder workshop was and childhood is increasing, both clinically Our focus is on applying multidisciplinary held to develop scope and strategy. and economically. In order to disentangle approaches using combined statistical, In 2015 Lyle will further develop the Adelaide the complex genetic and environmental epidemiological, genetic, molecular, Family Health Studies through collaborating determinants of key phenotypes in early life informatic and clinical disciplines to better with RRI genetic research experts and and childhood, large-scale and comprehensive understand and treat important diseases. developing key enabling informatic, statistical cohort resources are required. In 2014, Lyle’s focus was to initiate and lead and biospecimen banking resources. The Genetic Epidemiology Group aims to the Adelaide Family Health Studies. This understand the genetic and environmental project seeks to integrate existing world- Group Members determinants of complex disorders such as class research resources in SA with new Research Leader: Lyle Palmer preterm birth, preeclampsia, growth in utero, infrastructure. A leadership and protocol and development over childhood (ie growth, development group has been established,

Associate Professor Michael Ridding and Dr Julia Pitcher Neuromotor Plasticity and Development (NeuroPAD)

Investigating how early life events affect the development of the human brain and its ability to learn and remember, and to recover from injury or illness

Experiences throughout life constantly shape throughout the lifespan, and to develop Group Members and rewire the brain. This occurs through effective therapies and interventions to Research Leaders: Michael Ridding and Julia changing the strength of existing neural ameliorate the negative consequences. Pitcher connections and developing new ones, and In 2014, NeuroPAD began two significant Postdoctoral Researchers: Richard Harris, is known as neuroplasticity. Neuroplasticity 3-year projects, both funded by grants from Brenton Hordacre, Luke Schneider and Ann- Maree Vallence underlies our ability to learn and remember NHMRC. Michael is leading an international new skills, to forget information, and also multi-centre trial to determine the optimal time Research Fellows: Nicolette Hodyl and Mitchell Goldsworthy to recover from injuries to the brain. While to commence rehabilitation after patients this ability is life-long, the brain is at its most suffer a stroke. This trial includes developing Clinical Researchers: Nicholas Smith and Michael Stark plastic in fetal life and early childhood. This and optimising new non-invasive brain facilitates the rapid learning of our early stimulation techniques for rehabilitation. Julia Research Nurses: Louise Goodchild and Ros development, but it also makes the brain is leading a large cohort study investigating Lontis more vulnerable to adverse experiences and how altered stress hormone responsiveness PhD Candidates: Rebecca Collins and Sam injury in early life. During this time the brain is and epigenetic changes in various Darvishi less able to adapt appropriately to experiences neurological genes influences the learning Honours Students: Bianca Piantedosi and and recover from injury in later life. and memory difficulties common in children Robert Sadler The NeuroPAD team aims to understand and adolescents born preterm. This includes External Collaborators: Angela Clow how experiences and injuries alter human testing a number of brain training and non- (University of Westminster) and John Rothwell brain motor and cognitive function invasive brain stimulation interventions. (University College London)

Annual Report 2014 47 Associate Professor Michael Stark Neonatal Medicine

Ensuring life-long health for newborns born preterm

Events, illnesses and treatments in the Research highlights in 2014 include: projects focusing on evidence-based newborn period can have a profound and >> Completion of a study on early neonatal transfusion practice in the neonatal long-term effect on growth, development brain injury and cerebral oxygen kinetics population. and life-long health. Integrating clinical and >> Commencement of a randomised control basic science research projects is critical to Group Members trial of washed red blood cell transfusion advancing our understanding of the major Research Leader: Michael Stark in very preterm neonates to prevent morbidities that complicate preterm birth, and Clinical Partners: Chad Andersen, Ross significant neonatal morbidity to form the basis of novel interventions to Haslam and Andrew McPhee improve outcomes for babies born too soon. >> Adoption of the Reggio Emeilia philosophy Research Fellow: Nicolette Hodyl within the NICU The Neonatal Medicine Group aims to PhD Candidate: Natalie Aboustate >> integrate basic and clinical research to On-going world leading research into Senior Neonatal Fellow: Kathryn Martinello neonatal nutrition for the Future Foods for inform best practice in the care of preterm Postdoctoral Researcher: Vicki Xafis newborns. In 2014, the group focused on Australians CRE Consultant Neonatologist: Amy Keir four main themes: neonatal nutrition, oxygen In 2015 we aim to consolidate the physiology with a particular focus on the research themes with a particular focus on mechanisms that underlie neonatal brain neurodevelopmental outcomes for infants injury, transfusion medicine, and optimising born preterm, new projects focusing on neurodevelopmental outcome following the immune basis of bronchopulmonary preterm birth. dysplasia, and new international collaborative

48 Robinson Research Institute Professor Ray Rodgers Natural antioxidant selenium plays a crucial role in women’s fertility

It has been known for some time that mainly grown on selenium-deficient soils selenium is important to men’s fertility, but it are at risk. wasn’t until Professor Ray Rodgers teamed “Infertility is a significant problem in our up with Associate Professor Hugh Harris society, with one in six couples in Australia and PhD Candidate Melanie Ceko from the being infertile. Further research is needed School of Chemistry, that selenium was to better understand how selenium levels identified as playing a crucial role for healthy could be optimised, helping to improve a reproduction in women. woman’s chance of conceiving.” Using x-ray fluorescence imaging at the “Too much selenium can also be toxic, Associate Professor Hugh Harris Australian Synchrotron in Victoria, the and Professor Ray Rodgers so it isn’t just a case of taking multiple team identified 5 elements in the bovine supplements,” explained Ray. ovary, including selenium, which is highly This collaborative project resulted from the concentrated in the ovarian follicles. A cross-disciplinary researchers’ recognition that oxidative stress “Selenium is an essential trace element and its alleviation would be important in research project led to found in protein-rich foods like red meat, tissue remodeling processes and in protecting seafood and nuts. It is important for many the DNA of eggs from oxidative damage. the identification of the biological functions, such as immune They suspected these processes would likely response and thyroid hormone production, involve trace element biology in the ovary. and acts as an antioxidant, helping to trace element selenium The team then set out to identify parts detoxify damaging chemicals in the body.” of the ovary where particular elements in the bovine ovary. “Our findings are important, because they were concentrated at certain times during show that selenium and selenoproteins development and regression of ovarian (ie GPX1) are at elevated levels in large, follicles, and to begin to understand what healthy ovarian follicles,” said Melanie. biochemical processes were responsible for The team found that gene expression of observed concentration of trace elements GPX1 was significantly higher – in some in the ovary. cases double – in oocytes that yielded a With selenium they were able to identify pregnancy. the selenoprotein involved and how this “We suspect GPX1 plays a critical role as an was related to human oocyte quality by antioxidant during the late stages of follicle collaborating with Associate Professor development, helping to lead to a healthy Darryl Russell and Dr Michelle Lane. environment for the egg,” said Hugh. The next steps in this research are to identify Selenium deficiency is not usually a how selenium is concentrated in the follicle, problem in Western diets, although people to identify when and where oxidative stress who avoid certain food groups or eat food occurs, and to identify the causes of this stress.

Annual Report 2014 49 Associate Professor Simon Barry Molecular Immunology

Understanding the molecular basis for immune tolerance

How does a healthy immune system balance regulated in a coordinated way to control Group Members a swift response to fight off pathogens with normal function. Research Leader: Simon Barry maintaining tolerance to harmless challenges The group is developing a Treg cell therapy Research Fellows: Cheryl Brown and such as food and normal body tissues? A that could be administered to patients to Timothy Sadlon subset of immune cells known as regulatory reset or redirect the immune system to Research Assistants: Arunesh Mohandas T cells (Tregs) is believed to play a critical prevent autoimmune disease or transplant and Batjargal Gundsambuu role in determining such outcomes. Tregs rejection. In order to understand how PhD Candidates: Kristen Malatesta, Steve are essential for immune tolerance, and mutations alter immune tolerance we Pederson and John Walsh defects in this particular cell population are developed a new technology that is able to Honours Candidate: Vincent Wong implicated in autoimmune disorders affecting map interactions at long distances that form many children, such as type 1 diabetes and RRI Collaborators: Jennifer Couper, Wendy as a result of DNA looping. This will allow for Ingman, Sarah Robertson and Darryl Russell irritable bowel syndrome, as well as cancer the first time the identification of the gene and other diseases. External Collaborators: Marc Beyer (LIMES targets of point mutations associated with Bonn), Dan Campbell (Benaroya Research The Molecular Immunology Group seeks disease, by mapping them to the regions Institute), Thomas Duhen (Benaroya Research to characterise human Tregs under normal of the genome that they interact with. This Institute), Greg Goodall (Centre for Cancer conditions, with a view to understand what strategy allows us to then ask if the target Biology), Randall Grose (SAHMRI), Giovanna Lombardi (King’s College London), Kellie goes wrong with these cells in immunological gene expression is altered by the mutation. MacDonald (QIMR), Joachim Schultze (LIMES disorders. Using state of the art molecular The group aims to test this approach in Bonn), Raymond Steptoe (Diamantia Institute) biology, the group investigates all the genes patients with type 1 diabetes, to map how Tim Tree (King’s College London) and Kathryn involved in immune function in Tregs, and gene mutations lead to disease. Wood (Oxford University) aims to understand how key genes are

Professor Toby Coates Transplantation

Treatment of Type 1 diabetes with replacement beta cells

Type-1 diabetes is a major cause of of type-1 diabetes. Porcine insulin was the Group Members morbidity and mortality in children and adult mainstay of insulin therapy for many years Research Leader: Toby Coates Australians. It is caused by autoimmune in the clinic, and these cells are a model for Senior Scientists: Christopher Drogemuller, destruction of the pancreatic beta cells, the developing cell transplantation techniques. Chris Hope, Svjetlana Kireta, Jodie Nitschke only insulin secreting cell type in the body. The group also continued to work on novel and Danielle Penko The Transplantation Group performs clinical ways to alter the immune system and protect Senior Postdoctoral Researchers: Claudine islet cell transplantation as a part of South pancreatic beta cells by exploring the IGF-II Bonder, Shane Grey and Plinio Hurtado Australia’s only Nationally Funded Centre for pathway and transducing pancreatic beta Clinical Researchers: Rob Carroll, Shilpa Islet Cell Transplantation. In the laboratory we cells with programmed death ligand-2 (PDL- Jesudason and Chen Peh investigate new sources of insulin-secreting 2). This is a naturally occurring T cell death Postdoctoral Researchers: Claire Jessup and tissue for transplantation as well as novel ligand, which deletes both allo-reactive and Darling Rojas-Canales ways to protect transplanted pancreatic beta auto-reactive T cells (that cause destruction Technical Officer: Julie Johnston of the insulin secreting beta cells at the cells from destruction by the immune system. PhD Candidates: Mariea Bosco, Ernesto start of type-1 diabetes). In the longer term, In collaboration with A/Prof Mark Nottle, our Hurtado Perez, Bron Lett and Kisha Sivanathan this novel strategy may result in improved group generated insulin-secreting tissue Masters Student: Fredrick Chia treatments for this prevalent autoimmune from porcine embryonic stem cells. This is condition. Honours Students: Alexander fuss, Peter Rose a potentially exciting infinite source of beta and Sebastian Stead cells for transplantation and the treatment RRI Collaborator: Mark Nottle

50 Robinson Research Institute Professor Jennifer Couper Diabetes

Preventing type 1 diabetes and its complications

The incidence of type 1 diabetes in 1 diabetes (ENDIA) expanded into a Centre Sonographer: Roger Gent childhood has increased worldwide, doubling of Research Excellence with national and Research Coordinator: Megan Penno in Australia over the last 20 years. This international collaborations. Additionally, a Research Nurses: Sarah Beresford and suggests the modern changing environment randomised controlled trial to assess the Meredith Krieg plays a role in its development. Children efficacy of metformin in preserving vascular PhD Candidates: Jemma Anderson and with type 1 diabetes have an increased health in type 1 diabetes was completed, as Shiree Perano lifetime risk of heart, kidney, and eye disease was a study to help blood glucose control Masters Student: Myf Geyer due to the effect of the diabetes on their after meals in children with cystic fibrosis and blood vessels. These first subtle changes type 1 diabetes. RRI Collaborators: Simon Barry, Jodie Dodd and Lynne Giles can be detected from adolescence, when In 2015 we plan to continue our ENDIA they are still at a reversible stage. Therefore External Collaborators: Fergus Cameron study with national and US collaborators, (Royal Children’s Hospital Melbourne), Peter prevention and intervention during childhood follow up older children at risk of type 1 Colman (RMH and University of Melbourne), is very important. diabetes, conduct intervention trials, and Maria Craig (University of Sydney), Liz Davis The Diabetes Group conducts clinical and look at the treatment of cystic fibrosis related (Telethon Institute), David Dunger (University of Cambridge), Jo Forbes (University of laboratory research which focuses on: diabetes. Additionally, our group is the Queensland), Kim Donaghue (University of >> Environmental exposures that drive Australian centre measuring vascular images Sydney), Len Harrison (WEHI), Michael Horowitz the disease for an international trial to prevent diabetes (Royal Adelaide Hospital), Tim Jones (Telethon complications in adolescents. Institute), Tony Papenfuss (WEHI), Jo Petrosino >> Immune regulatory function (Baylor College of Medicine), Bill Rawlinson (University of New South Wales), Chris Raynar >> The protection of blood vessel health in Group Members (Royal Adelaide Hospital), Richard Sinnott children and adolescents Research Leader: Jennifer Couper (University of Melbourne) and John Wentworth In 2014, a national cohort study from Research Fellow: Jessica Philips (WEHI) pregnancy to determine how the modern Clinical Partner: Alexia Pena environment drives the development of type

Annual Report 2014 51 Professor Antonio Ferrante Developmental & Genetic Immunology

Molecular and cellular approaches to identify pathways responsible for chronic inflammatory diseases in childhood and treatment development

Children afflicted with autoimmune and on subpopulations of macrophages, a cell Group Members allergic inflammatory diseases experience type which plays a major role in inflammation Research Leader: Antonio Ferrante life-long pain and disability. Current anti- and disease development. Our work is the Senior Scientists: Charles Hii and Nick inflammatory treatments affect the ability first to identify the cytokine patterns which Gorgani of the immune system to combat infection, up or down-regulate CRIg expression on Scientists: Alex Quach, Bernadette Boog, which is greatly concerning for young macrophages. We also described the various Clare Mee and Yongqin Li children. Major efforts are underway to spliced forms of CRIg expressed and the Immunopathologist: Tatjana Banovic understand the key pathways that initiate functional consequences of cytokine-altered Jovanka King and maintain inflammatory conditions, to CRIg on the macrophages’ antimicrobial Paediatric Immunologist: improve diagnosis and management of activity versus cytokine production. Tumor PhD Candidates: Usma Munawara, Cheung patients. necrosis factor, central to the development Szevan and Marwah Basin Khlah Honours Students: David Shields, Hannah The Developmental and Genetic Immunology of these inflammatory conditions, decreases Sullivan and Nahan Huynh Group aims to identify novel pathways expression of CRIg in macrophages. This is Trainees: Saif Alsaif, Anh-Hong Nguyen and connecting cytokines, receptors and consistent with suppressing tumor necrosis Fiona Norris intracellular signalling molecules that are factor promoting inflammation, and a important in the pathology of inflammatory converse role for CRIg in inflammation. RRI Collaborators: Jennifer Couper and Declan Kennedy diseases, and to identify biomarkers for Our next steps will be examining whether diseases such as allergy, arthritis, diabetes anti-cytokine therapy works through External Collaborators: Catherine Abbott (Flinders University), Paul Anderson (University and inflammatory bowel disease. modulation of CRIg expression on of South Australia), Peter Hofmann (University In 2014 we focused on how cytokines macrophages and whether novel approaches of Adelaide), Suresh Mahaligam (Griffith regulate a newly identified complement (e.g. neutraceuticals or pharmaceuticals) University), Howard Morris (University of South can be taken to modulate CRIg, thereby Australia) and Susan Prescott (University of receptor called CRIg. This is a unique Western Australia) complement receptor expressed selectively providing a new approach to treating inflammatory diseases.

iPSC derived human cortical progenitor cells Claire Homan

52 Robinson Research Institute Professor Jozef Gecz Neurogenetics

Investigation of the genetics and biology of human neurological disorders

Intellectual disability, epilepsy, autism and During 2014 we identified and characterised Next we aim to translate genetic variation cerebral palsy are among the most frequent genetic mutations in multiple novel genes. and molecular pathways involved for better developmental disabilities, together affecting One example is USP9X - ubiquitin specific precision medicine for children and families 4% of children. Over the last decade protease - that is implicated in intellectual with intellectual disability, epilepsy, autism major advances have been made in the disabilities, epilepsy and multiple cancers. and cerebral palsy. understanding of the genetic architecture Additionally, using systematic whole exome of these disorders with thousands of novel sequencing of 200 singleton cases with Group Members genes and tens of thousands of mutations cerebral palsy and their parents, we revealed Research Leader: Jozef Gecz identified. Translating genetic variation to the (in collaboration with the Cerebral Palsy Senior Scientists: Lachlan Jolly understanding of the biology, cell and molecular Group) that at least 14% of cerebral palsy is Research Officer: Mark Corbett, Duyan Pham pathways involved in these disorders is very likely genetically derived. This is a major and Raman Sharma, crucial for improved diagnosis, management advance in the understanding of the causes Clinical Researcher: Bregje van Bon and treatment of these conditions. of cerebral palsy, as until now, perinatal Research Assistants: Renee Carroll, Alison The Neurogenetics Group seeks to identify complications were the most cited explanation. Gardner, Marie Shaw, Annie Sun and Josh Woenig We have also been involved in a major and interpret novel genetic variations PhD Candidates: Claire Homan and Stanley Tan associated with paediatric neurological international study of high-resolution genetic investigations of 33,000 patients with RRI Collaborators: The Cerebral Palsy Group - disorders, intellectual disability, epilepsy, Alastair MacLennan, Gai McMichael, Clare van autism and cerebral palsy. intellectual disability or autism, from which Eyk, Eric Haan, et al. numerous novel and candidate disease- associated genes have been identified.

Associate Professor Michael Gold Allergy and Vaccine Safety

To continue to improve health across generations, Michael leads two research groups in the areas of allergy and vaccine safety

Prevention and management of food Once completed, these studies will provide Surveillance. Results from both studies allergy and allergic disease evidence based feeding guidelines for will significantly advance how we evaluate Australian infants and mothers. vaccines in Australia. In westernised and developed countries there is an evolving epidemic of allergic disease that Development of new ways to monitor Group Members primarily affects children under 5 years of the safety of vaccines Research Leader: Michael Gold age. Recent studies have shown that one in Postdoctoral Researcher: Gabriella Lincoln ten Australian children aged 12 months have When a new vaccine or seasonal flu vaccine an egg allergy - the highest documented is licensed for use safety information about Research Nurses: Christine Health and Mary Walker rate in the world. The Allergy Group’s potential rare reactions is incomplete. The goal is to understand the immunological current system of surveillance for these PhD Candidate: Katherine Duszynski, Karen mechanisms associated with the prevention events lacks the capability to detect these Best, Merryn Netting and Adrianna Parella and management of egg allergy, and to reactions in a timely way. The Vaccine Safety Co-Investigators: Annette Braunack-Mayer, understand the role of exposure in the Group aims to address the current deficiencies Nigel Stocks, Nicole Pratt, Maria Makrides, Debbie Palmer and Imme Pentila development of tolerance to egg. in surveillance by exploring health provider reporting, active sentinel surveillance and RRI Collaborators: John Lynch and Helen During 2014 multiple trials were progressed e-Health, including data linkage. Marshall looking at early versus late introduction of egg into an infant’s diet, the possible In 2014, two studies continued: Vaccine therapeutic benefits of heat-treated egg, Assessment using Linked Data and and fish oil supplementation in pregnancy. Stimulated Telephone Assisted Rapid Safety

Annual Report 2014 53 Professor Jon Jureidini Critical and Ethical Mental Health

Critical appraisal and meta-research to promote safer, more effective and more ethical research and practice in mental health

Misinformation about mental health and During 2014 we focused on citation content misrepresentation and conflict of mental disorders in children and adults distortion/misrepresentation, the RIAT interest in the health arena. misleads health professionals, the media, (restoring invisible and abandoned trials) the public, and governments, jeopardising project in which we re-analysed an infamous Group Members the rational allocation of billions of dollars of study of antidepressants in children, and Research Leader: Jon Jureidini taxpayers’ money every year. we looked at social determinants of mental Research Fellow: Anne Tonkin The Critical and Ethical Mental Health health and ethical issues related to the Postdoctoral Researcher: Melissa Raven research group conducts research protection of participants in clinical trials. (particularly critical appraisal and meta- Our next steps are to critically review research), teaching, and advocacy in mental participant protection in psychiatric/mental health, to promote safer, more effective, and health trials, mortality associated with mental more ethical research, policy and practice in disorders, and early intervention in mental mental health. health. We also aim to delve into citation

Professor Declan Kennedy Sleep Disorders

Understanding morbidity associated with sleep disordered breathing and the effect on neurocognition and vascular function

Sleep disordered breathing affects between testing to identify children who need Group Members 3-10% of children, and even relatively mild treatment - such as adenotonsillectomy. Research Leader: Declan Kennedy condition has significant daytime effects During 2014 our group had two main Head of School: Kurt Lushington on neurocognitive domains and behaviour. objectives: Director Pulmonary Medicine: James Martin During the last three years we evaluated >> To assess neurocognition and the effect of sleep disordered breathing and Principal Scientist: Yvonne Pamula behaviour in young children awaiting found vascular function is different in those adenotonsillectomy (postoperative children who snore vs do not snore. We are evaluation to be completed in 2015) currently looking more closely at vascular function to ascertain whether the vessel >> To assess vascular function and changes we found are related to the severity inflammatory markers in children with of the child’s condition. sleep disordered breathing. The Sleep Disorders Group seeks to Our group collaborates with SAMHRI, delineate the effect of sleep disordered The University of Adelaide’s Engineering breathing on children’s health and develop Department, and The University of South Australia’s Neurovascular Research Unit.

54 Robinson Research Institute Associate Professor Helen Marshall Vaccines and Infectious Diseases

Optimising protection for babies, children and pregnant women against serious infectious diseases through improved immunisation strategies

Infections such as whooping cough, children who present with a high fever and Mark McMillan, Jane Tuckerman, Mary Walker meningococcal disease and influenza still are diagnosed with both meningitis and and Kristen Zyhajo cause death and disability in young infants. septicemia or were born preterm are more PhD Candidate: Bing Wang During the last whooping cough epidemic likely to have long-term complications Masters Student: Lexa Shrestha ten babies died, with most of these babies including disability. With our interstate RRI Collaborators: Simon Barry, Gus Dekker, under 4 months of age. One in ten children collaborators we have embarked on the Jodie Dodd, Mike Gold, John Lynch, Andy who are diagnosed with meningococcal largest study in the world, assessing the McPhee and Ben Mol disease will die from the infection and a safety and effectiveness of immunising External Collaborators: Ross Andrews further 40% will develop a long-term disability. newborn babies in the first week of life to (Charles Darwin University), Hossein Afzali The Vaccines and Infectious Disease Group provide better protection against whooping (University of Adelaide), Annette Braunack- cough infection. Mayer (University of Adelaide), Jim Buttery aims to improve protection and outcomes for (University of Melbourne), Katherine Edwards children from serious infections, and monitor In 2015 we will lead a national study to (Vanderbilt University), Stephen Lambert community acceptance of immunisations. further examine the long term effects of (Queensland Children’s Medical Research Immunising pregnant women is becoming meningococcal disease such as deafness Institute), Kristine McCartney (University of Sydney), Peter McIntyre (University of increasingly important and has a dual and neurological problems. Sydney), Terry Nolan (University of Melbourne), benefit; protection for the mother against Andy Pollard (University of Oxford), Julie serious infections and protection for her Group Members Ratcliffe (Flinders University), Peter Richmond newborn. Pregnant women who develop Research Leader: Helen Marshall (University of Western Australia), Matthew influenza during pregnancy have double the Clinical Researchers: Sue Evans, Suja Snape (University of Oxford), Rebecca Tooher Mathew and Trinh Tran (University of Adelaide), Steve Wesselingh risk of fetal death, whereas women who (SAHMRI), Nicholas Wood (University of are immunised against influenza during Postdoctoral Researchers: Joanne Collins Sydney) and Gregory Zimet (Indiana University) pregnancy provide protection for their and Adriana Parrella newborn in the first months of life. Research Manager: Michelle Clarke Our research into one of the most Research Scientists: Susan Lee and Jane serious and life-threatening infections, Tidswell meningococcal disease, identified that Research Nurses: Christine Heath, Verity Hill,

Annual Report 2014 55 Associate Professor David Parsons Cystic Fibrosis

Development of gene therapy for the prevention and treatment of cystic fibrosis airway disease

Cystic fibrosis is a relatively common chronic During 2014 the group demonstrated that Group Members and early-fatal genetic disease. It is caused CFTR gene transfer improved survival in Research Leader: David Parsons by a faulty gene known as CFTR, which must mice and that their techniques could also be Postdoctoral Researchers: Patricia be inherited from both parents in order for a successfully applied in ferret airways. Using Cmielewski and Martin Donnelley child to have the disease. In many sufferers it synchrotron x-ray imaging in mice, PhD Candidates: Nigel Farrow, Ryan Green, reduces lifespan to young adulthood, mostly the group can now non-invasively measure Chantelle McIntyre and Harsha Padmanabhan through its steady destruction of the lungs and the depth of the airway surface fluid that Honours Student: Sharnna Devereux and often due to the failure of other organ systems. controls airway health in cystic fibrosis. PhD Fiona Craig projects examined stem cell populations The Cystic Fibrosis Group aims to develop an Research Coordinator: Bernadette Boog and effective genetic therapy for the prevention in CF and normal mice, and how the gene Corrine Reynolds vector can be delivered by aerosolisation. and treatment of cystic fibrosis airway disease. RRI Collaborators: Simon Barry, Mark Nottle Research activities are focused on achieving Honours projects examined how airway and Paul Thomas pre-treatment influences lung gene effective lentiviral CFTR vector gene delivery, External Collaborators: Ivan Bertoncello transduction of airway stem cells in situ transduction in mice, and the effectiveness (Melbourne University), Ric Boucher (University to enable extended gene expression, and of the group’s viral gene vector compared of North Carolina), Andreas Fouras (Monash development of rapid and accurate outcome to other vector systems. University), Albert Juhasz (University of South Australia), Tim Kuchel (SAHMRI), Ivan Lee measures for assessment of airway disease In 2015 the group will continue to advance (University of South Australia), Maria Limberis and the effects of novel therapeutics. their work into clinically suitable protocols (University of Pennsylvania), Jonathan and agents. Related novel genetic treatments McQualter (University of Melbourne), Kaye using stem cells are also being explored, and Morgan (Monash University), Karen Siu (Monash University), Euan Smith (University of South x-ray imaging techniques are continuing to Australia), Karen Siu (Monash University), be developed. Kentaro Uesugi (JSDTI), Naoto Yagi (JASRI) and Roger Yazbek (Flinders University)

Cell clusters in the lung expressing marker genes after gene therapy in airway stem cells Dr Nigel Farrow

56 Robinson Research Institute Professor Michael Sawyer Research and Evaluation

Developing and evaluating new population-level interventions for the health and wellbeing of mothers and children

Optimal physical and mental health Staff in the Research and Evaluation Unit pragmatic preference randomised controlled is important for strong and resilient are working closely with clinical staff in the trial conducted within the community child communities. Unfortunately, many mothers community child health service in South health service in South Australia. Follow-up and children experience sub-optimal health Australia to develop and evaluate new assessments will conclude in 2015 and will and wellbeing - for example, 13% of new population-level interventions that have the compare this program with current standard mothers experience significant symptoms of potential to improve the health and wellbeing practice in the child health service. The results depression, while at any single point in time of the community. The effectiveness of these of the evaluation will refine the eMums program 14% of children and adolescents experience interventions is assessed in clinical trials, for future use. mental health problems. What is concerning conducted as part of routine service delivery is the repeated finding that only a minority in the community child health service. Group Members Research Leader: Michael Sawyer of those experiencing problems receive In 2014 Michael and colleagues trialled the help from professional services. There is a eMums program, a new intervention that PhD Candidates: Amy Kaim and Sara Pfeiffer strong need to develop new cost-effective combines the skills of community nurses Research Assistants: Olivia Carger, Christine interventions that will improve the health and and the Internet to reach large numbers Mpundu-Kaambwa, Jacqueline Peters and Christy Reece wellbeing of mothers and their children in the of mothers. The effectiveness of this general community. intervention is being evaluated through a Project Officer: Jennifer Clark

Associate Professor Cheryl Shoubridge Molecular Neurogenetics

Investigating molecular mechanisms and impact of mutations in genes causing X-linked intellectual disability, to assess molecular targets for therapeutic intervention

Approximately 1 in 50 people worldwide In 2014 we continued to identify novel During 2015 we will continue to build on suffer from intellectual disability, and the genetic causes that contribute to intellectual the progress we have made through mouse cost to Australia is estimated at $14 billion disability and seizures. We identified sub- modeling and will establish the behavioural annually. Intellectual disability is described as microscopic changes to the structure of the and seizure phenotype of these animals as a significantly impaired cognitive functioning, X-chromosome in those affected by delays baseline for treatment regimes. coupled with a deficit in adaptive behaviour to language and autistic spectrum disorder. Group Members with onset before the age of 18. In many Using mice with the intellectual disability Research Leader: Cheryl Shoubridge cases, therapies to prevent or ameliorate the gene on the X-chromosome we uncovered consequences of these genetic disorders are developmental deficits at the cellular level Postdoctoral Researcher: Kristie Lee not yet available. due to mutations in this gene. Using next PhD Candidate: Tessa Mattiske The Molecular Neurogenetics group seeks generation approaches we established Research Officer: Susan Hinze to uncover the genetic causes of intellectual the impact of these mutations on the Research Assistant: Ching Moey disabilities and seizures, with the aim of transcriptome of the developing brain, and RRI Collaborators: Jozef Gecz developing effective therapies to improve the uncovered evidence of the components of quality of life for patients and their families. the pathways implicated in disruption to External Collaborators: Gaelle Friocourt (INSERM), Nigel Jones (University of Melbourne), cognitive abilities and seizures. Jeffrey Noebels (Baylor College of Medicine) and Terance O’Brien (University of Melbourne)

Annual Report 2014 57 Fostering Research Excellence

To achieve our goal of delivering world-class advances in the knowledge of reproduction, pregnancy and child health, the Institute invests in people, networks and facilities.

Core Facilities genome and proteome data sets are - both cohorts and randomised controlled a powerful approach to generating trials - established before or at birth, or in The Institute’s core facilities enhance fundamental knowledge on systems and childhood. CIS and its resources enhance research capability, to deliver more efficient, processes in biology and disease. collaborations, support novel interrogations and cost effective research. Bioinformatic methods allow researchers of accrued data and enable pooling of studies. This will advance research to address complex Adelaide Research Assay to follow a complementary path in their challenges in reproductive and paediatric Facility (ARAF) research that promotes exploratory analysis and hypothesis generation, as well as health, now and into the future. Led by Professor David Kennaway focused analysis of previously identified CIS aims to align, maintain and enhance The Adelaide targets of interest. This can provide stronger cohorts, databases and related resources, Research Assay and more clinically applicable results from stimulate research that addresses prioritised Facility provides a research program, and yield publication, complex challenges in reproductive and specialised, high- funding, and patent outcome improvement. paediatric health, and increase participation throughput and high- in national and international consortia. This sensitivity assays Biostatistics Facility will lead to increased publications in high of physiologically Led by Dr Nancy Briggs quality journals and international invitations important analytes The Biostatistics to present findings, thereby ensuring wide for academic Facility provides dissemination of findings to an international researchers and commercial customers expert advice in audience. Australia-wide. research design, Gene Silencing and Expression ARAF provide services and consultation statistical analysis Facility (GSEx) for specialised measurements of analytes and presentation in human or animal biological fluids or cell of data. This service Led by Dr Jill Muhling culture / tissue extracts. These cover broad complements The Gene Silencing research areas including but not limited to researcher expertise and Expression endocrinology, neuroscience, physiology, through the provision of effective statistical Facility provides immunology, pathology and cancer. analysis that delivers clear and precise gene manipulation In 2015 the facility aims to test and validate a answers to their questions. services to Australian number of new reproduction and endocrine In 2015, biostatistics will continue to be researchers in a related assays and add them to the ‘library’ afforded to research leaders to improve the fully equipped PC2 of validated assays. likelihood of securing future NHMRC grants laboratory. The and to provide general research design advice facility offers custom Bioinformatics Facility for continuing and new research projects. production of lentiviral, AAV and retroviral Led by Dr Stephen Bent vectors, and stock viruses for purchase by Bioinformatics Cohort and Intergenerational the microlitre. In addition, customers can enhances the Studies Facility (CIS) access CRISPR, non-viral vector and other Institute’s capability Led by Professor Julie Owens cell and molecular biology services. in systems biology The Cohort and In 2014, GSEx produced over 50 viral vectors, approaches to basic Intergenerational of which approximately half were custom science and clinical Studies Facility requests. These viruses have been used to research investigating underpins the infect immortal cell lines and primary cell human and animal strategic utilisation cultures. GSEx demonstrated the effectiveness reproduction and of unique Adelaide of both lentivirus and AAV in mouse cumulus development. Strategies to design and generated oocyte complexes and cancer cell lines in analyse transcriptome, deep-sequencing, longitudinal studies rodents and humans. Additionally, the facility

58 Robinson Research Institute demonstrated robust reporter expression of CRISPR/CAS9 technology and expand 2014 recipients: following human T-cell infection. the services on offer to include production of >> Associate Professor Simon Barry conditional alleles. SA Genome Editing Facility (SAGE) >> Associate Professor Leonie Heilbronn >> Dr Nicolette Hodyl Led by Professor Paul Thomas Investing in People The SA Genome >> Associate Professor Wendy Ingman Editing Facility uses and Building Capacity >> Dr Michelle Lane RRI delivers a suite of programs and cutting edge genome >> Emeritus Professor Alastair MacLennan editing technology to scholarships to develop research and >> Associate Professor Helen Marshall generate mutant mice build skills and expertise in members. In for a wide range of 2014 more than $1 million in funding was >> Associate Professor David Parsons applications. Utilising awarded to groups and individuals within the >> Dr Carmela Ricciardelli Institute. Investment in research capacity and new CRISPR/CAS9 >> Associate Professor Rebecca Robker system technology, outcomes includes the following: the facility offers a number of services including generation of custom knock out, point mutation and tagged alleles. Investment for Success SAGE’s services are highly accessible This program aims to increase the Institute’s offering a significantly reduced cost and fast NHMRC funding by developing highly turnaround compared to traditional ES cell competitive project grant applications into methods - providing researchers an edge more competitive applications for the 2015 when applying for grants and publishing in round submission. high impact journals. Investment serves to enable proof-of- After commencing operations in August concept studies, experiments or analysis, to 2014, three mutant lines were produced ensure rapid publication of a pivotal paper with another eleven projects underway. In or increase scientific quality, significance 2015 SAGE aims to grow its understanding and innovation.

Jeffrey Robinson Honours Scholarship

Dexter Chan

In 2014, the Institute awarded Dexter’s work throughout his honours the Jeffrey Robinson Honours year has further deepened his interest in Scholarship to Dexter Chan. the field and he will commence his PhD under the supervision of Prof Sarah During his undergraduate degree at the Robertson and Dr John Schjenken in 2015. University of Adelaide, Dexter undertook a “I really enjoyed my honours year. I placement in Professor Sarah Robertson’s worked with so many researchers at lab as part of his genetics course. This different levels of their careers and made placement sparked his research interest some great friends through sharing the and he subsequently joined Sarah’s office with the other students.” group the following year as an honours student, undertaking the project The role “It was a very different experience to of miR146a in the peri-conception period my undergraduate degree and I was inspired by the incredible research being of early pregnancy. expenses and removed the need to work undertaken, both in my group and in other Dexter looked at whether miR146a has an part time - I was able to spend more time areas of the Institute.” effect on cytokine production during early on my research and refine my skills.” Dexter was both humbled and grateful for conception, and if pregnancy outcome is “I’m looking forward to commencing my the opportunity to be the Jeffrey Robinson affected by miR146a deficiency. Cytokines PhD and continuing to be a part of the Honours Scholar in 2014. produced in the peri-conception period amazing and potentially life-saving are key for a number of events including “It wasn’t until my supervisors notified research that’s being undertaken at the implantation and the establishment of me of the opportunity that I even Institute”, said Dexter. immune tolerance of the mother towards considered it. The scholarship provided the fetus. me an advantage as it paid for my living

Annual Report 2014 59 Career Development Fellowship

Dr Nicolette Hodyl and Dr Jessica Grieger

This fellowship funds the salary of ‘Emerging Star’ early career researchers. It aims to support career development to enable competitiveness for NHMRC Career Development Fellowship or similar. In 2014 the fellowship was awarded to Dr Nicolette Hodyl (left) and Dr Jessica Grieger, who will commence in 2015.

High Impact Paper Funding Innovation Seed Funding Collaborate to Publishing in high impact journals is a This pilot program supports early and Publication Success leading factor in research success and mid-career researchers to collaborate Major funding bodies increasingly value career development. This program provides across research groups and themes and to collaboration and co-publication. The financial support to enable the publication explore novel research questions. Its goal Institute initiated this program in 2014 to of research findings in prestigious journals is to refine and progress these concepts assist researchers to co-author research that attract an international audience. This towards competitive, fundable research that publications and increase publication output. provides heightened credibility and esteem addresses significant knowledge gaps. In 2014 Maria Gardiner from Thinkwell to our research achievements. This program supported eight projects in facilitated a series of workshops with leaders In 2014 five members received funding for 2014, bringing together 24 researchers. The from the Fertility and Conception theme to their high impact publications. following highlights the story and progress of progress joint publication ventures. one of the funded projects: Visiting Speakers The Visiting Speakers Program supports Innovation Seed Funding Recipient Story external research leaders to visit the Institute, and aims to encourage collaboration between Institutions, and provide insight and Dr Prabha Andraweera new perspectives on our research priorities. In 2014 the following visitors were supported Dr Prabha Andraweera from the Placental Development >> Professor Jeremy Grimshaw, University of Group teamed up with Drs Hannah Brown, Tina Ottawa, Canada. RRI Host: Philippa Middleton Bianco-Miotto and Stephen Bent to initiate the >> Professor Stanley Ulijaszek, Institute for project Identifying molecular pathways in the placenta Social and Cultural Anthropology, Oxford, implicated in the link between preeclampsia and later UK. RRI Host: Dr Megan Warin life coronary artery disease. >> Professor Bart Fauser, University of This project investigates genetic and processes in the human placenta that Utrecht, The Netherlands. RRI Host: epigenetic changes in the placenta that could be implicated in the link between Professor Rob Norman may be implicated in the link between preeclampsia and later life CAD. >> Dr Kara Britt, Peter MacCallum Cancer preeclampsia and coronary artery disease The group is seeking to uncover whether: Centre, Melbourne. RRI Host: Associate (CAD). Preeclampsia is a pregnancy Professor Wendy Ingman 1. Similar genes are implicated in the risk specific disorder and a leading cause for preeclampsia and CAD >> Professor Patrick Bossuyt, Academic of maternal and infant morbidity and Medical Center, University of Amsterdam. 2. Epigenetics changes in the placenta mortality, occurring in 2-8% of pregnancies RRI Host: Professor Ben Mol and accounting for up to 15% of maternal may have a role in both preeclampsia >> Professor Chittaranjan Yajnik, Diabetes deaths. There is increasing evidence that and later life CAD Unit, King Edward Memorial Hospital, the harmful effects of preeclampsia on a This research project builds on Prabha’s India. RRI Host: Professor Bill Hague woman’s health may not be restricted to PhD on the topic of Angiogenesis the duration of pregnancy, but it could regulating gene polymorphisms in adverse >> Professor Helena Teede, Monash represent an important risk factor for future pregnancy outcomes. Hannah and Tina University, Melbourne. RRI Host: cardiovascular events. have expertise in molecular genetics and Dr Lisa Moran The placenta plays a vital role in pregnancy epigenetics, and Stephen will identify >> Professor Geoffrey W. Tregear, Howard and is also a programming agent for later life transcription factors that may regulate Florey Institute, Melbourne. RRI Host: CAD. However, very little progress has so differentially expressed genes. Together Professor Ray Rodgers far been made in identifying the molecular they are well placed to achieve their goals.

60 Robinson Research Institute >> Professor John E. J. Rasko AO, Sydney Medical School, University of Sydney. RRI Travel Story Hosts: Dr Hannah Brown and Professor Jozef Gecz >> Professor Laura Bennet, The University of Auckland, NZ. RRI Host: Dr Julia Pitcher >> Louise Johnson and Karin Hammarberg, Victoria Assisted Reproductive Treatment Authority, Sydney. RRI Hosts: Professors Ray Rodgers and Darryl Russell >> Professor Chris O’Neill, University of Sydney. RRI Hosts: Dr Hannah Brown and Associate Professor Jeremy Thompson >> Professor David Gardner, Department of Zoology, University of Melbourne. RRI Hosts: Dr Hannah Brown and Associate Professor Jeremy Thompson >> Dr Anita Kozyrsky, University of Alberta, Dr John Schjenken USA. RRI Host: Associate Professor Vicki Clifton Dr John Schjenken from the Reproductive Immunology Group attended the 2014 Society for the Study of Reproduction Exchange Program conference in Michigan, USA. The Exchange Program seeks to build What was a highlight of the conference? transcripts, particularly miRNA may collaborations with interstate and I was fortunate to receive the International interact with the uterine epithelium to international researchers and to expand the Best Abstract Award from the Australia New influence the female immune response to international profile of the Institute - with Zealand region for my presentation: Novel coitus. Dr Krawetz showed strong interest the aim of increasing research capacity and immune mechanisms for seminal fluid action both in our work and exploring a future facilitating access to international funding, through the TLR4 signalling pathway. collaboration. databases and expertise. How has the experience supported In 2014 six visits were supported, building Did you meet any researchers or you? links with research groups from Denmark, collaborators of significance? the UK, and the USA. I was introduced to Dr Stephen Krawetz, I learnt about the latest research from who is a world-leading expert in RNA my peers, presented my work and Visitors to the Robinson transcripts in sperm and his publications received feedback, which is instrumental Research Institute have been highly influential in my field. We in my career development. Additionally, >> Professor David M. Olson, Department discussed new methods for extracting networking with researchers from around of Obstetrics and Gynecology, University RNA from sperm and my research - which the world who are working in the field of of Alberta, USA. RRI Host: Professor is seeking to understand how sperm reproductive immunology has broadened Sarah Robertson my scientific network >> Professor Tessa Roseboom, Academic Medical Center, University of Amsterdam, Denmark. RRI Host: Professor Ben Mol Hosts to Robinson Research Travel Grants Media Training Institute Members Supporting early career researchers to 9 institute members attended a one-day >> Professor Rebecca Simmons, Center travel so they can present and share their media skills course run by Science in Public. for Research, Reproduction and Women’s research findings at national and international Participants received professional insights Health, University of Pennsylvania, USA. conferences and meetings is essential for and guidance from highly experienced and RRI Visitor: Dr Kathy Gatford career development and building a strong talented television, radio and print journalists. >> Dr Lars Henning Pedersen, Department track record. The challenging and practical day included of Clinical Medicine – Obstetrics and Attendance at key conferences enables 1-on-1 media practice with the experts who Gynaecology, Aarhus University, Denmark. networking with peers, and the opportunity provided constructive feedback and coaching. RRI Visitor: Dr Luke Grzeskowiak to develop future collaborations. “The opportunity to speak directly with and >> Professor Lucilla Poston, Division of In 2014 this jointly funded program with the practice our skills on journalists was invaluable. Women’s Health, King’s College London, School of Paediatrics and Reproductive I’ll be putting into practice what I learnt.” Dr UK. RRI Visitor: Professor Jodie Dodd Health, allocated $70,000 to 54 research Megan Warin, 2014 participant. >> Professor Angela Clow, Psychophysiology staff and students who visited 27 conferences. and Stress Research Group, University of Researchers are encouraged to submit a brief Westminster, UK. RRI Visitor: Dr Nicolette story about their travel – above is what Dr John Hodyl. Schjenken had to say about his experience.

Annual Report 2014 61 Oocyte with lipid Associate Professor Rebecca Robker

62 Robinson Research Institute Robinson Research Foundation

The Robinson Research Foundation supports the life-giving research of the Institute and aims to: A message from the Chair >> Raise vital funds to seed new areas of innovative research, support the development of the next generation of researchers, and fund special enabling equipment Each year I learn more about the vital research >> Raise public awareness of the clinical and policy benefits of the work of the conducted by the Robinson Research Institute in order to enhance the uptake of research findings Institute. Its Research Leaders and Members are world class in their field and all hold To achieve this, the Institute works closely with the Foundation Committee, who an unwavering passion and dedication to generously offer their time, support and expertise. addressing major health issues in fertility, In 2014 two major engagement events were held: pregnancy and child health in our community. They are truly inspiring and particularly so, in Friends and Benefactors Event light of the challenging funding environment in Hosted by the University of Adelaide’s Engagement Branch, this event provided which they operate. the opportunity for University alumni and benefactors to gain an insight into The breadth and depth of research specific areas of research in need of funding. discoveries that emerge through the Institute Held in March, the event introduced the concept of ‘Healthy Children for Life’ needs to be widely recognised among the with a specific focus on preterm birth. Guests were provided insight and expertise general community – and this is an ongoing from Institute members Professor Sarah Robertson, Philippa Middleton and quest, where we can make a real difference. Laura Spencer. Thank you to all guests for attending and your ongoing support. The Foundation has a role in fostering Excellence in Research Dinner – Macquarie Private Wealth opportunities to raise awareness and funds that will in turn be used to support new Hosted by Macquarie Private Wealth, the Excellence in Research Series provides and ongoing research. This is essential to insight into the research from each of the University of Adelaide’s five research ensure our discoveries can continue to be Institutes. The Robinson Research Institute featured in September’s event – transformed into clinical care and policy for with Associate Professor Michael Stark presenting on the topic Born Too Soon: the health of all children and families, across Building better health outcomes. generations and global communities. Once again, funds raised on the evening were generously matched by Macquarie I would like to extend my personal thanks Private Wealth and will be directed towards ongoing research efforts into preterm to the Robinson Research Foundation birth. We thank both our supporters for their donations and for Macquarie Private Committee for their support and commitment Wealth for not only hosting this wonderful event but for matching donations raised. to the Institute throughout 2014. This year the work of the committee has moved closer to working in greater partnership with the University’s Engagement Branch and we Robinson Research look forward to further embedding the new Foundation Committee 2014 strategy in 2015. Neil Howells (Chair) To our supporters and donors – on behalf Joanna Close of the Foundation Committee, Research Paul Griffin Members and Staff of the Institute – thank Alf Ianniello you all so very much for your generous and ongoing support. E/Prof Colin Matthews I look forward to your continued engagement Ian Nightingale and encourage you to help us spread the Dr Dyann Smith word about the life changing research that happens here at the Robinson Research Institute. Neil Howells Chair Robinson Research Foundation

Annual Report 2014 63 Member list

Thank you to all of the Institute’s members who have contributed to another successful year. We would like to recognise the contribution of all members, with a special mention to the School of Paediatrics and Reproductive Health’s administration team led by Michael Guerin, School Manager.

Members Brown, Angela Couper, Jennifer Ferrante, Antonio Harryanto, Himawan Javadmanesh, Ali Aboustate, Natalie Brown, Cheryl Craig, Fiona Fraser, Louise Hartanti, Monica Jessup, Claire Akison, Lisa Brown, Hannah Cramp, Courtney Fullston, Tod Haslam, Ross Jesudason, Shilpa Anastasi, Marie Bubner, Tanya Crowther, Caroline Fulton, Kelly Hatzirodos, Nicholas Johan, Zahied Andersen, Chad Buckberry, Sam Daish, Tasman Fuss, Alexander Heath, Christine Johnston, Julie Anderson, Jemma Busuttil, Maureen Dalton, Julia Gagliardi, Daniela Heatley, Emer Jolly, Lachlan Andraweera, Prabha Butler, Thomas Darvishi, Sam Gardner, Alison Heilbronn, Leonie Julie, Tucker Archer, Maddison Carger, Olivia Dasari, Pallave Gatford, Kathryn Hetzel, Basil Jureidini, Jon Ashwood, Pat Carroll, Renee Dass Singh, Mansi Gecz, Jozef Hiendleder, Stefan Kaczmarek, Adrian Atashgaran, Vahid Carroll, Rob Davies, Chris Gent, Roger Highet, Amanda Kaim, Amy Bain, Emily Casey, Aaron Davies, Michael Geyer, Myf Hii, Charles Kannieappan, Ball, Vincent Cash, Sarah Dayan, Sonia Giles, Lynne Hill, Verity Lavern Banovic, Tatjana Cates, Lauren Dekker, Gus Glynn, Danielle Hinze, Susan Kaur, Manpreet Barry, Simon Champion, Dent, Stephen Gold, Michael Hodson, Leigh Keir, Amy Bartlett, Briohny Stephanie Deussen, Andrea Goldsworthy, Hodyl, Nicolette Kelsey, Meredith Basin Khalah, Chan, Hon (Dexter) Devereux, Sharnna Mitchell Holst, Caroline Kennaway, David Marwah Chen, Miaoxin Diener, Kerrilyn Gonzalez, Macarena Homan, Claire Kennedy, Declan (Victor) Bastian, Nicole Dodd, Jodie Goodchild, Louise Hope, Chris Khoda, Sultana Chia, Fredrick Beaumont, Greg Donnelley, Martin Gorgani, Nick Hordacre, Brenton King, Jovanka Chin, Peck Beresford, Sarah Dorian, Camilla Grant, Pat Horton, Dane Kireta, Svjetlana Chu, Vincent (Wing Best, Karen Drogemuller, Green, Ella Hughes, James Kirkham, Renae Hong) Bianco-Miotto, Tina Christopher Green, Ryan Hull, Louise Kong, Wee-Ching Clark, Jennifer Blue, Edwina Dunning, Kylie Grey, Shane Hummitzsch, Katja Kortschak, Dan Clarke, Michelle Boden, Michael Duszynski, Katherine Grieger, Jessica Hunter, Damien Krieg, Meredith Clifton, Vicki Bonder, Claudine Earl, Rachel Grivell, Rosalie Hurtado, Plinio Kuo, Gabriel Cmielewski, Patricia Bonner, Wendy Edwards, Suzanne Grutzner, Frank Hurtado Perez, Lane, Michelle Coat, Suzette Boog, Bernadette Estrella, Consuelo Grzeskowiak, Luke Ernesto Lassi, Zohra Coates, Toby Bosco, Mariea Evans, Sue Gundsambuu, Huynh, Nahan Laurence, Jessica Collins, Joanne Bouwman, Emmy Ewens, Melissa Batjargal Ian, Wright Lee, Kristie Collins, Rebecca Braunack-Mayer, Fairclough, Ashlee Hague, William (Bill) Ingman, Wendy Lee, Susan Copping, Katrina Annette Farrow, Nigel Han, Shanshan Isaacs, Nicole Leemaqz, Shalem Corbett, Mark Breed, William Fatohi, Anwar Harper, Kelly Jacob, Feuben Leigh, Chris Cornish, Tiffany Broadbent, Jessica Fernandez, Renae Harris, Richard Jarrett, Michaela Lett, Bron

64 Robinson Research Institute Li, Yongqin Moore, Vivienne Pullen, Allison Shute, Elen Warin, Megan Russo, Ray Lincoln, Gabriella Moran, Lisa Pyragius, Carmen Singh, Hameet Watson, Katherine Teede, Helena Liu, Bo Mpundu-Kaambwa, Quach, Alex Sivanathan, Kisha Watson, Laura Thompson, Suzanna Liu, Hong Christine Rattanatray, Leewen Smezja, Gosia Wechalekar, Harsha Weiland, Florian Lo, Anita Munawara, Usma Raven, Melissa Smith, Jacqueline Welch, John Xafis, Vicki Lokman, Noor Need, Eleanor Reece, Christy Smith, Nicholas White, Melissa Zander-Fox, Deirdre Lontis, Ros Netting, Merryn Reynolds, Corrine Smith, Kendall Whitrow, Melissa Professional Newman, Angela Lushington, Kurt Ricciardelli, Carmela Son Thach, Tran Whitty, Annie Staff Nguyen, Anh-Hong Lyrtzis, Ellen Ridding, Michael Spencer, Laura Williams, Nicole Craig, Imogen Nisenblat, Vicki MacLennan, Alastair Ritter, Lesley Spillane, Marni Willson, Kristyn Guerin, Patrick Nitschke, Jodie McLennan, Hanna Rivers, Karen Spronk, Fleur Wilson, Rebecca Hooper, Mairead Noordin, Siti MacPherson, Anne Roberts, Claire Srpek, Leanne Woenig, Joshua Irving, Kate Norman, Robert Maftei, Oana Roberts-Thomson, Stark, Michael Wong, Siew Kontic, Rachel (Rob) Kate Malates, Kristen Stead, Sebastian Wooldridge, Amy Spencer, Laura Norris, Fiona Robertson, Louise Marshall, Helen Stephanie, Zrim Wright, Megan Turner, Sarah Nottle, Mark Robertson, Sarah Martin, James Stevens, David Wu, Linda Walsh, Sarah O’Brien, Cecelia Martinello, Kathryn Robinson, Kaye Sulaiman, Siti Xafis, Vicki O’Leary, Sean Mathew, Suja Robinson, Jeffrey Sullivan, Hannah Xian Kang, Wan Oehler, Anita Mattiske, Tessa Robker, Rebecca Sun, Annie Xiang, Ruidong Oehler, Martin Mayne, Ben Rodger, Dianne Sun, Sally Yang, Sasha Olds, Liberty McAninch, Dale Rodgers, Raymond Sundernathan, Tulika Yann, Chow Owens, Julie (Ray) McCormack, Sylvester, Cyan Yelland, Lisa Pacella, Leanne Rodrigues-Osorio, Catherine (Dee) Szevan, Cheung Zainal, Nurul Padmanabhan, Nelida McCullough, Dylan Tan, Izza Zhang, Yu Harsha Rojas-Canales, McDowall, Melanie Tan, Stanley Zhang, Bihong Paleologos, Mary Darling McGuane, Jonathan Thomas, Paul Zhang, Sasha Palmer, Lyle Rose, Peter McIlfatrick, Stephen Thompson, Jeremy Zhao, Wang Pamula, Yvonne Rose, Ryan McIntyre, Chantelle Thomsen, Dana Zhixian, Sui Parange, Nayana Rumbold, Alice McMichael, Gai Thomson, Ella Zhuang, Zimin Parella, Adriana Russell, Darryl McMillan, Mark Tidswell, Jane Zivkovic, Tanya Parsons, David Ryan, Amy McPhee, Andrew Toldo-Flores, Zyhajlo, Kirsten Pederick, Daniel Sadler, Robert McPherson, Nicole Deborah Pederson, Steve Sadlon, Timothy Affiliate Mee, Clare Tonkin, Anne Pedige, Harshani Saif, Zarqa Members Meredith, Isabella- Tran, Thach Peh, Chen Salkeld, Mark Adelson, David Rose Tran, Trinh Peirce, Eleanor Sandemann, Lauren Alvino, Helen Middleton, Philippa Trengove, Karleah Pena, Alexia Sawyer, Michael Barry, Michael Miels, Yvonne Tuck, Astrud Penko, Daniella Schjenken, John Bertoncello, Ivan Mildren, Kathryn Tuckerman, Jane Penno, Megan Schneider, Luke Gustafsson, Johan Moey, Ching Vallence, Ann-Maree Perano, Shiree Sharkey, David Haan, Eric Moffat, Ruby Van Bon, Bregje Peters, Jacqueline Sharma, Raman Hoffmann, Peter Mohamed Jamil, Van Eyk, Clare Ezani Pfeiffer, Sara Shaw, Marie Irving-Rodgers, Varcoe, Tamara Helen Mohammad, Pham, Duyan Shehadeh, Helena Vassilev, Ivan Johnson, Neil Saidatul Phillips, Jessica Sheppard, Caroline Wahid, Hanan Lardelli, Michael Mohandas, Arunesh Piantedosi, Bianca Shields, David Walker, Mary Makrides, Maria Mol, Ben Piltz, Sandie Shoubridge , Cheryl Walsh, John Newman, Morgan Moldenhauer, Pitcher, Julia Shrestha, Lexa Wang, Bing Lachlan Shuaib, Entesar Omari, Taher

This list aims to be as comprehensive as possible and any omissions are unintentional.

Annual Report 2014 65 Publications

1. Abu Shamsi, N, Salkeld, M, Rattanatray, L, 9. Anuradha, S, Webb, PM, Blomfield, P, 19. Bontekoe, S, Heineman, MJ, Johnson, N, Voultsios, A, Varcoe, T, Boden, M & Kennaway, Brand, AH, Friedlander, M, Leung, Y, Obermair, Blake, D, 2014, ‘Adherence compounds in D 2014, ‘Metabolic consequences of timed A, Oehler, MK, Quinn, M, Steer, C & Jordan, embryo transfer media for assisted reproductive feeding in mice’, Physiology & Behavior, vol. SJ 2014, ‘Survival of Australian women with technologies’, Cochrane Database of 128, no. C, pp. 188-201. invasive epithelial ovarian cancer: a population- Systematic Reviews, vol. 2. based study’, Medical Journal of Australia, vol. Bosteels, J, Weyers, S, Mol, B & D’Hooghe, 2. Abumaree, MH, Alahari, S, Albrecht, C, Aye, 201, no. 5, pp. 283-288. 20. ILMH, Bainbridge, S, Chauvin, S, Clifton, VL, T 2014, ‘Anti-adhesion barrier gels following Desoye, G, Ermini, L, Giuffrida, D, Graham, CH, 10. Arentz, G, Weiland, F, Oehler, MK & operative hysteroscopy for treating female Huang, QT, Kalionis, B, Lager, S, Leach, L, Li, Hoffmann, P 2015, ‘State of the art of 2D infertility: a systematic review and meta- Y, Litvack, ML, Nuzzo, AM, Moretto-Zita, M, DIGE’, Proteomics - Clinical Applications, vol. 9, analysis’, Gynecological Surgery, vol. 11, no. 2, O’Tierney-Ginn, P, Powell, T, Rolfo, A, Salomon, no. 3-4, pp. 277-288. pp. 113-127. C, Serov, A, Westwood, M, Yung, HW & Lash, Bain, E, Wilson, A, Tooher, R, Gates, S, 21. Braakhekke, M, Kamphuis, EI, Dancet, GE 2014, ‘IFPA Meeting 2013 Workshop 11. Davis, LJ & Middleton, P 2014, ‘Prophylaxis for EA, Mol, F, van Der Veen, F & Mol, BW 2014, Report I: Diabetes in pregnancy, maternal venous thromboembolic disease in pregnancy ‘Ongoing pregnancy qualifies best as the dyslipidemia in pregnancy, oxygen in placental and the early postnatal period’, The Cochrane primary outcome measure of choice in trials in development, stem cells and pregnancy Database of Systematic Reviews, vol. 2, no. 2. reproductive medicine: an opinion paper’, Fertility pathology’, Placenta, vol. 35, no. SUPPL, pp. and Sterility, vol. 101, no. 5, pp. 1203-1204. S4-S9. 12. Bain, ES, Middleton, PF, Yelland, LN, Ashwood, PJ & Crowther, CA 2014, ‘Maternal 22. Breed, WG, Leigh, CM, Aplin, KP, Shahin, 3. Akison, LK, Boden, MJ, Kennaway, DJ, adverse effects with different loading infusion AAB & Avenant, NL 2014b, ‘Morphological Russell, DL & Robker, RL 2014, ‘Progesterone rates of antenatal magnesium sulphate diversity and evolution of the spermatozoon in receptor-dependent regulation of genes in for preterm fetal neuroprotection: the IRIS the mouse-related clade of rodents’, Journal of the oviducts of female mice’, Physiological randomised trial’, BJOG, vol. 121, no. 5, pp. Morphology, vol. 275, no. 5, pp. 540-547. Genomics, vol. 46, no. 16, pp. 583-592. 595-603. 23. Brennan, DJ, Hackethal, A, Metcalf, 4. Akkermans, J, Payne, B, Von Dadelszen, Balegar, KK, Stark, MJ, Briggs, N & AM, Coward, J, Ferguson, K, Oehler, MK, P, Groen, H, Vries, JD, Magee, LA, Mol, BW & 13. Andersen, CC 2014, ‘Early cerebral oxygen Quinn, MA, Janda, M, Leung, Y, Freemantle, Ganzevoort, W 2014, ‘Predicting complications extraction and the risk of death or sonographic M, Webb, PM, Spurdle, AB & Obermair, A in pre-eclampsia: External validation of the brain injury in very preterm infants’, Journal of 2014, ‘Serum HE4 as a prognostic marker fullPIERS model using the PETRA trial dataset’, Pediatrics, vol. 164, no. 3, pp. 475-480. in endometrial cancer - A population based European Journal of Obstetrics Gynecology study’, Gynecologic Oncology, vol. 132, no. 1, and Reproductive Biology, vol. 179, no. C, pp. 14. Barrett, H 2014, ‘Predictors of pp. 159-165. 58-62. Preeclampsia in Women in the Metformin in Gestational Diabetes(Mig) Study’, Journal of 24. Brien, FD, Cloete, SWP, Fogarty, NM, 5. Aloia, AL, Eyre, NS, Black, S, Bent, SJ, Diabetes & Metabolism, vol. 05, no. 07. Greeff, JC, Hebart, ML, Hiendleder, S, Edwards, Gaeguta, A, Guo, Z, Narayana, SK, Chase, R, JEH, Kelly, JM, Kind, KL, Kleemann, DO, Plush, Locarnini, S, Carr, JM, Howe, JA & Beard, MR 15. Beckmann, KR, Roder, DM, Hiller, JE, KL & Miller, DR 2014, ‘A review of the genetic 2014, ‘Generation of a chimeric hepatitis C Farshid, G & Lynch, JW 2014, ‘Influence of and epigenetic factors affecting lamb survival’, replicon encoding a genotype-6a NS3 protease mammographic screening on breast cancer Animal Production Science, vol. 54, no. 6, pp. and assessment of boceprevir (SCH503034) incidence trends in South Australia’, Asian 667-693. sensitivity and drug-associated mutations’, Pacific Journal of Cancer Prevention (APJCP), Antiviral therapy, vol. 20, no. 3, pp. 271-280. vol. 15, no. 7, pp. 3105-3112. 25. Brinkman, SA, Gregory, TA, Goldfeld, S, Lynch, JW & Hardy, M 2014, ‘Data resource 6. Amdany, HK & McMillan, M 2014, 16. Berkovic, S & Gecz, J 2014, ‘Phenotype- profile: the Australian Early Development Index ‘Metronidazole intravenous formulation use genotype complexities: opening DOORS’, The (AEDI)’, International Journal of Epidemiology, in in-patients in Kapkatet District Hospital, Lancet Neurology, vol. 13, no. 1, pp. 24-25. vol. 43, no. 4, pp. 1089-1096. Kenya: A best practice implementation project’, JBI Database of Systematic Reviews and 17. Bianco-Miotto, T, Trotta, A, Need, E, Lee, A, 26. Bromfield, JJ, Schjenken, JE, Chin, PY, Implementation Reports, vol. 12, no. 3, pp. Ochnik, A, Giorgio, L, Leach, D, Swinstead, E, Care, AS, Jasper, MJ & Robertson, SA 2014, 419-432. O’Loughlin, M, Newman, M, Birrell, S, Butler, L, ‘Maternal tract factors contribute to paternal Harris, J & Buchanan, G 2014, ‘Molecular and seminal fluid impact on metabolic phenotype in 7. Andraweera, P, Dekker, G, Thompson, S, structural basis of androgen receptor responses offspring’, PNAS, vol. 111, no. 6, pp. 2200- Dissanayake, V, Jayasekara, R & Roberts, to dihydrotestosterone, medroxyprogesterone 2205. C 2014, ‘Hypoxia-inducible factor-1α gene acetate and Delta(4)-tibolone’, Molecular and polymorphisms in early and late onset Cellular Endocrinology, vol. 382, no. 2, pp. 27. Brown, H & Russell, D 2014, ‘Blood preeclampsia in Sinhalese women’, Placenta, 899-908. and lymphatic vasculature in the ovary: vol. 35, no. 7, pp. 491-495. development, function and disease’, Human 18. Biggs, S, Nixon, G, Davey, M, Cicua Reproduction Update, vol. 20, no. 1, pp. 29-39. 8. Andraweera, PH, Dekker, GA, Thompson, Navarro, D, Kennedy, J, Lushington, K & Horne, SD, Nowak, RC, Jayasekara, RW, Dissanayake, R 2014, ‘Pediatric Sleep Survey Instrument - a 28. Brown, HM, Fabre Nys, C, Cognié, J & VHW & Roberts, CT 2014, ‘Polymorphisms in screening tool for sleep disordered breathing’, Scaramuzzi, RJ 2014, ‘Short oestrous cycles the fibrinolytic pathway genes and the risk of Sleep and Breathing, vol. 18, no. 2, pp. 383- in sheep during anoestrus involve defects recurrent spontaneous abortion’, Reproductive 390. in progesterone biosynthesis and luteal BioMedicine Online, vol. 29, no. 6, pp. 745-751. neovascularisation’, Reproduction, vol. 147, no. 3, pp. 357-367.

66 Robinson Research Institute 29. Buchanan, DD, Tan, YY, Walsh, MD, Ovary Syndrome: Characteristics and predictive 48. Collins, MG, Rogers, NM, Jesudason, Clendenning, M, Metcalf, AM, Ferguson, K, capacity’, Clinical Endocrinology. S, Kireta, S, Brealey, J & Coates, PT Arnold, ST, Thompson, BA, Lose, FA, Parsons, 2014, ‘Spontaneous glomerular mesangial 39. Cassar, S, Teede, HJ, Moran, LJ, Joham, MT, Walters, RJ, Pearson, SA, Cummings, M, lesions in common marmoset monkeys AE, Harrison, CL, Strauss, BJ & Stepto, NK Oehler, MK, Blomfield, PB, Quinn, MA, Kirk, JA, (Callithrix jacchus): a benign non-progressive 2014, ‘Polycystic ovary syndrome and anti- Stewart, CJ, Obermair, A, Young, JP, Webb, glomerulopathy’, Journal of Medical Müllerian hormone: role of insulin resistance, PM & Spurdle, AB 2014a, ‘Reply to J. Moline et Primatology, vol. 43, no. 6, pp. 477-487. androgens, obesity and gonadotrophins’, Clinical al’, Journal of Clinical Oncology, vol. 32, no. 21, Endocrinology, vol. OnlinePubl, no. 6, pp. 1-8. 49. Copping, KJ, Hoare, A, Callaghan, M, pp. 2278-2279. McMillen, IC, Rodgers, RJ & Perry, VEA 2014, 40. Chen, M, Wu, L, Wu, F, Wittert, GA, 30. Buchanan, DD, Tan, YY, Walsh, MD, ‘Fetal programming in 2-year-old calving heifers: Norman, RJ, Robker, RL & Heilbronn, LK 2014, Clendenning, M, Metcalf, AM, Ferguson, K, peri-conception and first trimester protein ‘Impaired glucose metabolism in response to Arnold, ST, Thompson, BA, Lose, FA, Parsons, restriction alters fetal growth in a gender- high fat diet in female mice conceived by In MT, Walters, RJ, Pearson, SA, Cummings, M, specific manner’, Animal Production Science, Vitro Fertilization (IVF) or ovarian stimulation Oehler, MK, Blomfield, PB, Quinn, MA, Kirk, JA, vol. 54, no. 9, pp. 1333-1337. alone’, PLOS ONE, vol. 9, no. 11. Stewart, CJ, Obermair, A, Young, JP, Webb, 50. Corrigan, F, Wu, Y, Tuke, J, Coller, JK, PM & Spurdle, AB 2014b, ‘Tumor mismatch 41. Chen, M, Wu, L, Zhao, J, Wu, F, Davies, Rice, KC, Diener, KR, Hayball, JD, Watkins, repair immunohistochemistry and DNA MLH1 MJ, Wittert, GA, Norman, RJ, Robker, RL & LR, Somogyi, AA & Hutchinson, MR 2014, methylation testing of patients with endometrial Heilbronn, LK 2014, ‘Altered glucose metabolism ‘Alcohol-induced sedation and synergistic cancer diagnosed at age younger than 60 years in mouse and humans conceived by IVF’, interactions between alcohol and morphine: A optimizes triage for population-level germline Diabetes, vol. 63, no. 10, pp. 3189-3198. key mechanistic role for Toll-like receptors and mismatch repair gene mutation testing’, Journal MyD88-dependent signaling’, Brain, Behavior, of Clinical Oncology, vol. 32, no. 2, pp. 90-100. 42. Chen, Y, Stewart, JM, Gunthart, M, Hawthorne, WJ, Salvaris, EJ, O’Connell, PJ, and Immunity, vol. 45, pp. 245-252. 31. Buckberry, S, Bent, SJ, Bianco-Miotto, Nottle, MB, D’Apice, AJF, Cowan, PJ & Kearns- 51. Cortez, D, Marin, R, Toledo-Flores, T & Roberts, CT 2014, ‘MassiR: A method Jonker, M 2014, ‘Xenoantibody response to D, Froidevaux, L, Liechti, A, Waters, PD, for predicting the sex of samples in gene porcine islet cell transplantation using GTKO, Gruetzner, F & Kaessmann, H 2014, ‘Origins expression microarray datasets’, Bioinformatics, CD55, CD59, and fucosyltransferase multiple and functional evolution of Y chromosomes vol. 30, no. 14, pp. 2084-2085. transgenic donors’, Xenotransplantation, vol. across mammals’, Nature, vol. 508, no. 7497, 21, no. 3, pp. 244-253. 32. Buckberry, S, Bianco-Miotto, T, Bent, SJ, pp. 488-493. Dekker, GA & Roberts, CT 2014, ‘Integrative 43. Chittleborough, CR, Mittinty, MN, Lawlor, 52. Couper, JJ, Haller, MJ, Ziegler, AG, Knip, transcriptome meta-analysis reveals widespread DA & Lynch, JW 2014, ‘Effects of simulated M, Ludvigsson, J & Craig, ME 2014, ‘Phases sex-biased gene expression at the human interventions to improve school entry academic of type 1 diabetes in children and adolescents’, fetal-maternal interface’, Molecular Human skills on socioeconomic inequalities in Pediatric Diabetes, vol. 15, no. SUPPL.20, pp. Reproduction, vol. 20, no. 8, pp. 810-819. educational achievement’, Child development, 18-25. vol. 85, no. 6, pp. 2247-2262. 33. Buckberry, S, Bianco-Miotto, T & Roberts, 53. Court, K, Dare, A, Weston-Webb, M, C 2014, ‘Imprinted and X-linked non-coding 44. Clow, A, Law, R, Evans, P, Vallence, AM, Hadden WE, Sim, R, Johnson, NP, 2014, RNAs as potential regulators of human Hodyl, NA, Goldsworthy, MR, Rothwell, JR ‘Establishment of lipiodol as a fertility treatment placental function’, Epigenetics, vol. 9, no. 1, & Ridding, MC 2014, ‘Day differences in the - prospective study of the complete innovative pp. 81-89. cortisol awakening response predict day treatment data set’, Australia and New Zealand differences in synaptic plasticity in the brain’, 34. Burgess, T, Braunack-Mayer, A, Crawford, Journal of Obsetrics and Gynaecology, vol. 54, Stress, vol. 17, no. 3, pp. 219-223. G & Beilby, J 2014a, ‘Australian health policy pp. 13-19. and end of life care for people with chronic 45. Cmielewski, P, Donnelley, M & Parsons, 54. Coussens, S, Baumert, M, Kohler, M, disease: An analysis’, Health Policy, vol. 115, DW 2014, ‘Long-term therapeutic and reporter Martin, J, Kennedy, D, Lushington, K, Saint, D & no. 1, pp. 60-67. gene expression in lentiviral vector treated Pamula, Y 2014, ‘Movement distribution: a new cystic fibrosis mice’, Journal of Gene Medicine, 35. Care, AS, Ingman, WV, Moldenhauer, measure of sleep fragmentation in children with vol. 16, no. 9-10, pp. 291-299. LM, Jasper, MJ & Robertson, SA 2014, upper airway obstruction’, Sleep, vol. 37, no. 12, ‘Ovarian Steroid Hormone-Regulated 46. Cmielewski, P, Farrow, N, Donnelley, M, pp. 2025-2034. Uterine Remodeling Occurs Independently McIntyre, C, Penny-Dimri, J, Kuchel, T & Parsons, 55. Cundy, T, Gardener, G, Andersen, C, Kirby, of Macrophages in Mice’, Biology of D 2014, ‘Transduction of ferret airway epithelia C, McBride, C & Teague, W 2014, ‘Fetoscopic Reproduction, vol. 91, no. 3. using a pre-treatment and lentiviral gene vector’, endoluminal tracheal occlusion (FETO) for BMC Pulmonary Medicine, vol. 14, no. 1. 36. Caruso, M, Fung, KYC, Moore, J, Brierley, congenital diaphragmatic hernia in Australia GV, Cosgrove, LJ, Thomas, M, Cheetham, 47. Coe, BP, Witherspoon, K, Rosenfeld, JA, and New Zealand: are we willing, able, both G, Brook, E, Fraser, LM, Tin, T, Ha, T & van Bon, BW, Vulto-van Silfhout, AT, Bosco, P, or neither?’, Journal of Paediatrics and Child Ruszkiewicz, A 2014, ‘Claudin-1 expression Friend, KL, Baker, C, Buono, S, Vissers, LE, Health, vol. 50, no. 3, pp. 226-233. is elevated in colorectal cancer precursor Schuurs-Hoeijmakers, JH, Hoischen, A, Pfundt, 56. Dalton, JA, Rodger, DL, Wilmore, M, Skuse, lesions harboring the BRAF V600E mutation’, R, Krumm, N, Carvill, GL, Li, D, Amaral, D, AJ, Humphreys, S, Flabouris, M & Clifton, VL Translational Oncology, vol. 7, no. 4, Brown, N, Lockhart, PJ, Scheffer, IE, Alberti, 2014, ‘”Who’s afraid?”: attitudes of midwives pp. 456-463. A, Shaw, M, Pettinato, R, Tervo, R, de Leeuw, to the use of information and communication N, Reijnders, MR, Torchia, BS, Peeters, H, 37. Caruso, NC, Radovanovic, B, Kennedy, technologies (ICTs) for delivery of pregnancy- Thompson, E, O’Roak, BJ, Fichera, M, Hehir- JD, Couper, J, Kohler, M, Kavanagh, PS, related health information’, Women and Birth, Kwa, JY, Shendure, J, Mefford, HC, Haan, E, Martin, AJ & Lushington, K 2014, ‘Sleep, vol. 27, no. 3, pp. 168-173. Gécz, J, de Vries, BB, Romano, C & Eichler, executive functioning and behaviour in children EE 2014, ‘Refining analyses of copy number 57. Dasari, P, Sharkey, DJ, Noordin, E, Glynn, and adolescents with type 1 diabetes’, Sleep variation identifies specific genes associated DJ, Hodson, LJ, Chin, PY, Evdokiou, A, Medicine, vol. 15, no. 12, pp. 1490-1499. with developmental delay’, Nature Genetics, Robertson, SA & Ingman, WV 2014, ‘Hormonal 38. Cassar, S, Teede, HJ, Harrison, CL, Joham, vol. 46, no. 10, pp. 1063-1071. regulation of the cytokine microenvironment in AE, Moran, LJ & Stepto, NK 2014, ‘Biomarkers the mammary gland’, Journal of Reproductive and insulin sensitivity in women with Polycystic Immunology, vol. 106, no. C, pp. 58-66.

Annual Report 2014 67 58. Davis, JS, McMillan, M, Swaminathan, A, 69. Dodd, JM, McPhee, AJ, Turnbull, D, 79. Dunning, KR, Russell, DL & Robker, RL Kelly, JA, Piera, KE, Baird, RW, Currie, BJ & Yelland, LN, Deussen, AR, Grivell, RM, 2014, ‘Lipids and oocyte developmental Anstey, NM 2014, ‘A 16-Year Prospective Study Crowther, CA, Wittert, G, Owens, JA & competence: The role of fatty acids and of Community-Onset Bacteremic Acinetobacter Robinson, JS 2014, ‘The effects of antenatal β-oxidation’, Reproduction, vol. 148, no. 1, pp. Pneumonia’, CHEST Journal, vol. 146, no. 4, dietary and lifestyle advice for women who R15-R27. pp. 1038-1045. are overweight or obese on neonatal health 80. Dyson, RM, Palliser, HK, Lakkundi, A, de outcomes: the LIMIT randomised trial’, BMC Waal, K, Latter, JL, Clifton, VL & Wright, IM 2014, 59. De Hundt, M, Velzel, J, De Groot, CJ, Mol, Medicine, vol. 12, no. 1. BW & Kok, M 2014, ‘Mode of delivery after ‘Early microvascular changes in the preterm successful external cephalic version: A 70. Dodd, JM, O’Brien, C & Grivell, RM 2014, neonate: a comparative study of the human and systematic review and meta-analysis’, Obstetrics ‘Preventing pre-eclampsia - Are dietary factors guinea pig’, Physiological reports, vol. 2, no. 9. and Gynecology, vol. 123, no. 6, pp. 1327-1334. the key?’, BMC Medicine, vol. 12, no. 1. 81. Fernandez, RC, Peters, S, Carey, RN, 60. Dewailly, D, Lujan, M, Carmina, E, Cedars, 71. 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