Brilliant Minds - What will we discover next?

BRILLIANT MINDS What will we discover next?

In 2016, Murdoch Childrens Research Institute celebrates 30 years of life-changing discoveries.

Thirty years ago, two visionaries imagined a better future for our children. Professor David Danks envisioned an independent research institute to study the genetic basis of childhood disorders. When genetic science was in its infancy, Dame Elisabeth Murdoch had the foresight to support the establishment of a genetics institute co-located with a children’s hospital. With the involvement of Sir Jack Brockhoff, the Scobie and Claire Mackinnon Trust, the Miller family and others the foundations were laid for a world-class centre of genetics research and clinical genetics services.

Since then, the Murdoch Childrens has grown to become the largest child health research institute in Australia. Our work encompasses a broad range of research from laboratory science to large population studies. We work alongside doctors and nurses to ensure the knowledge we create improves the lives of infants, children and adolescents both in Australia and internationally.

This year, we are celebrating our scientists – the unsung heroes making a real difference to the health of children – and looking back at the remarkable achievements throughout our history.

We’re incredibly excited about the next 30 years and beyond.

BRILLIANT MINDS What will we discover next?

For the lovers of science.

May you never stop marvelling at the possibilities.

Contents 01 02 06 08

Director’s foreword - Professor Kathryn North AM

12

Kidney disease Professor Melissa Little

51

14

Stem cells Professor Andrew Elefanty & Professor Ed Stanley

SKELETAL BIOLOGY Professor Ravi Savarirayan

& Amy

52

Obesity Associate Professor Matt Sabin

16

Reading & Literacy Professor Frank Oberklaid

54

Childhood development Professor Melissa Wake

18

Fragile X Doctor David Godler

55

20

Sleep Associate Professor Harriet Hiscock

Rotavirus Professor Graeme Barnes & Professor Ruth Bishop

57

GENETICS & RARE DISEASES Professor Kathryn North

Sleep techniques Doctor Anna Price

26

58

Food allergies Professor Katie Allen

& Jenson

Cancer Associate Professor Paul Ekert

60

28

Cystic fibrosis Associate Professor Sarath Ranganathan

62

30

Infectious diseases Professor Nigel Curtis

Premature babies Professor Peter Anderson & Doctor Karli Treyvaud

& Estelle

32

Neuroimaging Wirginia Maixner, Doctor Marc Seal & Doctor Joseph Yang

64

Exposures in pregnancy Professor Jane Halliday

34

Cerebral Palsy Professor Kerr Graham

66

Diabetes Professor Fergus Cameron

69

Education Professor Sharon Goldfeld

70

Allergies Professor Mimi Tang

& Ayden

72

Emergency medicine Associate Professor Franz Babl

74

inhaled vaccines Doctor Anushi Rajapaksa

75

Autism Professor Katrina Williams

76

adolescence Professor Susan Sawyer & Professor George Patton

78

heart surgery Associate Professor Yves D’Udekem

& Harry

22

36 40 42

Institute co-founder Dame Elisabeth Murdoch AC DBE Institute co-founder Professor David Danks AO Our history

Tropical infectious diseases Associate Professor Andrew Steer

& Julius Childhood Stroke Doctor Mark Mackay Anaesthesia Professor Andrew Davidson

43

Maternal health Professor Stephanie Brown

44

Maternal mental health Doctor Hannah Woolhouse

45

Refugee health Doctor Elisha Riggs

46

Mitochondrial disease Professor David Thorburn

48

Cardiac Stem cells Doctor David Elliot

& Zac

82

Sex development Professor Andrew Sinclair

Acknowledgements

Director’s Foreword As this book so vividly demonstrates, scientists deserve to be celebrated. For the 30th anniversary of the Murdoch Childrens Research Institute, we are celebrating some of our brightest and most talented minds and showcasing our greatest achievements.

This book celebrates the Murdoch Children’s heroes, or as I like to describe them, the ‘rock stars of research.’

It’s not often medical researchers themselves are in the spotlight, instead letting their discoveries make headlines. That is why we’ve profiled scientists from across the Institute – from the global experts, clinicianresearchers, laboratory scientists, research veterans, to up-and-comers – to show you the breadth and depth of talent working at the Murdoch Childrens. We learn about their desire to change lives, uncover clues and their determination to transform health and education.

We also meet some of the children involved in our research, and those who have benefited from our work.

At the Murdoch Childrens, children are at the heart of everything we do and we know that our work makes a difference to young lives worldwide. These are just a few of those stories.

As the fourth Director of the Institute in its 30 years, I feel honoured and privileged to be following in the esteemed footsteps of previous directors who nurtured our talented researchers and expanded the Institute.

Our inaugural director Professor David Danks was the visionary and human genetics pioneer who established the Murdoch Institute. Professor Bob Williamson took the helm in 1995, at a time when genetics was becoming a crucial part of research and treatment for cancer, heart disease and infection in children and adults. Under his leadership, the Murdoch Institute and The Royal Children’s Hospital Research Institute merged to form the Murdoch Childrens Research Institute, with a broader focus on child health research, including public health and clinical research. In 2005, under the leadership of Director Professor Terry Dwyer, the Institute underwent a major restructure which resulted in significant growth and increased scientific excellence.

The Institute is now home to more than 1900 worldclass staff, many of whom work tirelessly for years and even decades trying to solve complex scientific questions. We eagerly await what our dedicated team will discover next.

Professor Kathryn North AM Director, Murdoch Childrens Research Institute

1

“The career of a scientist is not an easy one and it is definitely not for all of us, but they depend on our generosity. We must do all that we can within our own capacity to help them in their quest for knowledge.”

D

ame Elisabeth Murdoch loved to be actively involved in her many philanthropic pursuits and the Murdoch Childrens was no exception. She was a regular visitor to the Institute and would chat to researchers about how their projects were going. Dame Elisabeth was a careful listener and would remember what the scientists told her previously.

“She probably knew more about what some of the researchers were doing than I did,” said former chairman Laurence Cox. “The very fact she came and wandered around the Institute inspired the researchers.

They just loved it.”

Professor Jane Halliday remembers these visits.

“We used to just sit around in the tea room with her and have a chat. It was a small place. We all knew her very well.”

2

Being involved was one of Dame Elisabeth’s mantras.

She once told the ABC: “If you’ve got money it’s perfectly easy to give it away and nothing to be particularly proud of. But it’s being involved and knowing you’re helping and really being committed... it’s very rewarding when you feel that you are making a difference to the lives of other people.”

Dame Elisabeth’s passion for child health was sparked at the tender age of 16 when her talent for knitting a

record number of baby singlets earned her a trip to the then Children’s Hospital. She was so upset at the sight of babies emerging crying from theatre she promised herself to do whatever she could for the hospital.

She was associated with our campus partner, The Royal Children’s Hospital, for more than 70 years. Dame Elisabeth helped to establish the Institute in 1986 and since that time she and her family have demonstrated unparalleled generosity, helping the Institute to improve the health and wellbeing of children globally.

Dame Elisabeth passed away on December 5, 2012 at the age of 103. Without her foresight, the Murdoch Childrens Research Institute could not have grown to become one of the world’s leading child health research centres.

“When I was young, conditions like polio and small pox were the big health issues, now you hardly hear of them thanks to tremendous advances in medical research. Today, the health of children is challenged by issues such as obesity, diabetes, cancer and depression. Medical research is vital to solve not only these problems, but emerging problems we will face tomorrow and many years from now.”

dame

Elisabeth Murdoch AC DBE

3

Co-Founder, Murdoch Childrens Research Institute

February 8, 1909 DECEMBER 5, 2012

April 30th 2009 Dear Laurie, Warmest thanks for the very enjoyable party you, Terry and the MCRI gave me.

It gave me so much pleasure to see so many members of the Institute and a number of my family.

4

I was thrilled to hear about the overseas scholarships being awarded toward my 100th birthday How wonderfully glorious the members of the Centenary Circle are!

It is such a comfort to have you as the Chairman of the Board, many, many thanks for all you do for the MCRI Fond regards Yours ever Elisabeth

This letter was written by Dame Elisabeth to Mr Laurence Cox AO on the occasion of her 100th birthday.

In his final year as Chairman of the Murdoch Childrens – after 25 years on the Board of Directors and a long relationship with Dame Elisabeth – Laurie and former Director Professor Terry Dwyer AO hosted her centenary birthday celebrations.

Dame Elisabeth wrote to Laurie to thank him and the Murdoch Childrens family in particular for the new research fellowship which had been announced in honour of the milestone, supported by the generous members of the Centenary Circle.

5

6

“David was a remarkable doctor, scientist, teacher, mentor, family man, friend, and champion of good causes. His immense vision, talent, energy, tenacity, unflinching appetite for excellence, and warm and caring nature remain a shining inspiration to us all.”

Professor Andy Choo, Esteemed Honorary Fellow, Murdoch Childrens Research Institute

Professor

David Danks AO

H

ailed as the pioneer of human genetics research in Australia, Professor David Danks founded the Murdoch Institute with the vision that genetics would one day become part of standard patient care.

David started his paediatric career at The Royal Children’s Hospital (RCH). Although he was a muchloved doctor, mentor and teacher, it was clear David’s passion lay in research, specifically clinical genetics, which in the 1960’s had not yet found its way in to mainstream medicine.

Undeterred by the challenge of bringing the discipline to the fore, David received training in the United Kingdom and United States from the very best in the clinical genetics world and bought this valuable knowledge with him on his return to Melbourne. In 1967, he set up the Genetics Research Unit, a small research outfit based at RCH. David, along with Dame Elisabeth Murdoch and other supporters, formally established the Murdoch Institute for Research into Birth Defects in 1986. He led the Institute as founding Director until his retirement almost a decade later.

Co-Founder, Murdoch Childrens Research Institute

June 4, 1931 July 8, 2003

David’s personal research achievements were also impressive. In a series of landmark papers published in the early 1970’s, David and his team showed that Menkes syndrome, a condition that can lead to brain damage, retarded growth and death, was a disease of copper absorption. He maintained his interest in the disease throughout his career and was one of a team that found the genetic cause of the condition.

Under David’s leadership, the Murdoch Institute became the premier centre for genetics research worldwide, growing to more than 200 staff by the time he retired in 1995. Since merging with the RCH Research Institute, the Murdoch Childrens Research Institute has expanded into all areas of child and adolescent health. Now Australia’s largest child health research Institute, the 1900 staff and students of Murdoch Childrens continue to be inspired by Professor Dank’s appetite for discovery and excellence.

7

Our history

1870 1936 1960 1962 1973

Melbourne Hospital for Sick Children founded.

1990

The hospital establishes a Medical Research Committee The Royal Children’s Hospital Research Foundation established under Committee of Management President Elisabeth Murdoch

Professor Andrew Sinclair and team identify the sex-determining gene SRY. The discovery attracts worldwide media attention and finally provides an answer to one of our most fundamental questions – what makes us male or female?

The Genetics Research Unit established by Dr David Danks Rotavirus discovered by a team of researchers led by Professor Ruth Bishop.

1992

Adolescents are enrolled in an ongoing study looking at mental health and substance use.

Researchers set up the Victorian Infant Hearing Screening Program – one of the first whole-of-state screening programs in the world to detect congenital hearing loss.

1986

1993 The Murdoch Institute for Research in Birth Defects founded by Professor David Danks with support from Dame Elisabeth Murdoch and her family, Sir Jack Brockhoff, the Scobie and Clare Mackinnon Trust, the Miller family and others. It quickly becomes a world-class centre of genetics research and clinical genetics services.

1994 1995 1999

8

The Institute’s focus on Menkes syndrome culminates in the co-discovery of the Menkes gene led by Professor David Danks and Professor Julian Mercer.

Landmark study by Professor Kerr Graham proves the safety and effectiveness of Botulinum toxin A – Botox – for children with cerebral palsy.

Professor Bob Williamson AO appointed Director of the Institute after David Danks retires.

A trial of rotavirus vaccine developed by MCRI researchers, RV3, found the immune system was successfully stimulated and therefore protected against the virus.

2000 Sarah Murdoch becomes an ambassador Victorian Clinical Genetics Services, an amalgamation of clinical genetics services and genetic pathology laboratories, is established. It is a wholly-owned subsidiary of MCRI.

1988

Deputy Director Professor Dick Cotton develops a new ‘chemical cleavage of mismatch’ technology, adopted by scientists worldwide for screening genes for mutations.

for the Institute. She later joins the Board of Directors.

The Murdoch Institute and The Royal Children’s Hospital Research Institute merge to form the Murdoch Childrens Research Institute.

2003

2013

Professor Ruth Bishop awarded the CSL Florey Medal for her lifetime’s work on rotavirus.

The Bruce Lefroy Centre established by the Lefroy family and their friends. The Centre conducts research into genetic diseases.

Research led by Professor Katie Allen discovers low levels of Vitamin D in infants with Australia-born parents is linked to an increased risk of food allergy.

Professor David Danks passes away, aged 72.

2004 2005 2010

Professor Terry Dwyer AO appointed director, a position he holds until 2012.

Launch of early childhood literacy initiative Let’s Read, encouraging parents to read to pre-school-aged children.

Research by Katie Allen’s team contributed to the recommendation that parents introduce cooked egg into their child’s diet between four and six months, not 10 months as previously directed.

2014 2015

Adults conceived through IVF and other assisted reproductive technologies have mostly grown up as healthy individuals, an MCRI study finds.

A clinical trial led by Professor Mimi Tang finds 82 per cent of children involved in the study with a peanut allergy can tolerate peanut after treatment with a probiotic taken in conjunction with peanut protein.

Professor Melissa Little leads a research group that successfully grows a ‘mini kidney’ from stem cells in a dish.

Bill and Melinda Gates Foundation award $1.4 million to Murdoch Childrens researchers to help combat childhood pneumonia by improving pneumonia vaccines.

2011

Professor Kathryn North joins the Institute as its new Director.

MCRI moves into its new world-class facility, co-located with The Royal Children’s Hospital. The facility is officially opened by Her Majesty Queen Elizabeth the next year.

The Melbourne Children’s Trials Centre is established.

The Australian Genomics Health Alliance (AGHA), a national network of 47 partner organisations, led by Professor Kathryn North and Professor Andrew Sinclair is established.

Rupert Murdoch contributes a $10 million grant on behalf of his family to the Institute.

The Fontan registry is established by A/ Prof Yves d’Udekem. The Registry collects health information on Fontan patients living in Australia and New Zealand.

2012

Murdoch Childrens patron Dame Elisabeth Murdoch passes away on December 5th.

A study shows that behavioural sleep techniques known as “controlled comforting” and “camping out” are an effective way to help infants sleep better and reduce mothers’ depression levels.

2016

Murdoch Childrens Research Institute celebrates its 30th anniversary.

VCGS celebrates 50 successful years of newborn screening in Victoria.

9

10

11

Professor

Melissa Little

12

In 2015, Melissa relocated to Melbourne, bought a house, wrote scores of grant applications, published a pile of research papers and then pretty much achieved science world domination with a cover story in the highlyprestigious journal Nature about the development of ‘mini-kidneys’.

The publication attracted the most media attention she had ever experienced. The stem cell researcher found herself fielding interviews from around the world in the middle of the night. The story featured in the Wall Street Journal, made front page news in the Netherlands and was picked up in the UK, Germany, Spain and of course, Australia.

The excitement was over the successful development of mini-kidneys – called organoids – grown in a dish from stem cells derived from adult skin or blood cells (pluripotent stem cells).

The mini-kidneys included eight to nine different types of cells, mimicking kidney development in the embryonic stage.

Importantly, the organoids – which take about three weeks to develop – appeared to respond to toxic drugs. And therein lies the future of this research to help the one in 1000 children born every year with kidney defects.

The mini-kidneys are being used to model diseases and will potentially be used to screen for drug toxicity, saving patients from being exposed to drugs that could damage their kidneys.

The head of the Institute’s Kidney Research Laboratory, Melissa has devoted the past 20 years to the biology of the kidney, while the mini-kidney project was a “dream” with its genesis about 15 years ago.

The tragic death in 2001 of her colleague Dr Toshiya Yamada impacted heavily on Melissa and she began to question the purpose of her research.

The seminal finding in 2006 that a stem cell could be made from any cell in the body, including skin or blood cells, prompted Melissa – then based at the University of Queensland – to investigate whether these cells could be turned into kidneys.

Melissa stumbled onto kidney work completely by chance, working on the organ in her honours year and later accepting a job – her first – in cancer genetics focusing on a kidney cancer.

Although her father was also a scientist, this wasn’t necessarily her obvious career choice. In fact, she was leaning towards art, after topping her high school year in both this and English.

“I’m not sure that science was a choice as much as an accident,” Melissa says. Her school principal wanted her to enrol in medicine but she “thought it sounded more fun to be a zoologist or something like that”.

But she says science probably suits her more than art, although she still paints when she can find the time and describes the process of producing images for her scientific manuscripts as one of her greatest joys.

Outside the lab, Melissa has an equally full agenda with a political involvement in science and an impressive list of leadership roles.

While many individuals have influenced her career, she believes her success comes from being alert to all the possibilities and grasping those opportunities when they arise. “It’s very much about seizing the day.”

“It made me wonder why I was doing this, why we were all working so hard towards relatively esoteric outcomes. I think Toshi passing made me want to achieve something with the science that I do for those around me,” Melissa says.

13

kidney disease

O

ne question parents ask paediatrician Ravi Savarirayan often meets with silence.

“What can you do to help my child”?

“We had no answer for that,” says the energetic geneticist, who specialises in bone disorders. “I decided I’d like to spend my time trying to see if we could answer that question.”

This turning point came about five years ago. Ravi, who studied medicine at Adelaide University before specialising in paediatrics, moved his research towards trying to find treatments for genetic diseases.

One of those is achondroplasia, the most common type of dwarfism.

For a start, children with the genetic condition are seven to eight times more likely than other babies to die from Sudden Infant Death Syndrome (SIDS) in the first year of life. They also have spinal, leg and hip problems which can cause pain and will likely require surgery down the track.

New treatments are not just about correcting short stature but trying to avoid the need to undergo operations.

Ravi leads the Melbourne arm – the largest site worldwide – of an international trial testing a drug on the growth of children with achondroplasia.

The trial involves 20 children in Melbourne and 36 worldwide. Results to date are extremely encouraging, with the drug shown to be safe and effective.

“The first six months of treatment increases the growth of the kids by 50 per cent,” Ravi says. “They were growing at around four centimetres a year and now they are growing six centimetres a year – a 50 per cent increase.

“It’s been a wonderful story and now it looks like we are going to have funding to continue this trial for at least seven years of treatment because there are no serious side effects.”

14

Ravi likens the overactive gene responsible for achondroplasia to a tap that gets turned on and overwaters the plant, stopping its growth.

The drug, injected under the skin, doesn’t turn the tap off, but puts a kink in the hose to allow normal bone growth to resume. The drug, which is injected under the skin, uses a natural human protein that stimulates bone growth.

“It’s about minimising and decreasing the medical complications of this condition with a targeted therapy, rather than making people with dwarfism taller,” he says.

The next phase of research will look at starting treatment earlier, at six months of age rather than four years.

If it continues to prove effective, hundreds of thousands of children around the world could benefit. There are 30,000 children in India alone with achondroplasia so Ravi is intent on ensuring it’s not just kids in places like Australia, the UK and Europe who benefit, but those in developing countries too.

It’s a cause close to Ravi’s heart. His parents, both doctors, migrated to Australia from South India and settled in the South Australian town of Whyalla, where Ravi grew up.

While his heritage meant he looked different to those around him growing up, it certainly hasn’t held Ravi back. He oozes charisma, positivity and enthusiasm. Now a father-of-four – an 18-year-old, 15-year-old and 11-year-old twin girls – he channels his energy not only into his work but into a charity he started with his wife and two friends.

The Yatra Foundation establishes schools in India to increase access to quality education for the most severely disadvantaged children.

“My attitude is that you can do a hell of a lot and it’s what we can do that scares us, not what we can’t do,” Ravi says.

Now he gets the response from parents he wants when they ask him what can be done for their sick child.

“It’s very exciting. They can’t believe it,” he says. “And that’s very empowering.”

Skeletal Biology

E

very mother knows those anxious few moments after giving birth, waiting to be told their child is healthy. For Meagan Bourne, those words didn’t come. She was told shortly after having her second daughter, Amy, following an emergency caesarean section, that her baby had achondroplasia, or dwarfism.

Professor

Ravi Savarirayan & Amy

It was a shattering moment. The first year, she admits, was the hardest. But her worries eased ever so slightly when she learned Amy was otherwise well.

“You learn that she is healthy and she’s smart, and she’s still going to be Amy,” Meagan says.

“She’s just going to be little.

“Once you get your head around all those positives, it does make it a little bit easier.”

Meagan remembers asking Professor Ravi Savarirayan if there was a cure for achondroplasia. The answer was no, but there was hope.

Amy, now eight, is one of a small group of Victorian children involved in the Australian arm of an international trial testing a new drug treatment on children with achondroplasia.

Amy’s growth was measured for two years before she became part of the trial. She now receives daily injections of the drug.

Meagan was concerned about the long-term health impact on the bones, joints and spine associated with achondroplasia and was keen to help Amy in any way possible.

“I thought if there is a chance of reducing some of those health concerns, I’m interested,” says Meagan.

She also felt Amy’s sunny personality meant she would cope well with the rigours of a trial.

Amy, she says, is “divine”, has lots of friends, adores her 11-year-old sister and has a great imagination. Her short stature doesn’t hold her back from physical activity, either. Her favourite activities are running and swimming.

“She just loves life and is a kind, happy person,” says Meagan. “That’s why I thought she would be suitable for the trial.”

Happy tears cloud Meagan’s eyes as she talks about the staff involved in the research at the Murdoch Childrens. She is awestruck at how excited Amy is when she visits the Institute so she can see the staff again.

Meagan is hopeful the research will not only help Amy to live a healthier life, and continue her love of running and swimming, but also benefit other kids in future. “That’s what it is all about.”

15

As

a young boy, Frank Oberklaid would visit the local library twice a week during school holidays and borrow a stack of books.

Television, he recalls a little shyly – lest he give away his age – was yet to infiltrate family homes.

“My mother always loved reading and I always loved reading. Hopefully, I have passed that on to my kids,” the researcher says.

Now Frank wants to pass this love of reading on to a new generation of children. The softly-spoken paediatrician with a handshake like a hug is the driving force behind the ‘Let’s Read’ campaign, which encourages Australian parents to read to their kids.

The program addresses troubling data that more than one in five Australian children start school developmentally vulnerable or at risk. Brain development research over the past 20 years has indicated that the first five years of a child’s life is incredibly important not only for future learning but also health and wellbeing.

This shone a light on the importance of early childhood development.

“The foundations of literacy are laid down well before kids get to school,” says Frank. “Language develops naturally. Reading doesn’t. You have to be taught.”

The building blocks of reading, Frank adds, include learning the alphabet, understanding that the letters have particular sounds and becoming familiar with the way words appear in books, from left to right. The best way to establish this before school is to simply read to children.

“In the same way we immunise children against the risk of infection, the best way to immunise your child against the risk of reading failure is to read to them from a very early age,” Frank says.

“We are not trying to turn kids into readers by the age of two or three. But reading is a lovely thing for parents to do with their young child. If it’s on a daily basis from an early age, kids start to anticipate it, they start to enjoy it.

“Then they get interested in books and there’s every chance that by the time they get to school they are eager to start to read.”

Frank’s passion for early intervention and prevention was sparked early in his career, during his four years at Harvard and the Boston Children’s Hospital paediatrics department. One of his mentors used to say: “Every time a child is admitted to hospital it represents a failure of the healthcare system,” Frank recalls.

16

He returned to Melbourne to establish Australia’s first department of ambulatory paediatrics, a term then used in the USA to refer to children who had problems that didn’t require admission to hospital.

The department has grown to 200 staff and is now known as the Centre for Community Child Health, which Frank still leads today. He proudly points to three landmark projects to emerge from the group’s research: the government-funded Raising Childrens Network parenting website (his favourite feature is ‘Baby Karaoke’ ); the Australian Early Developmental Index, a population-measure of children’s health and wellbeing at age five (“we have data now on 97 per cent of all Australian five-year-olds”); and the Victorian Infant Hearing Screening Program, which screens babies for deafness soon after birth.

“We have put a lot of effort in recent years into translating the research at the Murdoch Childrens and elsewhere around the world so it informs public policy, service delivery, clinical practice and parenting,” says Frank.

Professor

Frank Oberklaid OAM

17

Reading & literacy

Doctor

David Godler

18

“I think improving people’s lives is a big thing, not just so that you are remembered, but so other people will live better lives.�

D

avid Godler knew from a young age he wanted to combine his love of biology with a desire to change lives.

“I always admired scientists who made a difference,” the geneticist says. “When I was young I thought, ‘what is the best way to contribute?’

“I think improving people’s lives is a big thing, not just so that you are remembered, but so other people will live better lives.”

David, who fled with his family to Australia from the war-torn former Soviet Union in 1991, understands what it is like to want a chance at a better life. “Everyone wants to leave something behind,” he says.

David was 12 when his family left the USSR (his birthplace is now known as the Republic of Moldova).

He remembers running into demonstrations on his way to school. “You had to run in the other direction very quickly,” he recalls. “If you were stopped and you couldn’t speak the native language fluently, you were in trouble.”

But his family, who had relatives in Australia, could not move as soon as they would have liked because of restrictions associated with his parents’ jobs. When the state collapsed, the family was allowed to leave. They took the first flight they could.

Through his research, David’s dream of helping others is coming true. He hopes to improve the lives of children and their families affected by genetic conditions including fragile X syndrome.

Fragile X, which affects one in 4000 children born every year, is a common genetic cause of intellectual disability and autism. The inherited disorder is caused by a faulty switch of an important gene called FMR1, located on the X chromosome.

The syndrome is estimated to cost the Australian economy up to $180 million a year, or $2.5 million per child.

David and his team have already developed world-first genetic tools that may make possible the inclusion of fragile X as part of the newborn heel-prick test.

This blood test screens babies for more than 30 congenital disorders.

The team is now investigating – in the world’s largest fragile X study – how often the syndrome occurs and how well the test works on 100,000 male and female newborns.

“Whilst it is known that large numbers of new families are diagnosed with fragile X syndrome each year, this diagnosis is often not made until children reach school age,” says David.

“By this time parents may have had another affected child. A delayed diagnosis and failure to recognise and manage fragile X syndrome also means that families may not receive the best early interventions.”

David and his team believe that some children with fragile X syndrome might be missed altogether because there is no routine testing for all children.

“This project will give us some idea of how many children or young people with fragile X syndrome remain undiagnosed and whether routine newborn screening would fill this gap,” says David.

“If the condition is detected early it would also give families more options for the future, including the choice to have children using preimplantation genetic diagnosis through IVF, who would be unaffected.”

David and his team will also collect information on the cost of raising a child with fragile X to show government that routine screening is cost effective.

The same technology underpinning the fragile X test is being used by David and his colleagues to develop newborn screening and diagnostic tests for three other genetic conditions – Prada Willi Syndrome, Angelman’s Syndrome and Chromosome 15 duplication syndrome.

“We are now developing different diagnostic and screening tests based on the technology initially developed for fragile X which will pick up all four conditions from one tiny portion of DNA,” says David.

Thousands of children and families touched by fragile X and these other disorders now stand to benefit from his research, bringing David a step closer to fulfilling his childhood dream.

Fragile X

19

Professor

Graeme Barnes PROFESSOR

Ruth Bishop AO

20

Ruth Bishop still remembers her first glimpse of rotavirus cells beneath the microscope. It was the most beautiful image she had ever seen.

So captivating, in fact, that the circular particle shape is now immortalised in a silver necklace gifted to her from colleagues who were part of the landmark discovery of the virus, led by Ruth, in 1973.

It was a major breakthrough in one of the most significant causes of global infant mortality at the time. About 10,000 Australian children were being hospitalised with the disease every year.

In most cases, doctors didn’t know what was causing the acute gastroenteritis.

That was until Ruth and her team identified the virus under an electron microscope.

Ruth’s colleague of 40 years, Graeme Barnes, was overseas at the time of the discovery. When he returned, he recalls a very excited Ruth meeting him at the airport, exclaiming “We’ve found it!”

Four decades later, vaccines have been developed as a direct result of the breakthrough, which Graeme likens to the discovery of polio and esteemed immunologist Sir Gus Nossal once described as a ‘great hallmark of Australian science’.

It earned Ruth, who is now in her eighties, the prestigious Florey Medal in 2013 – the first time a woman was honoured with the award.

Since the discovery, hospital admissions for acute gastroenteritis in Australia have dropped to under 2,000 a year. The gastroenteritis ward at RCH no longer exists. It isn’t needed.

However, the fight against rotavirus isn’t over. Tragically, the life-threatening diarrhoeal disease still kills about half a million children under the age of five a year, mostly in developing countries.

An oral rotavirus vaccination has been part of the National Immunisation Program for all Australian infants since July 2007. The World Health Organization in 2009 recommended all children be vaccinated against rotavirus infection in an effort to reduce child mortality.

Current rotavirus vaccines are given to infants from six to eight weeks of age but this leaves newborns at risk of early infection in developing countries, where families have limited access to healthcare.

A world-first vaccine developed by the Institute specifically for newborns could save millions of children’s lives in these developing countries over the next decade.

This immunisation – RV3 – is another legacy of Ruth’s pivotal research. It uses a different strain of rotavirus discovered in 1975 by Ruth and her colleagues in healthy Melbourne babies who displayed no symptoms and were protected against severe gastroenteritis.

“The benefit we anticipate from RV3 is that it can be given shortly after birth,” says Ruth. “The advantage of it in developing countries is that the only contact between mother and baby and the health services is at birth so a birth dose is very attractive in most of these countries.”

Ruth also featured in a portrait snapped by world-renown photographer Annie Liebovitz, part of a series of artworks celebrating vaccine pioneers, commissioned by the Bill and Melinda Gates Foundation.

The new vaccine is an exciting culmination of more than four decades of work and a long professional association between Ruth and Graeme, who still share an office at the Institute’s laboratories.

Despite the development of other vaccines given at six weeks of age, the RV3 immunisation promises to fill a significant gap.

“It became clear there was actually a niche setting for us for this serendipitously-found strain, which can be given at birth. And it’s seen to be appropriate to be developed by other people as well, including Bill Gates, and the World Health Organization,” says Graeme.

Although Ruth has taken a step back from the vaccine’s development she has enjoyed watching it evolve. “I am very grateful for the tenacity and enthusiasm of others, in particular Bill Gates, whose support for the vaccine development has been crucial.”

The potential for this low-cost vaccine to save millions of babies’ lives worldwide and completely eradicate rotavirus caught the attention of philanthropists Bill and Melinda Gates, who have generously funded trials of the RV3 vaccine in Australia, New Zealand and Indonesia.

Rotavirus

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K

athryn North has a fascination for solving problems and particularly loves a good cryptic crossword. It’s no surprise then that the dynamic leader of the Murdoch Childrens has devoted her life to finding solutions for some of the more unusual disorders affecting children.

says. She paid tribute to her mum in a recent Mother’s Day magazine special. “My mother was a force in my life,” she told the Australian Women’s Weekly. “A fierce advocate of equal opportunity, she drilled into me from an early age that I could achieve anything I put my mind to.”

From investigating birth defects caused by thalidomide to researching neurofibromatosis and muscular dystrophies – and treating children with these conditions – Kathryn’s interest has always been piqued by the rarer diseases.

Guided by her lifelong mentor, Professor Robert Ouvrier – “he’s like my medical dad” – Kathryn trained as a paediatrician and neurologist, then undertook her doctorate on neurofibromatosis. The condition, which came to fame as the ‘Elephant Man’ disease, affects one in 3000 people.

It’s perhaps fitting that she finds herself at the helm of the Murdoch Childrens, an Institute founded 30 years ago by Professor David Danks, a man who shared her intrigue for rare disorders.

Kathryn’s enthusiasm for research was sparked during her medical degree when she took a year off to research birth defects linked to thalidomide.

During her paediatric training she found another passion – working with children.

“In paediatrics, kids are open books,” she smiles.

“As soon as they’re feeling better, they’re up and about.”

“I love children, just dealing with them.

You can love your patients. You can give them a cuddle. When you work with them over many years, as I do, you become part of their families.”

Kathryn’s own family – she is the youngest of four children – was an even earlier influence on her career.

Her father was diagnosed with stomach cancer when she was just 12 and he passed away two years later.

It was a very early exposure to the medical world for the young Kathryn, but it had a lasting impact.

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Her mother, who had given up work to raise her children, returned to the workforce after her husband’s death. She encouraged her children, especially the girls, to do well.

“She was determined that her daughters would get a good education.

She went back to work to make sure I could go to university,” Kathryn

During her doctorate Kathryn established a clinic to look after patients with neurofibromatosis. The demand was astonishing – the clinic saw more than 200 patients in the first six months. It became obvious that many of these children were experiencing learning difficulties and she began to study why – research she continues to this day.

Her foray into muscular dystrophies began in the United States, where she snared a job in the Harvard Genetics Program, based at the Boston Children’s Hospital. She worked in the lab of Dr Louis Kunkel, who identified the dystrophin gene which causes Duchenne and Becker muscular dystrophy.

Kathryn is internationally recognised for the discovery of the gene ACTN3, which she initially thought may be linked to muscular dystrophy. She identified a change in the gene that stops the ACTN3 protein from being expressed in skeletal muscle – but rather than causing disease, it is a normal variant, occurring in one in five Australians and more than 1.5 billion people worldwide. Her studies in elite athletes have demonstrated that ACTN3 is a major determinant of skeletal muscle performance.

Dubbed the “gene for speed”, it was found in the majority of elite sprint athletes but is not necessary for endurance performance. Kathryn’s team recently proved that variations in ACTN3 influence disease severity and progression in Duchenne muscular dystrophy. They are now studying how it influences muscle-wasting associated with age and cancer.

Perplexed as to why it was so common, Kathryn delved deeper and traced its origins back to evolution. It became more widespread when man migrated out of Africa during the last Ice Age, says Kathryn. Without ACTN3, people have slower glucose metabolism so they use energy from food more effectively.

Their bodies are also more efficiently equipped to generate heat in the cold. “Not having ACTN3 became so common because it gave you a survival advantage during times of famine and cold in the Ice Age,” Kathryn says. But in modern times with sugarladen diets, it may well be linked to increased risk of diabetes and obesity.

In 2012, Kathryn was awarded a Member of the Order of Australia (AM) for service to medicine in the field of neuromuscular and neurogenetics research, paediatrics and child health.

After three decades in Sydney (apart from her stint in Boston), Kathryn was drawn to the Murdoch Childrens in 2013. It was a big move. The attraction was the integration of research with The Royal Children’s Hospital in a purpose-built facility alongside the University of Melbourne and the Victorian Clinical Genetic Service, providing a unique opportunity to translate the latest discoveries into clinical practice. In a short time, she has established a clinical trials centre and placed the Institute at the forefront of the genomics revolution.

Advances in genetic technology mean all genes can now be sequenced quickly and cheaply, and the information used to predict, diagnose and treat rare diseases and inherited forms of cancer.

Kathryn envisions a future where genes for more complex disorders including mental health disorders, diabetes and cardiovascular disease could also be identified, and the newborn heel-prick test screens for thousands of disorders.

Kathryn and Deputy Director Andrew Sinclair lead the Australian Genomics Health Alliance, working towards integrating genomics into healthcare nationwide.

“This is an ambitious goal,” Kathryn says. “But this place has just got the feeling that you can make anything happen.”

Genetics & rare diseases

Professor

Kathryn North AM

“This is an ambitious goal, but this place has just got the feeling that you can make anything happen.�

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25

K

atie Allen’s young patients are often surprised to discover that, like them, she has food allergy and carries an EpiPen.

food allergy in children ever mounted. The second is SchoolNuts, a population-based study of 10,000 school kids aged 10 to 14.

But unlike her patients, Katie developed the condition as an adult. After the birth of her first child, she noticed whenever she would devour her beloved peanut butter sandwiches, her throat started swelling. “This started getting worse every time I ate it. I’d eat some, then have this really swollen throat, then I would start to drool,” she says. “I went to get some tests and they said I had adult-onset peanut allergy, which I didn’t even know existed.”

Research led by Katie has identified three hypotheses – which she summarises as the Five Ds – contributing to Australia’s high rates of allergy. These are dry skin and diet, dogs and dribble, and Vitamin D.

The paediatric gastroenterologist and allergist, who is a world-leader in food allergy research, can empathise with her patients and provide advice based on her team’s research.

This research has begun unravelling the mystery behind the rising food allergy epidemic in the modern world.

Her findings could potentially help prevent allergy in millions of children worldwide.

When Katie first immersed herself in food allergy research a decade ago, she says there was a perception rising food allergy rates were a myth or a media beat-up.

But her research has proven otherwise, with her team the first to confirm the rising allergy epidemic in Australia.

About five per cent of Australian children have a food allergy. But Melbourne is a hotspot, with one in 10 babies having a food allergy at 12 months – the highest incidence of food allergy reported in the world.

Food allergy sparks a strong reaction in the community – something Katie’s own condition has allowed her to observe. “It’s very complex and people have very strong views one way or the other. It doesn’t exist, or it does exist, or they’re hyper anxious.

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“My view is that we should empower people to be able to eat what they need to eat, that’s safe for them. That doesn’t matter if it is coeliac disease, an intolerance, or an allergy.”

Katie’s two large cohort studies are behind most of the Institute’s food allergy findings. HealthNuts involves 5300 children, diagnosed with food allergy at age one.

It’s the largest single-centre population based study of

One of the biggest impacts of the research is its influence on Australian and American infant feeding guidelines, which were changed to advise parents that introducing egg earlier in their baby’s diet is not only safe, but may even prevent egg allergy.

‘Dogs and dribble’ relates to findings that exposure to more bacteria in the home – whether from older siblings, a dog or a dummy dropped on the floor and popped back in bub’s mouth – was not necessarily a bad thing for kids’ immune systems. In fact, a few extra germs might even have a protective effect.

Dry skin refers to an eczema gene, found to increase the risk of food allergy, and diet to delaying allergenic solids such as peanut.

Low Vitamin D levels are suspected to play a role too.

Katie is now leading a trial, Vitality, involving 3000 babies, to see whether food allergy can be prevented in the first year of life by supplementing infants with Vitamin D drops.

Allergy rates are lower in northern Australia, where there is more sunlight and therefore less Vitamin D deficiency in kids. Melbourne, with its lower levels of sunlight, is an allergy hotspot.

Unlike North America and Europe, where infants are supplemented with Vitamin D drops and the population consumes dairy products fortified with the vitamin, no such policies exist in Australia.

A more recent finding published this year suggests Asian children may be predisposed to food allergy but environmental factors in Asia are protective.

Children with the highest rates of food allergy across Victoria were found to be those who were Australianborn but whose parents were born in Asia. However children born in Asia who migrated to Australia in the first five years of life were completely protected.

All of these factors form a different piece of the puzzle put together by Katie and her team.

“We really feel like we are on the edge of something because we know food allergy has risen over the past 20 years. So if it’s happened that quickly, then we must be able to stop it,” Katie says. “There’s something we should be able to identify. It’s just so tangible.”

Food Allergies

Professor

Katie Allen & Jenson

S

ally Dunn was grateful for the ambulance depot at the end of her street the day she fed her 11-monthold baby scrambled eggs. Little Jenson Park vomited and broke out in hives. His cry, Sally remembers, sounded hoarse. When he stopped crying and became floppy, Sally made the call.

“I was just standing out the front with him in my arms,” Sally recalls, as she waited for the ambulance she could hear coming.

Jenson started to improve on his own but was treated in hospital where he was diagnosed as anaphylactic.

But exactly what he was allergic to – the egg or the milk – was uncertain.

It turned out Jenson was allergic to both.

Just one month later, at his 12-month immunisations, he joined the HealthNuts study, led by Katie Allen’s team at the Murdoch Childrens.

Jenson’s egg allergy was the most serious. “The first time they did a raw egg challenge with him he suffered an anaphylactic reaction and had to be given adrenalin,” says Sally.

“Whilst that was incredibly scary, it was really good for me to see what he looked like because it was very different to the reaction I saw at home.

It was very fast. It was a cough, then his face swelled. After that my husband and I knew what an anaphylactic reaction looked like, we knew what to do, and we knew that the adrenalin works. That was such a confidence builder.”

Around the time Jenson turned two, he was also testing positive to allergies for tree nuts including cashews and pistachios. While he still has these allergies, the regular testing by the HealthNuts team determined he can now tolerate baked egg.

Being involved with the HealthNuts study allowed Sally, a first-time mum, to better understand what her son was going through and to relax. Now Jenson is older, it’s easier because he can communicate when something hasn’t gone down well.

A recent cashew challenge tasted ‘egg white funny’, while a pomegranate didn’t taste so great either, Sally says.

“I said ‘is it cashew funny or different funny?’ He said ‘different funny. Kind of like, too much sugar funny’,” she laughs.

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ASSOCIATE Professor

Sarath Ranganathan

P

aediatrician Sarath Ranganathan witnesses firsthand the impact a cystic fibrosis diagnosis has on families. “Parents usually have no idea there is anything wrong with their children and often they haven’t heard of cystic fibrosis,” says the researcher. “It has a very strong negative psychological impact on families at the time of diagnosis.”

In Victoria, cystic fibrosis is screened for at birth and can be detected before any symptoms appear. The condition affects about one in 2800 Australian children, with one in 25 people carriers of the disease-causing gene.

The disorder mainly affects the lungs and digestive system, but it also affects a number of other organs.

The malfunctioning gene causes mucus in these organs to become excessively thick. This can lead to bacteria becoming trapped in the lungs, causing frequent infections. Lung failure is the major cause of death for people with cystic fibrosis and in the past they were not expected to survive into adulthood.

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Life expectancy has improved but it’s a difficult and costly disease to manage with daily supplements, physiotherapy and medication to help digestion and breathing. Affected individuals have to avoid being in the same room as others with the condition, because they can pass on specific infections to each other. So it takes a social toll. Depression is about three to four times higher in this group – individuals and caregivers – than the rest of the community.

Sarath’s world-leading research pivots on the window of opportunity afforded by the early diagnosis at birth.

It’s what drew him to Australia and in particular, Victoria, where newborn screening for cystic fibrosis has been in place since 1989.

“In the past we only really reacted to symptoms, but now we are much more proactive and aggressive, even trying to introduce treatments before symptoms present like coughing, shortness of breath and poor appetite,” he adds.

As a PhD student in London, Sarath investigated a novel technique to test babies’ lung function. The test mimicked the classic lung function test, spirometry, used in adults and older children. The research showed lung function abnormalities, an early indicator of lung problems especially in children with cystic fibrosis, could happen earlier than previously thought.

Sarath’s team established the world’s first study to introduce a treatment – using a drug called azithromycin which is used in older children – to prevent lung scarring occurring in babies.

At that time newborn screening for cystic fibrosis wasn’t offered in the UK. “What we wanted to do was extend the work into babies who were diagnosed really young so we could test them as early as possible before they developed respiratory symptoms,” he explains.

Sarath relocated to Melbourne in 2004 to continue his research at the Murdoch Childrens. He juggles fatherhood – he has three children aged 15, 12 and nine – with a busy research and paediatric career, including his role as director of a clinical department.

He’s a polished professional, but the challenges facing some of his patients are still keenly felt.

“When you’ve got your own kids and you see someone your own children’s age in front of you, going through some difficult times, it’s always more poignant,” he says.

Sarath’s research at the Institute has shown that lung abnormalities, including lung scarring, could be present in the first few months of life after infections and inflammation associated with cystic fibrosis. These lesions can make individuals more susceptible to further infection and cause a decline in lung function, which can ultimately lead to death due to respiratory failure.

In the past, drugs for cystic fibrosis treated the symptoms of the disease but new medications are emerging that promise to be game-changers. These ‘disease modifiers’ target and correct the genetic defect of cystic fibrosis.

The drugs, which could significantly improve the quality of life for people with the condition, are usually only prescribed to children aged six and over.

“The idea of our research is that the lung disease associated with cystic fibrosis starts really early. To prevent it, you’ve got to start these sorts of treatments much earlier, as soon as diagnosis really,” says Sarath.

“What we are really hoping to do is to introduce these disease modifying treatments to babies. So we’ll be studying those in the near future, using the same sorts of trial designs, to try and prevent the lung scarring before it has a chance to develop or become serious.”

Sarath – who develops close ties with patients he sees from birth until 18 – says some have gone on to become elite athletes. One former patient is now a professional jockey. Even the Wallabies have a player, Nathan Charles, with the condition – the only athlete in the world playing a contact sport with the disease.

“These people are an inspiration to others with cystic fibrosis and to lesser mortals like myself!” he says.

Cystic Fibrosis

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Professor

Nigel Curtis

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Infectious Diseases

Nigel Curtis always imagined himself working as a doctor in Africa or Asia. The infectious diseases expert worked for short periods in the Solomon Islands, Gambia, Zimbabwe and South Africa early in his career to try the dream on for size.

But he realised that path wasn’t going to have the impact he wanted.

“The way to reduce child mortality is to make better vaccines, diagnostic tools and treatments that affect lots of people,” says Nigel. “And we can best do that on a large scale by using the resources we have in wealthy countries.”

The British-born paediatrician landed permanently in Australia in 1998 with his wife, their three-year-old daughter and a six-week-old son after an intrepid journey from the UK, via a Fellowship in Canada.

He set up the infectious diseases unit at RCH, a department he continues to lead while also juggling projects investigating better diagnostic tests and preventative measures for tuberculosis.

His research into tuberculosis – a disease that kills half a million children worldwide every year despite the availability of a vaccine (called BCG) – unexpectedly led to a new study asking an intriguing question: is it possible the vaccine invented for tuberculosis could prevent infections and also allergies in Australian children?

His question led to the establishment of MISBAIR, the Melbourne Infant Study: BCG for Allergy and Infection Reduction. It involves more than 1400 babies, with half of those to be given the tuberculosis BCG vaccine.

The babies will be followed for five years to determine whether the vaccine reduces infections in general as well as food allergy, eczema and asthma. Meanwhile, further research will investigate how BCG boosts the immune system, because that is, surprisingly, what it does.

Studies have shown babies given the vaccine have half the mortality rate of infants who don’t get it. “What it seems to do is protect against the infections – like sepsis and pneumonia – that normally kill babies in countries with high infant mortality,” says Nigel.

“This vaccine is made from bacteria that turns out to be very good at providing a kick-start to the developing immune system very early in life.”

The immune system is also important for allergy, Nigel explains. If it is not busy fighting infection it can turn on itself. Several small studies suggest the vaccine might prevent allergy in babies so the Institute decided to test this on a large scale and launched MISBAIR. The BCG vaccine has been around since 1921 and is given shortly after birth in most countries, except in places where the disease has almost been eradicated like Australia, New Zealand, North America and some western European nations.

The vaccine is imperfect as it does not always prevent the disease. Tuberculosis is also particularly difficult to diagnose in children and is becoming increasingly resistant to drugs.

Nigel recently treated a patient with a strain of tuberculosis resistant to multiple drugs – eight or nine different antibiotics were tried. The child’s treatment will take two years and costs tens of thousands of dollars. A country like Australia can afford it, but the same situation in a third world country would be a death sentence.

Treating children on the wards with incredibly rare and unusual infections seems worlds away from his research sometimes, says the father-of-three children, now aged 20, 17 and 15. Occasionally, it does hit close to home.

“I remember a patient who died of meningococcal disease who was born the same month as my daughter.

That hit me really hard. It’s times like these that really puts things into perspective.”

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Wirginia Maixner

W

irginia Maixner is renowned for her lead role in the epic surgery to separate conjoined twins Krishna and Trishna in 2009. Most of her daily operations however, are on childhood epilepsy patients.

The neurosurgeon and her research colleagues Marc Seal and Joseph Yang are changing the lives of hundreds of children with severe epilepsy via brain surgery with the aid of newly-developed sophisticated imaging technology.

Diffusion MRI measures the movement of water in the brain to map white matter tracts. These tracts are the communication highways linking brain regions.

Surgeons want to avoid damaging these during delicate operations to preserve language, memory, speech and other functions. Diffusion MRI tractography has been used in adult brain surgery but it has now been adapted for use in children by Joseph as part of his recently completed PhD. Wirginia says it enables surgeons to meticulously plan operations with greater accuracy than previously possible. It has allowed lesions to be removed from children’s brains that otherwise would have been too risky to touch.

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“It’s like trying to navigate from A to B without a map,” Wirginia says. “When you’ve got a map, telling you all the turns, it makes surgery much simpler.

You’ve got much more confidence.”

Neuroimaging

About 100 children from Australia, New Zealand and Asia have now been operated on at RCH in the past three years with the assistance of the technology.

“For us, it’s not just about whether you can measure tracts, it’s the children’s health. It’s the notion that a child is in a family,” says Marc.

In adults, when surgeons are faced with the same scenario, patients are operated on awake so they can talk and move their limbs to indicate function.

Joseph’s research will investigate the brain changes that take place by using MRI scans during the surgery itself.

But it would be impossible for a child to be awake during such a confronting procedure. This technology gives surgeons a crucial road map to the brain so the surgery is safer, more effective and has as little impact on the child as possible.

Wirginia recalls a 10-year-old patient who had a tumour in the centre of her language cortex. It was initially thought she could not be operated on until adulthood because the surgery would have destroyed her ability to communicate. But using tractography took away the ‘Oh my God’ factor and turned it into a very clear surgical pathway that preserved her crucial white matter tracts devoted to language.

“Incredibly, the brain actually undergoes dynamic and sizeable movements at key points during surgery, such as when the position of the head is moved, to the skull being opened, opening the brain covering and excising the lesion that needs to be removed,” Joseph says.

“The whole point of this research is so that we can improve the accuracy of surgery, by predicting what happens to the brain during the operation.”

While the tractography has given neurosurgeons a clearer picture, these images can also help parents understand their child’s complex operation.

Wirginia has clearly enjoyed working quietly away on this ground-breaking area of neurosurgery.

“So then you can take it out, she can wake up and she can still talk and she can understand. And you sit there and go, wow, that’s pretty cool,” says Wirginia.

“I’m not somebody who particularly likes being in the spotlight. I like getting on and doing the things I like doing,” she says.

The prospect of such an intricate surgical procedure on the body’s most crucial organ can seem incomprehensible to the lay person, but it is a challenge Wirginia relishes. Her steely determination is obvious from her training as a neurosurgeon, when she persevered through her studies after having her daughter. She was the first person granted maternity leave by the Royal Australasian College of Surgeons and underwent her final exams with a two-year-old, often studying until 2am.

“Neurosurgery is fun,” she adds. “It’s the children.

They’re the fun part of it. Watching a sick kid get better and knowing if you stop someone from having seizures, you’ve changed their life for the better.”

doctor

Joseph Yang

And although she wasn’t aware of it until she picked up an inflight magazine, she comes from a long line of trailblazing women in the medical field – her aunt was Australia’s first female flying doctor.

When she began studying neurosurgery it was, and still is to a certain degree, a male-dominated field.

She believes her legacy, as the first female in Australia to have a child while training, has highlighted the importance of family in working life – to both male and female colleagues.

The notion of family weighs heavily on the mind of Marc Seal, who leads the Institute’s Developmental Imaging group. As the neuroimager and also researcher, he’s interested not only in ensuring surgery goes successfully, but that children will be able to finish school, develop relationships and go on to have families of their own. For this reason, his group felt a huge responsibility.

doctor

Marc Seal

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Professor

Kerr Graham

N

othing warms Kerr Graham’s heart more than a “Where are they now?” story from a former patient.

The researcher and orthopaedic surgeon, who pioneered the use of botulinum toxin A – Botox – to treat children with cerebral palsy, forms close bonds with the children he sees from birth until age 18.

He’s often contacted by former patients charting their stories of trekking through Cambodia, excelling at disabled sports or being promoted to a cabinet minister’s office in Canberra. One childhood patient he treated has returned to the lab as a university student researcher.

“We do forge very strong links and we do get some very heart-warming stories,” says Kerr, who established the world-leading Hugh Williamson Gait Laboratory at RCH to treat cerebral palsy patients. “It’s what gets you up in the morning and helps you keep going; it’s very rewarding.”

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Cerebral palsy is a life-long physical disability that affects movement and posture, caused by damage to the developing brain either during pregnancy or shortly after birth.

Over the past 20 years, the combination of Botox, surgical treatment and the clinical and research work of gait laboratories – there are labs now in almost every Australian capital city – has dramatically improved the lives of children with cerebral palsy, which affects an estimated 17 million people worldwide including 120 newborns in Victoria every year.

“Children leaving the program in 2016 generally have a much higher level of physical functioning, confidence and mobility than those we were typically seeing in the early ‘90s,” Kerr says.

Originally from Belfast in Northern Ireland, Kerr trained in gait analysis – evaluating the effect of orthopaedics treatment on walking disabilities – at The Hospital for Sick Children in Toronto in 1988. Serendipitously, elsewhere in the hospital the first tests were underway on a new drug, botulinum toxin A. This was well before Botox became a popular cosmetic surgery enhancement.

Kerr was the first to think there might be a role for Botox to manage the spasticity associated with cerebral palsy in children. But he would need to measure its effects.

He returned to Northern Ireland and carried out research that showed botulinum toxin did indeed improve the growth of muscles in an animal model of the disease. With the help of the company who patented Botox, he established his first gait laboratory.

“It was visionary that they would fund a completely new technology when I was a pretty young researcher with a limited track record,” Kerr recalls.

“By 1994, I decided that gait analysis was fundamental technology and I’d never work anywhere where I didn’t have access to it, because it’s the key that unlocks all the secrets. I couldn’t do my Botox research without it.

I couldn’t do my surgical research without it.”

The purpose-built gait laboratory employs a unique mix of engineers, physiotherapists and doctors.

A combination of cameras, infra-red technology and high-tech equipment measure patients’ walking.

The lab has allowed Kerr and his team to run long-term clinical trials and translate research findings quickly into better treatments for patients.

“This laboratory is the best-known clinical laboratory in the world and has produced the leading research on treating children with cerebral palsy,” says Kerr.

The addition of Botox to Australia’s Pharmaceutical Benefits Scheme in 2000 was a significant moment for Kerr. It then became more widely available to children with cerebral palsy, whereas previously it was restricted to children in research studies.

In January 2016, the journal Nature published a special edition, commissioning Kerr Graham and his team as lead authors, dedicated to cerebral palsy. It was a milestone event signalling to the international research world that the team had ‘arrived’ as global leaders.

He adds, jokingly, he can now hang up his boots.

“That’s probably it for me,” he smiles. But you get the feeling he is content.

He was drawn to Australia in 1994 to start the nation’s first hospital-based gait laboratory at RCH.

Cerebral Palsy

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It

was meant to be a routine boat trip to a remote Fijian island. But two hours in, the engine cut out and stubbornly refused to restart. The radio, of course, didn’t work. The wind whipped up the waves, rocking the stranded vessel. A member of Andrew Steer’s research team heaved over the side of the boat while one person with the tiniest amount of phone reception called for help.

Luckily for this professor, the story didn’t turn out like Gilligan’s Island and the group was rescued by another boat.

It was just one of many unusual occurrences Andrew has encountered while working in the Pacific region on a range of neglected common tropical diseases, including scabies, rheumatic heart disease and rheumatic fever.

In this case, he was running a scabies treatment program comparing three different treatments in three remote Fijian island communities.

Scabies research “is not particularly sexy,” Andrew admits, “but it’s really important.”

It’s also an insidious disease which torments those it infects in developing countries – something Andrew knows all too well.

“Scabies causes great misery,” he says. “I’ve had it. It’s horrible. You scratch, you can’t sleep, you can’t think.”

The disease is caused by a microscopic mite that burrows into the skin, sparking extreme itchiness affecting sleep, work and study. The skin can become infected with the Streptococcus A bacteria which can be fatal if it enters the blood stream but also causes potentially deadly diseases including rheumatic fever, rheumatic heart disease and kidney problems.

About half a million people every year die prematurely from these diseases in developing countries worldwide, including those in Australia’s indigenous community.

Andrew believes conditions like scabies can be eradicated. And his research in the Fijian islands has shown it is possible.

Scabies was virtually eliminated when an entire community in the 2015 trial was given an oral drug called ivermectin. One year after the mass administration, the prevalence of scabies declined by 94 per cent.

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A standard cream treatment and mass administration of the same cream, permethrin, was tested in the other two remote island communities. Scabies declined by

64 per cent in the mass cream group and 49 per cent in the standard-care group, showing that ivermectin was really the way to go to eradicate scabies completely.

“The problem with the cream is that you treat individuals who go home to their families and friends who have all got it and they just get it back again,” Andrew says. “That’s the idea behind ivermectin – you treat everyone at the one time and you just knock it out. And it works.”

The potential to rid communities of infectious diseases – illnesses he first observed as a medical student – is an exciting culmination of his dedication and hard work. An uncertainty about practising adult medicine prompted him to take a year off medical school and work in Samoa, where he developed a love of paediatrics.

It was here he observed the prevalence of rheumatic heart disease and helped diagnose it in children. He fondly remembers being welcomed into schools where a lavish lunch would be laid on, attended by the whole community. Visiting guests would be sent home with a pig.

Andrew later spent three years living in Fiji, moving there when his firstborn was just six months old, to complete his doctorate on Group A Strep infections.

This involved screening children for rheumatic heart disease using echocardiograms. In Fiji, this disease is the second most common cause of death in people aged five to 29. More than 10,000 Fijian children have now been screened and the New Zealand government has devoted $3 million towards continuing the program.

While Andrew spends a great deal of time in the Pacific islands, the father-of-two continues to see patients in Melbourne where he practices as a paediatrician specialising in infectious diseases.

Here, he sees rheumatic heart disease in patients with Pacific Islander and Aboriginal backgrounds.

To understand why these groups are contracting the disease, he co-leads the world’s largest international study investigating genetic susceptibility to the disease.

There is now a groundswell of interest globally in the mass administration of drugs to beat widespread tropical diseases. While much of Andrew’s work on these diseases has been beyond the nation’s borders, the results will reverberate in Australia – with our own indigenous communities likely to benefit.

Tropical Infectious Diseases

ASSOCIATE Professor

Andrew Steer & Julius

J

ulius Ibrahim was a happy, healthy boy who loved his sport, especially football. But about two years ago, his mother Selena noticed how lethargic he was after a game. After Julius had fallen, exhausted, into bed, one of his five siblings worriedly told his mother that Julius was burning up. With his temperature pushing 41C, Selena rushed him to RCH. By this time, his feet were so swollen he would scream in pain if he put any pressure on them. He was literally carried into emergency.

A range of tests were inconclusive and Julius was sent home, only to return several days later because Selena was convinced something was very wrong with her son, who by this stage wasn’t eating or drinking.

More than a week later, Andrew Steer walked into the room and immediately identified the problem.

Andrew, who spent a year in Samoa while he was a medical student, was able to address Julius and Selena in their native Samoan language. Overnight, he diagnosed Julius with rheumatic fever. But a few days later, the diagnosis had become more serious. Julius had rheumatic heart disease (RHD), which is damage to one or more heart valves due to inflammation after acute rheumatic fever. If left untreated, it can cause heart failure.

The conditions are both related to infection with the Group A Streptococcus bacteria. Andrew was particularly familiar with the diseases, which he first observed in Samoa.

But 10-year-old Julius contracted the disease in Melbourne. The bacteria entered his system through an open wound from a scratched mosquito bite three weeks earlier.

The normal treatment involves regular penicillin injections, but Julius suffered an allergic reaction to the antibiotic and now takes an alternative antibiotic treatment daily to control the disease.

Julius visits the Strep A expert on such a regular basis, he now calls him Uncle Andrew. His four-year-old sister, who has accompanied Julius and Selena to every visit, cheerfully waves goodbye to “Uncle Andrew”, too.

Andrew, Selena says, was a godsend.

The relief she felt when Andrew walked into her son’s hospital room and greeted her in their native language laid the foundations for a strong bond between the paediatrician and Selena’s family.

Andrew organised for Julius and Selena to attend a weekend away organised by a charity, where Julius opened up for the first time since his diagnosis and formed new friendships.

“Without Andrew, I don’t know where we’d be,” Selena says. “I don’t think I would have my son.”

“I say to a lot of people, if there was something I could do for that man, I would do it in a heartbeat.”

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39

DOctor

Mark Mackay

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Childhood stroke

T

ime is of the essence when it comes to treating stroke patients. Up to half of adult stroke patients get to hospital within the four-and-a-half hour timeframe required to administer some clot-busting treatments. But what happens when newborns or babies have a stroke?

Mark Mackay, who is establishing studies to measure the true incidence of childhood stroke, says on average it takes 24 hours for stroke to be diagnosed in children and most of the delays occur after they arrive at hospital. By that time, the window for early intervention to prevent lifelong disability from brain injury is firmly closed.

“Children will never benefit from those treatments unless we develop strategies to improve recognition of stroke symptoms in the community, and recognition of stroke by emergency doctors who are seeing these children when they come into hospital,” says Mark.

“The catch cry is ‘time is brain’,” he continues. “Once the symptoms start the clock is ticking.”

“The sooner you can get that patient diagnosed, the sooner you can give the treatment, the better the outcome.”

He embarked on research in Australia, interviewing parents, emergency call takers and paramedics, to investigate the delays in getting these children to hospital.

When the study featured at an American Heart Association conference, it notched up 4.6 million hits on the association’s website. It was only a small Australian cohort – 34 parents of 28 childhood stroke patients were interviewed. “Obviously, because nobody had done that research before, it was seen to be very important,” he says.

His study revealed less than half the parents recognised the symptoms of stroke and called an ambulance.

“They knew something was seriously wrong with their child. But they didn’t think it was a stroke,” Mark says.

Stroke symptoms in children are the same as adults and include face and arm weakness, and speech interruption. However, babies aged one month and under present with seizures. Two registries are therefore being established, led by the Institute, to look at these different age groups.

Mark is now leading studies to develop information for groups including triage nurses and paediatricians to better recognise symptoms of stroke in children and to diagnose these children using MRI scans, so treatment can be given quickly.

About three to 10 children per 100,000 will suffer a stroke, with half of these affected before age five. It’s more common in newborns – those figures are one in 2500. Stroke is the most common cause of cerebral palsy in children born full-term.

His team is also participating in a US-led international study investigating the causes of stroke in pregnancy and newborns. The medical records of babies who have suffered a stroke will be analysed, along with DNA samples, to explore what led to the stroke and identify any genetic causes.

Mark started working as a paediatric neurologist, specialising in epilepsy, more than a decade ago.

Within several years, he and his colleagues had recognised the need to develop a dedicated childhood stroke service and a research program in parallel.

Mothers will also participate in a questionnaire about their pregnancy and labour. It is hoped the information collected will be used to develop methods to screen women and unborn babies for stroke risk in future.

“A decade later, we are the second biggest contributor globally to collaborative international research into causes and outcomes from paediatric stroke,” he says.

His doctorate, focusing on developing strategies to increase awareness of stroke and improve the accuracy and timeliness of diagnosis in children, garnered huge international interest. It came after a US-based study to test the safety and effectiveness of clot-busting drug TPA in children was abandoned after 18 months because no children could be recruited to the trial. This was unsurprising to Mark – the children simply weren’t getting to hospital in the required timeframe to be eligible for treatment.

“The cause of stroke in pregnant women and babies is unknown. This research hopes to understand how often and why these strokes occur.”

Working with childhood stroke patients has its challenges but Mark is satisfied when he can give families relevant information so they have a better understanding as to why their baby had a stroke.

“That’s why I enjoy working here so much,” he says.

“You’ve got a world-class research institute combined with a world-class children’s hospital so you can provide the best care to families.”

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A Professor

Andrew Davidson

ndrew Davidson is a fourth generation alumni of the Murdoch Childrens and RCH. His mother, a microbiologist, worked with rotavirus founder Professor Ruth Bishop. His grandmother was a nurse at the hospital and his great uncle a doctor, who at the turn of the century moved interstate to become the first paediatrician in Queensland.

Andrew leads the Melbourne Children’s Trials Centre (MCTC) and anaesthesia research at the Institute.

The different roles keep him so busy that his clinical work, as a paediatric anaesthetist alongside brain surgeon Wirginia Maixner, fits into one day a week.

It’s a day he relishes.

During surgery there’s no phone or internet access. He can just switch off and do his job. “People think it’s quite strange I can do neuro-anaesthesia for relaxation,” he says. “Some people have a hobby where they go home and build a table or something like that.

“Anaesthesia is my therapy.”

During his decade at the Institute, Andrew has become renowned internationally for his research into the intriguing realm of childhood anaesthesia. He investigated theories that children were experiencing awareness and therefore may have been awake for periods during anaesthesia. He also led studies around children’s experience of delirium upon waking from anaesthesia.

The father-of-two girls, aged five and nine, also leads two multinational trials exploring the effects of anaesthesia on babies’ brains.

Preliminary results showed no adverse effects on the brains of infants following hour-long surgery, when the children were followed up at age two. However, these children are being assessed again when they are five to be sure there are no adverse impacts. Another new trial will investigate the outcome after a longer period of anaesthesia.

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Andrew hopes the research will ultimately end fears that anaesthesia harms the developing infant brain.

“We call it the T-Rex project because we want it to be the one that kills the whole issue. And the project is huge,” he adds.

As Medical Director of the MCTC, established to be a leading centre for paediatric trials worldwide, he facilitates research with a focus on innovation.

“We want to be ahead of the pack when it comes to paediatric trials. We don’t want to just catch up,” he says.

Anaesthesia

F

amily violence is a challenging issue but Stephanie Brown believes the time has come to talk openly about it.

The Victorian Royal Commission into Family Violence has recommended sweeping changes to the way that family violence is dealt with in our community – Stephanie was called as an expert witness to the commission’s hearings to discuss research she led at the Institute.

More than 10 years ago, Stephanie established a longitudinal study of more than 1500 mothers and their first-born children to investigate women’s health at the time they had their first child. The study found that one in five women experience emotional or physical abuse – or both – in the first year after having a baby.

“It’s the first study of mothers and children that has included a rigorous measure of family violence and followed the trajectories of those in families where intimate partner abuse was present,” says Stephanie, who joined the Institute in 2007.

By the time the children in the study turned four years of age, more than one in four families had been affected by family violence.

Maternal health

It has provided a snapshot of Aboriginal women’s experiences during pregnancy, including family and housing problems affecting women’s social and emotional wellbeing.

Women and children in this study will be followed up when the children turn five or six.

Stephanie’s group focuses on the strong links between maternal and child health – something that Stephanie, as a mother and grandmother, feels passionately about.

“When you are pregnant with your first child, everyone is very interested in how you and your baby are,” she says.

“Once the baby is born, everybody’s focus goes straight to the baby. I even find myself doing it, because babies are very captivating.

It’s actually really important for babies’ survival that they captivate us, because they are a lot of work and need all our attention.”

Professor

Stephanie Brown

“But as a researcher, I could see there was a gap in what we were doing to understand the impact of pregnancy, childbirth and bringing up children on mothers’ health and wellbeing.

That’s why we are also focusing on the health of the mother.”

“That really puts into perspective what a significant problem this is for our community,” says Stephanie. “We are only just beginning to understand the implications for women’s and children’s health.”

The study found that two out of every five mothers who were depressed in the first year after having a baby were experiencing family violence. Children whose mothers experienced family violence were twice as likely to have emotional and behavioural difficulties.

Stephanie is also passionate about her group’s research with Aboriginal women and children. She is working with organisations and communities in South Australia to conduct the Aboriginal Families Study.

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doctor

Hannah Woolhouse

H

annah Woolhouse remembers the turning point after the birth of her now six-year-old daughter, when she realised she was not coping.

“One day I went to put something in the kitchen bin and it was full, and I just wept,” she says.

“I just could not find the energy to take that rubbish bag to the outside bin. I was like, that’s not okay. It was a little thing that I couldn’t cope with, emptying the rubbish bin.”

Hannah is not accustomed to sharing her experience of depression. It’s not something she has talked publicly about before. While having depression after the birth of her daughter was a very painful experience, Hannah admits it has been valuable to her work.

She understands what other women with postnatal depression are going through.

“Having a baby myself made me realise what an upheaval it is,” she says.

Her experience as a first-time mum cemented her interest in a research career as she felt passionately about supporting other mothers through this challenging time.

Several papers she authored as part of a major study of first time mothers, led by Professor Stephanie Brown, have had a significant impact.

One key finding was that depression was more common in mothers in the second six months than during pregnancy or the first few months after the birth.

Depression was also more common four years after the birth of a woman’s first child than at any stage in the first year after the birth.

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An additional finding to garner national and international interest was about the importance of new mothers having time for themselves. Hannah found women with a six-month-old baby who had time for themselves once a week were less likely to experience depressive symptoms than those who had less time for themselves.

A greater cultural shift may need to take place to ensure the demands of raising children are shared more between new mothers, their partners and support networks, says Hannah. This is particularly relevant in Western society, where there are strong messages for women to immerse themselves completely in motherhood.

“The more we can share the demands of looking after a new baby, the healthier new mums will be.”

Maternal mental health

Refugee Health E

lisha Riggs is constantly reminded of the immense burden carried by the refugee and migrant communities she works with. The trauma they have endured, the violence they fled, are vivid experiences still being endured while these people adjust to life in a different country.

The public health researcher is awestruck by the capacity of people to keep going in the face of such adversity.

“Refugees have survived unimaginable things,” she says. “They have had to make tough decisions to flee their homes and start a new life elsewhere to keep themselves and their families safe.

They are so resilient.”

She has also co-authored a study about the experience of Afghan families having a baby in Australia. This research led to a new statewide program, Bridging the Gap, which aims to improve refugee maternal and child health.

This has led to a pilot program in Melbourne’s west with the Karen community – an ethnic minority from Burma – trialling a new way of delivering antenatal care in a group setting. The program has captured the attention of other hospitals and maternal child health services in Victoria keen to introduce it with their own refugee communities.

“I think most people really do care and want to do the best they can for refugees,” says Elisha. “But we don’t have all the answers, which is why we have to try new ways of working.”

Her admiration for this resilience drives Elisha to improve the health of refugees and migrants. Already, she has made her mark – the young researcher was awarded a 2015 Tall Poppy Award for up-and-coming scientists.

Her 2011 doctorate on oral health inequalities in refugee and migrant communities was one of the catalysts for the Victorian government to offer free, priority dental care for refugees and asylum seekers.

With a new wave of refugees continuing to arrive in Australia from the Iraqi and Syrian conflicts, Elisha says it’s important health services can respond to the changing needs of a new community.

Elisha joined the Institute in 2012, after taking a few months off to travel across Africa where she volunteered in a tiny Kenyan village, Lieta, supporting the training of local community health workers.

Since joining the Institute, she has continued to pursue research in refugee and migrant children’s oral health – an interest of hers that developed around a decade ago after discovering it was common for some Muslim communities to use a therapeutic tree twig – called Miswak – to clean their teeth.

doctor

Elisha Riggs

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D

avid Thorburn’s love of science flows through his family. His wife is a scientist and their two children have followed their parents into the medical field.

“I fear we have science clones,” he says. He sheepishly admits his inner nerd extends to a love of the Star Wars films. He has been known to wisely quote Yoda.

A 25-year veteran of the Institute, David researches some of the world’s rarest diseases. When it comes to mitochondrial disorders – his area of expertise – these can be “ultra-rare”.

“We can document that at least one in 5000 births will give rise to a child with mitochondrial disease,” says David of his team’s research. “That’s about 60 kids in Australia each year.

“Rare diseases affect one in 2000 or fewer. So collectively mitochondrial disorders are rare diseases and individually a lot of them are ultra-rare.”

David’s career, he says, has been a series of “fortunate events”. Changes in mitochondrial DNA had just been discovered when David joined the Institute in 1990. With the support of founding director David Danks, who thought the area “ripe for study and to make a difference”, David became a “self-taught mitochondriac” and began investigating ways to improve the diagnosis of these mystifying diseases.

Mitochondria are the cells’ power plants, breaking down molecules from sugars, fats and proteins we consume to generate energy, like burning coal to produce electricity. This process produces a molecule called ATP to fuel the body.

Amazingly, each day we turn over about 65 kilograms of ATP. “There’s enormous demand for energy so if you have a problem converting those fuels into energy, it can affect any or all of the body’s systems,” David says.

There are more than 250 known genes in both nuclear and mitochondrial DNA in which changes can cause mitochondrial diseases. These disorders can cause almost any symptom, at any age, which is why the conditions have traditionally been incredibly difficult to diagnose.

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The most common mitochondrial disease in children is Leigh Syndrome. Children appear healthy when born but can go downhill from about six months of age, often after a viral illness when they experience an episode such as a seizure or loss of consciousness which may cause death. If the child recovers, however, they usually deteriorate again further down the track and typically, they die by age three.

At the more severe end of mitochondrial disease, babies die within days of birth.

During his time at the Institute, David’s group has focused on improving the diagnosis and prevention of mitochondrial diseases.

Preventing the conditions is complicated. It involves, where appropriate, helping families to conceive a healthy child in subsequent pregnancies. David’s group is internationally recognised for defining when approaches like prenatal diagnosis or pre-implantation genetic diagnosis can be suitable for a specific couple.

Initially, it was pretty tough work identifying genes in families but the whole area has been transformed by new technologies that can sequence all our genes.

In collaboration with researchers at the Broad Institute of Harvard, David’s group was one of the first in the world to apply these technologies to large numbers of patients with complicated genetic disorders and to discover novel disease genes - his team has now discovered more than 20.

Mitochondrial dysfunction also plays a key role in common conditions like diabetes and Parkinson’s disease, says David. His group is now collaborating with the Institute’s Stem Cell Research groups to understand the mechanisms of disease in heart and brain cells to develop better treatments. These new therapies will likely benefit many of these other conditions, says David.

Meanwhile, diagnosis of mitochondrial diseases continues to improve. The Australian Genomic Health Alliances, led by the Institute, is starting to move genomic technologies into wider medical practice here.

“That’s been enormous fun over the past few years, because now it looks like we can get these diagnoses in at least two-thirds of families,” says David, adding that as recently as a few years ago you’d be lucky to get a genetic diagnosis in a quarter.

“There is still work to do.

But we can get an answer for most of these patients.

It’s transformative.”

Professor

David Thorburn

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Mitochondrial disease

T

he night Zac Sherlock’s parents were told their son had leukaemia was the night the family’s world fell apart.

“When my husband and I were given the diagnosis, I felt like running out and punching a wall,” Lynda Sherlock says.

“You think, what have I done? What have we done?

How did he get this, and why?”

Less than a week earlier, Lynda Sherlock took eightyear-old Zac to the GP with virus-like symptoms including a runny nose and fever. He hadn’t been eating much. They were told it was likely a virus but to return if the fever didn’t subside.

Days later, they were back in the doctor’s office and given antibiotics to kill off whatever was causing the persistent fever. But Zac couldn’t keep the antibiotics or any painkillers down and he had developed a rash.

He was admitted to hospital and diagnosed with Acute Myeloid Leukaemia (AML), a form of leukaemia more common in adults. Only about 50 children are diagnosed in Australia each year.

He had also developed pneumonia as his immune system started to collapse. Within five days of the first GP visit, he was transferred to RCH and hooked up to chemotherapy.

It was the start of a rollercoaster seven-month journey in the hospital’s cancer ward. The chemotherapy hit Zac hard. The main side effect was a brutal abscess he developed on his bottom, which took a long time for specialists to understand how to treat and to control the chronic pain he experienced.

It also took a toll on the family’s life. Lynda and her husband have three other children, including Zac’s twin sister, who all witnessed their sibling’s pain. Lynda was

by Zac’s side the whole time and would only see her other children about once a week. Her husband visited as often as he could.

Despite the toxicity of the treatment, Zac is now in remission. But the chemotherapy damaged Zac’s heart.

The nine-year-old is now part of a study led by Dr David Elliott into cardiotoxicity in childhood cancer patients.

The study aims to determine which patients are more susceptible to heart damage caused by chemotherapy.

The hope is that patients in future will be tested for susceptibility to cardiotoxicity and their cancer treatment tailored to avoid heart damage.

Lynda says the family are happy for Zac to be a part of research that will help others like him avoid cardiac issues.

Zac, she says, is now back to being ‘normal Zac’. He remembers everything that happened to him in 2014, but chooses not to think about it.

“That’s in the past now,” says Lynda. “We are on the other side of it and we are the luckiest people in the world, we believe, very lucky.”

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doctor

David Elliot & Zac

Cardiac Stem Cells T

here’s a sad fact about survivors of childhood cancer that doesn’t sit well with stem cell researcher David Elliott.

While survival rates for children with cancer following treatment are now almost 90 per cent, drug regimes like chemotherapy can be toxic to the body’s organs.

Chemotherapy patients are nine times more likely than the general population to die of heart failure.

It’s a frightening statistic for someone of any age. But for a child, it’s inconceivable.

“It’s not okay if you are five,” says David, himself a father of three young children.

“There’s a lot of life to go.”

This can come as a shocking revelation to parents after the family has endured a painful journey to rid their child of cancer.

“It’s another stress on the family,” says David. “We’ve been able to treat the cancer, but they’ve still got this ongoing issue.”

Damage to the heart from chemotherapy is known as cardiotoxicity and it’s an unwelcome hurdle after recovery from cancer. This is why chemotherapy patients need to get their heart checked annually after treatment stops.

About 30 per cent of people who undergo chemotherapy are at risk of cardiotoxicity. The problem is there is no way of predicting who is susceptible, or who may be resistant.

That’s where David Elliott and his team come in.

David and his colleagues, Professor Andrew Elefanty and Professor Ed Stanley moved their lab from Monash University to Murdoch Childrens in 2012 to continue their stem cell research alongside clinical patients and medical practitioners.

In one particular study led by David and clinician scientist, Dr Rachel Conyers, the records of 400 children who have undergone chemotherapy in the past five years are being analysed. Of those, 17 developed severe cardiac problems in the first year after the treatment. Another 64 experienced some degree of compromised function while the rest were unaffected.

In 2016, as part of the study, patients will undergo genetic screening. Stem cells from the 17 most severely affected children will be compared to stem cells of unaffected patients, to understand what it is genetically that makes patients either resistant or susceptible to heart problems after chemotherapy.

“We hope to identify some genetic changes that we can quickly screen for before people start chemotherapy,” David says.

It’s a sign of the rapid pace at which stem cell research is moving, in the direction of personalised medicine.

David and his team are also undertaking broader research to understand heart development and heart disease, to underpin the cardiotoxicity study.

“We’ve got to understand what it takes to make a heart that sits comfortably in your chest and beats two to three billion times in your life. How do you make that robust sort of beast? And the other thing is, what happens when something goes wrong?” says David.

In the lab, where pop music provides a cheerful soundtrack for scientists peering down microscopes, stem cells derived from samples of blood or skin are the starting point.

The induced pluripotent stem cells can be used to make any cell in the body. In this lab, they are turned into cardiomyocytes – a heart muscle cell that generates the cardiac force to make the organ pump blood around the body. Amazingly, under the microscope, these cardiomyocytes visibly pulsate.

While the cardiotoxicity research is among the most important of David’s career, he is lesser known for a more obscure finding – that hearts evolved only once from a common ancestor six hundred million years ago – in a study examining the heart development genes in gastropods including octopus, squids and cuttlefish.

The finding made the cover of the prestigious scientific journal, Development.

Joining the Murdoch Childrens is a recent career turning point. “We touch wood every day. We love it,” says David. “This is a brilliant place, absolutely brilliant.

“There is a lot of enthusiasm and a lot of support here. You can go and talk to the oncologist or the cardiologist so you get a feeling for their patient load and the problems they want addressed. It makes it much more rewarding to work in this setting.”

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Ed

Stanley and Andrew Elefanty are not just colleagues. After working together for more than 15 years, the stem cell researchers share a friendship and a long-term collaboration that undoubtedly benefits the burgeoning area of stem cell research worldwide.

The professors initially worked together studying stem cells in mouse models at Melbourne’s Walter and Eliza Hall Institute before establishing a laboratory at Monash University in 2002 to advance work on human embryonic stem cells.

Professor

Ed Stanley

They were later joined by Dr David Elliott. When all three joined the Murdoch Childrens in 2012, a jovial colleague dubbed them the Three Amigos. An image of the sombrero-wearing trio, with the scientists’ faces photoshopped in place of the originals, is tacked to the office whiteboard.

This camaraderie makes their particular way of working that little bit more special, Andrew says.

“That stability has been very important to progress our research,” he says. “It’s much more gratifying to do that with colleagues you share a lot of experience and a lot of values with. It makes for a very interesting and stimulating work environment.”

The move to the Institute has allowed the stem cell experts to accelerate their research and apply it to human diseases, particularly those affecting children.

The two professors are world-renowned for a particular technological innovation involving the genetic modification of human stem cells to generate ‘reporter cell’ lines. These contain jellyfish genes that glow fluorescent green, red or blue when particular cell types are made in the culture. This allows scientists to visualise and study, for example, blood cells, insulinproducing cells or beating heart cells – which are the focus of their team’s laboratories.

Professor

Andrew Elefanty

“If we need to confirm we’re making an insulinproducing cell, for example, we take the stem cell line carrying the green fluorescent insulin gene tag through the differentiation process. We can then look down the microscope and say, ‘there’s a green cell, that’s the one we want’, and we can study that cell,” Ed explains.

These coloured cell lines have been sent to more than 100 labs around the world and the lab continues to receive requests for them weekly.

Back on home turf, Andrew and Ed are busy collaborating with researchers across the Institute.

The work of the stem cell laboratories is in demand as scientists are keen to incorporate the technology into their particular areas of research.

“An exciting facet of our work is the opportunity to collaborate with many world-class researchers studying illnesses that affect children,” says Andrew, adding that the team is working with scientists on diabetes, childhood leukaemia, mitochondrial diseases and congenital heart disease – and the list goes on.

“Our aim is to create ‘disease in a dish’ models for these conditions,” Ed says. “These models will allow us to understand more about the illnesses and develop new treatments that will improve the lives of children and their families.”

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Stem Cells

Associate Professor

Matt Sabin

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M

att Sabin launched into his doctorate on obesity more than a decade ago. At that time, people wondered why he’d chosen to study obesity – surely it was just a matter of getting kids to exercise more and eat better?

“There are a lot of myths and presumptions about obesity,” the researcher says. “They’re all based on the notion that if we get children to run around a bit more and eat a bit better, the problem will go away,” he says.

“We clearly know that’s not the case anymore. There’s really strong genetics that have geared some individuals to become obese. From an evolutionary point of view, it’s quite protective.”

The father-of-two, who leads the largest tertiary-hospital paediatric obesity clinic in Australia at RCH, moved from the UK to Australia with his wife in 2006 to continue his research.

About a quarter of all children in Australia – an estimated 330,000 in Victoria – are either overweight or obese. While obesity rates have stabilised over the past decade, 25 per cent of kids are still obese – an unacceptably high number, says Matt.

“For a quarter of all kids to be overweight or obese, that’s far too high,” he says.

Obesity is also increasing in severity.

Over the past three to five years, Matt has seen more patients who are heavier than ever, including three-year-olds who are 35kg and 15-year-olds who are 250kg.

Although Matt hasn’t had a patient die from obesity-related causes, he worries this is inevitable.

“We are not far away from seeing a number of adolescents dying from obesity-related health problems. I think we will begin to see that over the next five to 10 years.”

However, it’s not the level of obesity but the duration – when it started – that determines the likelihood of developing obesityrelated complications such as heart disease, type 2 diabetes and cancer, according to one of his major research findings.

Another encouraging finding was that obese children who shed kilos and maintain a healthy weight into adulthood return their health status to having the same risks of diabetes and heart disease as if they had never been obese.

“It was quite reassuring and exciting to know there is not memory in the system,” says Matt. “It’s probably the biggest impetus for us to try and do something about kids who are obese today.

get good results, and it’s not that uncommon for us to get good results, that’s really heartening and the families love it.”

About 80 per cent of young children who attend the hospital’s weight management service improve their body composition and about one third reduce their diabetes and heart disease risks, Matt says.

Unlike adults, children can avoid regaining the weight they lose.

Other studies have shown obese adults who shed kilos often gain it again over several years as the body vigorously defends against weight loss. Matt is leading research to understand whether this phenomenon also occurs in children and teenagers. He hopes it will reveal at what age the body begins to defend a heavier body weight.

Helping kids resolve their weight issues is not just a medical matter. It can reverberate throughout their life, improving their overall wellbeing, social life and schooling, says Matt, and it’s what makes his job so special.

“The joy you get from curing kids from weight problems, and particularly seeing them emerge from their shell to become young adults who are completely selfconfident, who have done well at school, who are heading off to university, that’s really rewarding.”

“That has really enthused me to do something about every single patient that we see. When we

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Obesity

Childhood development Professor

Melissa Wake

T

here’s a surprisingly fun element to many of Melissa Wake’s studies.

The recent roadshow-style Child Health CheckPoint, says the bubbly paediatrician, was like a “research Cirque du Soleil”.

A convoy of trucks with a team of researchers in tow travelled to 12 cities around the country, measuring the health of about 2000 children aged 11 to 12 via a suite of fun, interactive and high-tech activities.

Over three hours, kids went through a series of health tests at different stations with names like ‘Tooth Booth’, ‘Lung Fun’, and ‘Bone Zone’. They wrote essays about what they thought life would be like at age 25 and took home photographs of the back of their eyeballs. How cool is that?

It’s hoped the CheckPoint will highlight early indicators of chronic diseases that present later in life.

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“Essentially we are looking at what lies between early life and disease,” says Melissa, who leads the Institute’s Community Health Services Research Group. “What’s really beginning to overwhelm national health budgets now, and will continue into the future, is diseases of ageing like heart and respiratory conditions, cancer, diabetes and osteoporosis.”

Originally from Auckland in New Zealand, Melissa arrived at the Institute in 1992.

Some of her earliest research was conducted into grommets, the small tubes inserted into the ears of children to drain fluid, and a particularly controversial study which concluded teething in babies does not cause fever and illness. “It really falls into the category of myth,” says Melissa.

Her research focuses on improving children’s health and development at a population level.

“I love to try and walk in children’s shoes and think, well, if I was a kid, or a parent wanting the best for my kids, what are the sorts of things that I would want help with? And what would work?”

Melissa says.

Following her doctoral degree, the motherof-two led a series of trials on hearing, literacy, obesity, behaviour, mental health and sleep, and whether early interventions maintained their effectiveness when rolledout to universal health care.

She’s particularly proud of her students’ achievements, starting with infant sleep studies by her first PhD student Harriet Hiscock. The interventions to help parents train their babies and children to sleep have been rolled out statewide.

More recently, Dr Valerie Sung hit the international news with her research into probiotic drops for babies with colic.

“We often say, we are not about the really heart-wrenching congenital defects or childhood cancer, those rare terrifying illnesses,” she says. “We are about the common conditions every family experiences.”

Harriet Hiscock is the kind of woman that sleep-deprived new mothers want to bundle up and whisk off home with them.

She helped dozens of parents across Melbourne improve their babies’ sleep with one-on-one support during her doctoral research.

The hugely-successful study not only helped solve baby sleep problems, it also showed improvements in mothers’ sleep and maternal depression up to two years’ later – and saved the health system dollars by reducing admission rates to mother and baby hospital units.

School nurses were trained to deliver the intervention, working with parents. “This was the first time nurses had worked face-to-face with parents and they loved it,” she says.

Meanwhile, a survey by her team showed kids with ADHD were far more likely to have sleep problems than other children.

The kids with sleep problems on top of ADHD had worse behaviour and quality of life, while their parents had diminished mental health and quality of life.

A large-scale intervention trial, published in 2015, showed “we could improve sleep, behaviour, quality of life and working memory in the classroom,” Harriet says.

Rewards like stickers and encouraging parents to introduce limit-setting, are some of the techniques.

A new study will trial an intervention targeting anxiety in kids with ADHD and autism – 70 per cent of whom have sleep issues, Harriet says.

The sleep program was rolled-out statewide to maternal and child health nurses, helping thousands of tired mums across Victoria.

She is acutely aware of the impact lack of sleep is having on parents – something she’d like to investigate in further studies.

“My sleep program is now the intervention for the eight-month Maternal and Child Health visit,” says Harriet, who had two children of her own after completing the study. The program is also available online to practitioners throughout Australia and internationally.

“It affects their relationship with their child, but also the relationship with their partner.

The child’s sleep problem is often a source of tension because everyone is exhausted and cranky,” says Harriet. “It’s a health issue for parents.”

Harriet has turned her attention to sleep problems in children in their first year of school, and those with ADHD and autism.

Working with her PhD student, Jon Quach, an intervention was developed for prep students with sleep problems stemming from worry, anxiety or a lack of parental limit-setting.

associate Professor

Harriet Hiscock

sleep

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“We found that this brief sleep program had no longterm effects,” Anna says of the children followed up at six years of age, whose mental health, wellbeing, parental relationships and cortisol (stress) levels were measured.

“This told us that the program, which improves children’s sleep and mothers’ wellbeing, is safe to use in the long-term.”

The concerns about techniques like controlled comforting, Anna believes, stem from brain development research showing that severely neglected children who are not touched or cuddled for months or years can have poorer health and development outcomes.

“It’s understandable that parents worry about how quickly they should respond to their children. However, the short intervals used in these sleep techniques are totally different to long-term, sustained neglect,” she says.

“One of the best bits of advice my supervisors gave me was to emphasise the evidence,” she says. “Big community-based studies like this give us evidence about what works for the community as a whole. This means the findings are based on facts, not opinions. This is really important for emotive issues like babies’ sleep, where parents want facts about what works and is safe to use.”

Doctor

Anna Price

Anna went on to investigate optimum sleep duration in babies and children, finding a huge range of normal sleep times. For example, infants sleep anywhere between 10 and 18 hours over a 24-hour period. A subsequent study showed that school-aged children who go to bed earlier have better quality of life, but this research has raised more questions that need answering.

B

aby sleep techniques like “controlled comforting” are among the most controversial parenting topics.

Anna Price followed up an original Murdoch Childrens trial that helped improve babies’ sleep to measure any impacts on children five years later.

“When managing babies’ sleep, there was a great deal of uncertainty in the community about whether it is okay to leave your child for short periods of time, as in controlled comforting,” says Anna of the original trial, led by Harriet Hiscock.

Now embedded in Victoria’s free maternal and child health service, the program uses different methods to help babies older than six months resettle without sleep associations such as feeding or rocking.

Parents choose which techniques they want to use.

Options include “controlled comforting”, where parents go in and out of their child’s room at regular, short intervals. Another method, “camping out”, involves parents staying in their baby’s room on a stretcher or chair and gradually moving out over a number of nights. Both methods help babies learn to fall back asleep unassisted.

“We are hoping to reassure parents about the big range of normal sleeping patterns. Ultimately, what matters is that your child is happy, able to pay attention, and has enough energy during the day.”

Anna, who has a 15-month-old, found her research gave her an extra confidence boost as a parent of a newborn.

“It’s wonderful having evidence-based research to help my parenting. I feel like I know where to get reliable information, so I’m not looking at random blogs at 2am.

I felt like we had the tools to help us do our best.”

Sleep techniques

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L

ike many teenage boys, Paul Ekert once swore black and blue he wouldn’t follow in his father’s footsteps.

But the cancer researcher admits he is now doing just that. His oncologist father worked at RCH at a pivotal time for cancer treatment in the late 60s and early 70s, when the introduction of chemotherapy and bone marrow transplants began to transform the lives of childhood cancer patients.

“This difficult work was an ever-present feature in our family life,” Paul recalls.

At the time, childhood cancer and in particular leukaemia was changing from a 100 per cent certainty of death to becoming curable. He credits his father with pioneering the introduction of chemotherapy for childhood cancers at the hospital.

“That must have been an amazing time full of hope and tremendous disappointments when things didn’t work,” he says.

“When the first bone marrow transplants were done in this hospital for cancer, these were done by my dad and his team. And that must have been hair-raising!”

Paul now finds himself at a similar tipping point, when new drugs and genomics are beginning to offer even more hope for patients with types of cancer that previously did not respond well to treatment.

After a long association with the Institute and RCH dating back to 1987, when he began his career as a paediatric trainee on the campus, Paul now leads the Cancer Research Group at the Murdoch Childrens.

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The team is investigating the molecular basis of childhood cancer, to understand how this can be translated into better diagnostic tests and treatments.

The lab has a long-standing interest in the way molecules called cytokines stop cell death.

Cell death or apoptosis as it relates to cancer is an area Paul has been interested in since he stumbled into it while working at The Hospital for Sick Children in Toronto in the early 90s. After returning to Australia, he worked part-time as a neonatologist while researching apoptosis at the Murdoch Childrens and the nearby Walter and Eliza Hall Institute.

The great hope, he says, is that by understanding the biology and genetics of changes that take place in a cancer cell, researchers will be able to find these cells’ ‘Achilles Heel’ and develop drugs that specifically target those changes.

These new therapies will be less toxic than chemotherapy, which kills not just the cancer cells but all cells that are dividing rapidly. This causes ulcers in the lining of the gut and the mouth, leading to inflammation and the nausea and vomiting commonly associated with chemotherapy patients. It causes patients’ hair to fall out and is why children run the risk of becoming infertile.

“All of these things are an enormous price to pay,” says Paul. “More often than not, the price is still worth paying. But nevertheless, everyone wants to find better and less toxic ways to treat. It’s impossible to do that unless you understand what it is you are dealing with.”

His lab is using new technology that allows researchers to quickly decode genetic sequences. Using tissue samples donated by families of children with cancer, the team looks for particular genes that fuse together in a cancer cell and drive the cancer growth.

Although he is one step removed from these patients, his work still tugs at the heart strings. The emotional drain of working with families in the neonatal unit was one reason he closed the door on this area of his career after 16 years, although the main reason for the move was to concentrate on the, arguably, equally emotionally challenging area of childhood cancer research.

“It never does researchers any harm to understand what things mean for people and what things mean for families,” he says. “In fact, it’s really important. It doesn’t mean you should be paralysed by grief. But you would be inhuman if it didn’t in some way impact on you. It’s not a bad thing to admit your humanity at times.”

Associate Professor

Paul Ekert

Paul has a unique insight into what some parents with sick children face. His adult daughter was diagnosed at 14 with type 1 diabetes and he found himself not only a doctor and a researcher, but a consumer of the kinds of information and services he provided to others.

It was an unpleasant but revelatory journey, he says, that opened his eyes to what parents want.

“Researchers shouldn’t feel guilty because they can’t come up with a cure tomorrow,” he says.

“What families want to know is that people care and can offer their abilities to think about the problems their children, or children like their children, will have in the future. That is such an important aspect of what we do here. We have to do that because it’s our responsibility.”

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cancer

Professor

Andrew Sinclair

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The finding was published in the journal Nature and lauded by the editor as one of the greatest genetic breakthroughs of the last century.

It’s the all-important question that every parent wants to know about their newborn– is it a boy or a girl?

But what happens when no clear answer can be given?

Disorders of sex development (DSDs), which can be as frequent as one in 250 or as rare as one in 4500 births, can result in ambiguous genitalia, infertility and are associated with paediatric cancers of the testes and ovaries.

“Uncertainty about a child’s sex is extremely traumatic for the individual, parents and other family members and carries profound psychological and reproductive consequences for the patient,” says Deputy Director Andrew Sinclair, who is internationally renowned for his work researching DSDs. The cause of these problems is often a breakdown of the complex network of genes responsible for proper development of testes or ovaries in the embryo.

In 1990, Andrew began unravelling the mystery surrounding some of these disorders when he identified the gene responsible for testis development, called SRY – for sex region on the Y chromosome.

The finding was published in the journal Nature and lauded by the editor as one of the greatest genetic breakthroughs of the last century.

The importance of this discovery cannot be overstated. The SRY gene kick-starts the development of testis in the embryo. It provided an answer to one of the most fundamental questions – what makes us male or female?

It has allowed Andrew’s team to substantially improve the diagnostic rates for DSD patients. However for about 60 per cent of cases, a diagnosis can still prove elusive.

“For many of these children, no precise diagnosis can be given. That means there is no way to work out what the proper management should be,” Andrew says.

For example, some forms of DSDs can result in individuals with XY chromosomes, who would normally present as male, being female. Likewise, individuals with XX chromosomes can be male. Andrew’s team has substantially improved diagnostic rates for this group of DSD patients.

“A lot of our work is about understanding how ovary and testis development occurs normally, and how we can, by understanding those genes, provide a better diagnosis to these children and their families.”

“By using genomics – sequencing all of an individual’s genes – we have more than doubled DSD diagnoses,” says Andrew, who with Institute Director Kathryn North is leading the nation in a move to place genomics squarely within the Australian health care system.

At the same time as the SRY discovery, Andrew also identified a new family of related genes, called SOX, which play huge roles in normal human development. Over the years, his team has identified many more genes associated with DSD and developed a rapid diagnostic genomic technique for the disorders. It is hoped this technique will this year be translated into a clinical test through the Victorian Clinical Genetics Service to lift diagnostic rates further.

Andrew also leads a national group of researchers trying to find the underlying cause for the most common DSD affecting one in 250 boys, hypospadias, where the urethra develops abnormally.

are offered the option to freeze their eggs, should they wish to use IVF to conceive later in life.”

By studying a large cohort of these women, Andrew’s team has identified new genes associated with early ovarian failure. Importantly, these genes are also implicated in a range of other developmental conditions and cancers, providing an even greater impetus to inform affected individuals as early as possible of the impacts to their overall health.

The father-of-two teenagers, aged 15 and 13, Andrew balances his roles at the Institute with the Executive Director position at the Victorian Clinical Genetics Services. He and his family enjoy films, theatre, surfing and bushwalking - when time allows.

He’s an environmentalist at heart, a passion he traces back to an early love of biology and one shared by his wife, a senior lawyer at the Environment Protection Authority.

It’s perhaps this keen sense of social justice that drives him to provide answers for DSD patients. With one in 4500 babies born with ambiguous genitalia, Andrew’s lab receives DNA samples from individuals around Australia and the world seeking diagnostic answers.

“It is a very fraught area,” says Andrew.

“It influences so much about how you see yourself in society and how people treat you. It can be very difficult for people to navigate their way through life without a clear answer – we aim to find a diagnosis to give them clarity.”

Girls who experience early ovarian failure could also benefit from his research. Premature ovary insufficiency, which can occur in teenagers and causes infertility, is a devastating revelation for adolescents. “Essentially, when there is the collapse of the ovary function, it just stops working,” says Andrew. “Obviously these girls are going to be infertile, but there are also hormonal effects that can be quite distressing. Early diagnosis means girls

Sex development

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Professor

Peter Anderson Every year in Australia, about 20,000 babies are born prematurely – before 37 weeks of gestation – and about 5000 of these are born very early – before 32 weeks. The VIBeS group focuses on those born very premature.

“The thing that fascinates me is why some children have very similar clinical journeys but have either a very good, an okay or a poor outcome,” Peter says. “One of my passions is to work out why we see this variability.”

Children in the VIBeS study had MRI scans of their brains at birth, at age seven and now at age 13.

The group’s research has found these scans are more predictive of long-term outcomes than any other medical factors used in the past, including babies’ birth weight, prematurity, lung injury severity and time in hospital.

Scientists now know, following findings of further research led by Karli, a host of other factors also impact on premature children’s development.

“My particular area of interest is observing parenting,” says Karli. “Not just relying on questionnaires but looking in detail at how the parent and child are interacting together.”

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The first few weeks and months of a very premature baby’s life are a battle for survival. Their tiny bodies, covered in tubes keeping them alive, are cradled by their worried parents. But what happens after these babies leave hospital? How do they and their parents cope?

Peter Anderson and Karli Treyvaud have been working closely together for more than a decade to figure this out.

They want to predict the developmental outcomes for very premature babies and work with families to improve the outlook for these special children.

“Back in the 70s, the percentage of those children who survived was pretty small,” says Peter, who joined the Institute as a research assistant in 1990. “Now most very premature babies survive. The issue is improving the lives of these kids. Over 50 per cent will have a developmental impairment of some type.”

The psychologist leads the world’s largest long-term brain imaging and developmental study of very premature children. The Victorian Infant Brain Study (VIBeS) recruited pre-term babies between 2001 and 2003, along with a group of full-term babies – about 300 kids in total – and followed up these children at two, five, seven and now 13 years of age.

The group’s research has shown parenting styles at age two not only predicts how well the child is developing at that age but also how this will impact how well they do at school.

“Warm, affectionate parenting with lots of smiles, eye contact and playful interaction was associated with better outcomes for premature babies,” says Karli. “Ultimately, these children are more likely to have higher IQ, better language and academic performance.”

The research has also looked at the mental health of the children and their parents. It showed very premature children had a three times higher risk of disorders like autism, anxiety and ADHD. “That’s been shown in other studies before but we were able to show it for the first time in an Australian cohort,” says Karli. “We looked at early predictors of those outcomes and showed that children’s brain development and the history of their emotional development is a good predictor of where they will be at seven.”

Meanwhile, parents of very pre-term babies are more at risk of mental health problems like depression and anxiety, not only when the babies were little but right up until the children went to school, Karli’s research found.

The group is now responding to these findings by developing an intervention program for families. This was first carried out at home with visits by physiotherapists and psychologists but is now being adapted into a web-based model with guidance offered via phone calls.

In addition to the study, the researchers also work closely with a support group for premature babies’ families, Life’s Little Treasures.

“We’re really good at getting up at conferences and talking to scientists and clinicians about our research findings,” says Peter. “But often the families who are part of our studies don’t really hear much about what we’ve found. I believe it’s really important we get much better at actually sitting down and talking with them to give them answers.”

doctor

Karli Treyvaud & Estelle

T

he first few months of Estelle Richards’ life were tumultuous. The two-year-old was born very prematurely at just 26 weeks. And she wasn’t born alone. Estelle was an identical twin. Her sister, Layla, passed away five days after birth as a result of complications.

“At first you have this euphoria,” says the girls’ mother, Angela Richards, of the birth experience. “Even though they were born early I was very hopeful that everything was going to be okay.”

But that all changed when it became clear Layla was struggling to survive.

“Once we realised Layla wasn’t going to make it, the nurses helped myself and my husband, Matthew, hold the two of them together, while they were both alive,” Angela says.

“That was very special.”

Estelle, although the stronger of the two twins, also had a fight on her hands. On the day the couple buried Layla, they received a telephone call from the hospital to tell them Estelle had a collapsed lung.

She was in hospital for three months until she reached her expected full-term delivery date. Going home with their precious bundle was bittersweet for the couple and terrifying for Angela, as she struggled with feeding Estelle.

“Being in hospital was actually a beautiful experience,” Angela recalls. “Even though it was scary, you have a lot of support from the doctors and nurses. When it’s time for the baby to come home, you cannot wait. But it is the most petrifying thing. You are not used to not having a nurse or doctor to ask what’s happening.”

It was at this time Angela developed “pretty intense” anxiety.

It’s under control now but she wonders if the worry that kicks in every time Estelle gets sick, is the anxiety talking, if she is overreacting or if it’s because the situation is real.

What Angela does find reassuring is being involved in the very premature baby research led by Peter Anderson and Karli Treyvaud. Estelle and her parents are part of the Victorian Infant Brain Study (VIBeS) which focuses both on the baby’s development and their parents’ wellbeing.

Angela says it has been helpful to know how Estelle is developing and that if there were any concerns, the family would be steered towards early intervention services. “I know we are helping the researchers but really, they help us,” Angela says.

As for Estelle, she is a happy two-year-old who adores her daddy. “She’s obsessed with her father, loves her dad,” Angela says. “She’s gentle and caring. She’s no better, no worse, she’s just awesome, because I love her.”

Premature babies

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J

ane Halliday was a young mother of two little children when she began her long-standing career at the Murdoch Childrens more than 30 years ago.

She fondly recalls director and founder, David Danks, explaining why he’d given Jane her first research job: “You said, ‘I love being with my children, but I want to do something for myself’,” he told her, clearly impressed.

“I love that story,” says Jane, who exudes warmth and is renowned for her cohesive relationship with her team of researchers.

In the early days, Jane pulled together the first report on prenatal diagnosis in the state. In 2015, a summary of 38 years of these data was published in the British Journal of Obstetrics and Gynaecology.

The epidemiologist remembers the days when the Institute’s founding patron, Dame Elisabeth Murdoch, would pop in. “We used to just sit in the tea room with her and have a chat. It was a small place. We all knew her very well.”

Jane knew her especially well. Dame Elisabeth was a friend of her parents and a fan of Jane’s choral conductor husband, Michael Leighton Jones, attending many of his concerts.

Jane completed her PhD in 1994 and ran the Victorian Government’s Birth Defects Register until 2009, while also working part-time at the Institute. She has worked with all the directors and has never had the inclination to work anywhere else. “Everything I did here kept changing; the people and the environment. I really enjoyed what I was doing.”

Research can be serendipitous, she adds, with numerous grant proposals resulting in an often eclectic mix of studies, depending on what is funded. She considers the ongoing research she leads into the long-term effects of IVF on individuals and alcohol in pregnancy in this “hotch-potch” category, although all under the umbrella of genetics and epidemiology.

Researchers have collected detailed information about drinking during pregnancy from nearly 1600 women and followed up their children at one and two years of age to assess the impact of different amounts of alcohol on the unborn child.

There is so much conflicting evidence about the impact of drinking low amounts of alcohol in pregnancy that people don’t know what to believe, says Jane. Also, sporadic binge drinking – for example, before women know they are pregnant – is another area of research being explored.

“Our focus is on the low levels and the sporadic binge drinking early in pregnancy – they are the two groups that we are really interested in comparing to all other groups.”

“It’s okay to say no alcohol is the safest – that’s right – but it’s not always practical. We are trying to put more information out there for people to use in whatever way they can.”

Jane hopes the research will shed light on how to deal with the 30 to 40 per cent of women who experience unplanned pregnancies, when alcohol is often a factor.

“How do you get people thinking about alcohol, even though they are not thinking about pregnancy? That’s the biggest challenge.”

After more than three decades, Jane is ready to scale-back her Murdoch Childrens life. She will work part-time and focus on other interests, especially her grandchildren.

“I feel that I’ve been very fortunate to have a fantastic group of researchers around me. It is a really great place to work and there have been some wonderful opportunities for collaboration and friendships. It’s an exciting place to be.”

Her world-first IVF study of Victorians who were conceived using the procedure found they grew up to enjoy a similar quality of life and educational achievement compared to those conceived naturally.

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She also leads topical research into the effects of alcohol drinking during pregnancy on children’s health and development to answer the longstanding question – what is a safe amount of alcohol to drink in pregnancy, if any?

exposures in pregnancy

Professor

Jane Halliday

The epidemiologist remembers the days when the Institute’s founding patron, Dame Elisabeth Murdoch, would pop in. “We used to just sit in the tea room with her and have a chat. It was a small place. We all knew her very well.”

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Professor

Fergus Cameron

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Diabetes

M

ost people know children with type 1 diabetes require daily insulin injections, skin-prick tests to check their blood sugar levels and to watch what they eat.

What they may not know is what diabetes researcher Fergus Cameron has discovered: that swinging blood sugar levels are disrupting the brains of children with this condition.

What concerns Fergus, who is also a paediatric endocrinologist at RCH, is that the brains of children with diabetes are still developing and any disturbance is going to have consequences.

“I look at things through a prism of developmental outcomes,” says Fergus.

“The most important outcome is to grow a good brain. You can’t transplant a brain. You can’t get a new one.

“Why is that relevant in diabetes? The fuel for the brain is glucose. And diabetes is the chronic condition, bar none, that upsets blood glucose levels. It’s a perfect storm,” says Fergus, a straight-talker with a love of the vernacular. “It made intuitive sense to me that this was a very important area to look into.”

Fergus began his career at the Institute as a doctoral student with now Deputy Director Andrew Sinclair. His investigations into childhood diabetes began after his return to Melbourne in 1998 from stints at London’s Great Ormond Hospital and the Hospital for Sick Children in Toronto. He landed at RCH, running the diabetes clinic.

Fergus collaborated with Associate Professor Lis Northam in a landmark Murdoch Childrens study involving 133 children with diabetes.

It revealed a disturbing rule of thirds: a third of the children with diabetes developed a mental health disorder, a third did not finish high school, a third did not stay in adult care and they lost a third of a standard deviation in their full scale IQ.

The mental health issues are clinically significant.

Initially it was thought the daily burden of managing diabetes – the jabs, skin-prick tests and diet were the cause. But it has since emerged, through research led

by Fergus, that these underpinnings may be biological rather than just lifestyle-related.

“The whole paradigm has shifted,” he says.

A follow-up study using functional MRI imaging provided the biological proof. Blood sugar levels of children with diabetes were lowered and raised while they undertook memory tasks. The MRI scans painted a moving picture of what was happening in their brains.

“Even when the children had recovered – their blood sugar returned to normal – their brains had not recovered,” Fergus says. In a classroom situation, this would impact on learning.

Fergus is keen to emphasise, especially to parents, it is not all doom and gloom. The blood sugar swings appear to only impact on high-level executive function with only subtle influences on day to-day life. However, his team want to discover how to protect these children’s brains from the harmful swings. And there is a list of things waiting to be tested to provide that protection.

The next step is an intervention study, using the same design as the previous trial but adding a protective element – a medium chain triglyceride found in coconut oil – to build a “bullet proof vest around the brain”.

“The greatest fear of parents is that their kids may have prolonged and severe hypoglycaemia, resulting in seizure and death. Thankfully, this is an extremely rare event but the fear still looms large.

Ultimately, we want our kids to be able to get up in the morning and take a tablet or a powder and know that regardless of what happens to their blood sugar during the day, their brain is protected.”

Together with Professor Ed Stanley and his team, Fergus is also investigating the effects of blood sugar levels on brain stem cells to see whether developing neurons are impacted. This research is also relevant to gestational diabetes, where the foetus is exposed to fluctuating glucose levels in mothers with the condition.

Between consulting patients and conducting research, Fergus – who lives on a farm – still finds time to muck around with cattle, horses and dogs. His family are enthusiastic horse riders, although Fergus – who was a doctor at regular equestrian events including at the Sydney 2000 Olympics – has wound back a bit since parting company with the saddle one too many times.

The daily commute between the family property and work affords time to “think about the bigger picture research stuff”.

“Research is the engine that drives clinical care,” he says. “You are always asking yourself new questions.”

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Professor

Sharon Goldfeld

The research is a randomised control trial, with 722 mothers recruited into the intervention or control group in Victoria and Tasmania, and is the largest study of its kind in Australia.

She also heads two other research projects aiming to improve the lives of children at a population level. The Kids in Communities study explores how neighbourhood-based physical and social environments influence children’s development, while the Classroom Promotion of Oral Language trial focuses on how to make education better for children, especially those in more disadvantaged schools.

S

haron Goldfeld knew early on in her career how she wanted make a difference – and who she wanted to help.

The paediatrician and public health physician is passionate about righting inequities facing children.

And she believed the best way she could do this was to inform government policy.

“I’ve always been particularly interested in children living in adverse circumstances,” says Sharon, who spent 10 years working in state government in health and education before returning to full-time research at the Institute in 2010.

“It became clear to me that policy was a really important way of making a difference.”

Sharon, who is co-group leader of Child Health Policy, Equity and Translation, heads a number of major trials and large analytic programs at the Institute focusing on children with additional health and developmental needs, mental health issues, and children with diverse language backgrounds.

She leads Right@Home, a project that could potentially transform the way maternal and child health services are delivered. It involves 25 nurse home visits in the first two years of a child’s life, with a focus on supporting parents with feeding and sleeping, responding emotionally to their child and helping with the development of language and learning at home.

Australia may be a wealthy, first-world country but children from poorer backgrounds tend to perform worse at school than their wealthier classmates, says Sharon.

“When children have an inability to do well at school it really is a predictor for poorer health, employment and life outcomes right through until adulthood,” she says.

“That’s got substantial implications for Australia as a country, for its human capital, for its gross domestic product, for everything that makes it important for us to be a well-functioning first-world country.

“The moral imperative is that in a country as rich as ours, we shouldn’t have these kinds of inequalities.”

Education

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W

hat if peanut allergy – the most deadly of all food allergies – could be cured?

Research led by Mimi Tang has shown this may no longer be just a pipe dream.

Only about 17 per cent to 30 per cent of those treated gained tolerance.

So why did she think a probiotic might hold the key?

A peanut allergy – the most common cause of lifethreatening anaphylaxis – is more likely to result in death than any other reaction to food. And it has been steadily on the rise. In the last 20 years, peanut allergies have increased more than 350 per cent.

The seeds of this idea were sown over a decade ago.

Mimi has long been intrigued by probiotics and healthy gut bacteria, and studies emerged showing probiotics taken in the last weeks of pregnancy and the first few months of a child’s life could prevent the development of eczema in babies.

Mimi’s study combined a probiotic and peanut protein – the first time ever a probiotic had been coupled with oral immunotherapy – with astonishing results.

This original study used bacteria called lactobacillus rhamnosus – the probiotics used in Mimi’s PPOIT study – which seemed to promote tolerance responses in the gut.

Eighty-two percent of children with peanut allergy who underwent the therapy in her Melbourne-based trial were able to tolerate peanut, compared to four per cent in the placebo group.

“I had an idea. Literally, it was just an idea,” says Mimi.

It was more than researchers could have hoped for.

These kids could now go to parties, school camps and travel overseas without fear of death from accidentally consuming peanuts. It was a relief for children and it was a weight lifted off the shoulders of their stressed parents.

“If you treated nine children, seven would benefit,” Mimi explains of the study, the Probiotic and Peanut Oral Immunotherapy for treatment of peanut allergy trial (PPOIT). “When we started, we thought the probiotic would improve the ability for oral immunotherapy to induce tolerance. But we had not expected that improvement would be of such a huge magnitude.

“We were very excited.”

So, it seems, is everyone else – researchers and allergy sufferers alike. As interest and momentum built following the study, Mimi decided to step aside as head of Allergy and Immunology at RCH to focus on the research.

“I thought if we presented a probiotic, together with the allergen, that probiotic may be able to provide the right environment to encourage the immune system in a different direction to its current default. That’s why I did it.”

The internationally-renowned allergist is not content to stop at peanut allergy. In future, she wants to see if the combined therapy works for other foods, if it works for adults and to refine the therapy.

But for now she is full of gratitude, pride and satisfaction the 10-year journey has culminated in what all medical researchers ultimately want.

“It is just a wonderful feeling that we have made a difference, finally. That’s what medical research is all about. We all want to make a difference.”

Emails flood into her inbox daily from people outside Melbourne wanting their children to be involved in further trials. Some interstate parents have even considered moving their families to Victoria. But they may not have to make such a drastic move – the next study in 2016 will be a $2.8 million multi-centre trial across Perth, Adelaide and Melbourne involving 200 children.

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Mimi hopes the new trial will answer two questions.

Firstly, to prove adding the probiotic does give a benefit over and above oral immunotherapy alone, and secondly, to see if the combination therapy can give allergy sufferers longer-lasting tolerance.

Most other studies using oral immunotherapy alone to induce tolerance, Mimi says, have limited success.

Allergies

Professor

Mimi Tang & Ayden

T

here was a time when Nadine Schnabel couldn’t bear to leave her son Ayden at a party by himself.

Well-meaning parents would try and ease her worry, assuring her they would be careful that nothing with even a trace of peanuts would cross his lips. But the risk of an anaphylactic reaction to peanut was too much.

Nadine would stay.

Ten-year-old Ayden was just three when he first reacted to peanut butter, scratching his eye with a finger dipped in the sticky spread. His face blew up and he broke out in hives.

Anaphylaxis was diagnosed and from that time on, he never left home without an Epipen.

“Having a child with a lifethreatening condition is horrible, you don’t want them out of your sight. You want to keep them safe.”

was such a big thing because we knew the difference it could make to his life. We just kept experimenting, how can we get him to eat the product? In the end, we gave it to him in a Nutella sandwich. That was fantastic. He was totally fine with it.”

A few years later Nadine heard about a study set to take place at the Murdoch Childrens, led by Professor Mimi Tang, aiming to induce tolerance to peanut allergy.

It wasn’t until the end of the study that the family discovered Ayden had been taking the peanut protein in conjunction with the probiotic – because it was a blind, randomised control study. The result was an amazing outcome for Ayden and his family – he had developed tolerance to peanut.

It sounded promising and she wanted Ayden to be a part of it.

It came as a huge relief to know that Ayden is now safe from a life-threatening anaphylactic reaction.

At first, it was hard to get Ayden – who obviously had a very strong aversion to being anywhere near a peanut – to take the protein. But she persevered.

Nadine no longer worries like she used to.

“As a parent, sometimes you’ve got to get your child to do something they don’t want to,” Nadine says. “This

“It’s life-changing, totally life-changing,” she says. “You don’t stress, you don’t worry about what he’s eating or what someone else is going to feed him. We are so grateful, so grateful for this.”

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associate Professor

Franz Babl

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On

any given Sunday afternoon, emergency physician Franz Babl has witnessed one child after another admitted to the children’s hospital emergency department with concussion from playing sport.

“Sometimes you can literally put half a football team together of children who have concussion in the department,” Franz says.

More than 3000 children are admitted to RCH with head injuries every year.

The rise is partly due to an increased awareness, says Franz, but it’s still a real and growing problem.

“There is a true increase but there is also an increase in the recognition of concussion and head injuries in general,” says German-born Franz.

“In the past, people thought concussions were just part of game play and you just shake it off. Now we know that a certain proportion of children have ongoing problems. It’s not just in the next game if they return before they have fully recovered. It particularly impacts on the biggest job that children have – which is learning in school.”

The researcher leads a large study of 20,000 children who present at Australian and New Zealand emergency departments with head injuries of all severities. The study aims to determine which children will need CT scans to detect brain injury.

This can be a vexed issue because physicians need to balance the importance of diagnosing an injury with reducing radiation exposure as much as possible. Another study is trying to determine what advice to give to parents, coaches and teachers of children who suffer concussions.

The causes of head injuries vary by age. In younger children it can be the result of an infant falling off a change table or the inevitable falls when toddlers start to walk and explore.

But in teenagers, head injuries are overwhelmingly a result of playing sport, says Franz. Sports-related head injuries often lead to concussion or mild traumatic brain injury when the brain jars inside the head, either from a direct blow or indirectly when the body is moved violently.

He can empathise with parents who are understandably concerned about whether to let ‘little Johnny’ play his favourite team sport. Franz is the father to seven-year-old twins so it’s something he has given serious thought to.

“I don’t think you should prevent children from playing sports. If kids are really, really keen on playing contact sports with a higher risk, I think the role of the parents is to check that the clubs and the coaches are very aware of the issues surrounding concussion and that the sport is played safely,” says Franz, who appears slightly relieved his children have so far chosen to play non-contact sports.

Many sporting codes have online materials and sometimes quite elaborate guidelines about managing possible head injuries, Franz says.

“As we found in another study, the problem is that these guidelines are often not followed at the front line and parents know little about head injuries. Plus there is often an element of panic if something does happen on the pitch. Our team developed a head injury app called HeadCheck which takes parents, coaches and first aiders through the decision-making process after a possible head injury.”

Franz trained in paediatrics, emergency medicine and infectious diseases in the United States between 1991 and 2001, where he met his Australian wife. They moved to Australia in 2002.

Head injuries are not his only research focus. He’s also been drawn to a particularly worrying form of seizure in children, called status epilepticus. It’s a seizure that doesn’t stop.

“It is the scariest thing for parents, they think their children are dying,” says Franz. “The seizure can continue until you put the kids under general anaesthetic. We use medicine that has to be given slowly because it has a lot of side effects. We don’t actually know how well it works because it has not been studied well. Now we are doing a study which compares that old drug with a newer drug, which can be given quickly and has few if any side effects.

“It’s a world-first study. Once we have the results, it will likely change practice, not only here but worldwide.”

His research aims to shed light on the grey areas of emergency medicine where there hasn’t been enough evidence-based practice in the past.

“There were a number of conditions that have been recurring themes over my training and career where we just don’t know what to do. Research that I’m doing is essentially chipping away at these dark corners.”

Emergency medicine

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doctor

Anushi Rajapaksa ensure the vaccines survived the process and remained intact to preserve their biological function.

When the experiment worked, Anushi says the nebuliser’s potential seemed limitless. “Vaccination is just one option. There’s no reason why it couldn’t also be used for stem cell delivery and other therapeutics via inhalation as well.”

Until then, the research had been a high-risk side project to her PhD that she was encouraged to explore if she had ‘spare time’, but it quickly became the new focus. “It was this amazing discovery we didn’t envisage,” Anushi says of the research. “That was the beginning of everything – my whole career.”

The discovery earned her Engineers Australia’s Young Biomedical Engineer of 2010 award.

While the matchbox-sized device has wide-reaching potential, Anushi’s research with Associate Professor David Tingay and the neonatal research team is to pursue its use to deliver immunisations non-invasively.

It would be especially beneficial and cost-effective to deliver vaccines to children in third world countries, she says. “The nebuliser technology can be made portable and only requires a few batteries for operation.

There is huge potential for this work to be used for mass vaccination programs especially in developing countries with limited resources.”

Anushi Rajapaksa remembers the moment that launched her career.

She had just completed a successful experiment using a new technology that showed a liquid vaccine could be inhaled, rather than injected.

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The experiment, using one of the most fragile vaccine types, showed that the particles survived the transformation from liquid to an aerosol mist. This was a potentially new, non-invasive and pain-free way to deliver vaccines – and would be especially useful for newborn and premature babies, and people in developing countries.

The nebuliser technology uses a microchip, similar to that found in a mobile phone, but modified to incorporate fluid. Sound waves from the chip converted the liquid into an inhalable mist. The challenge was to

Inhaled vaccines

The nebuliser would deliver droplets containing the vaccine that could then be inhaled to be deposited on the deep surfaces of the lungs. Influenza is one of the first targets of the technology. Most germs enter the human body via the lung and it would be important to have a strong first line of defence. Anushi’s research is testing whether delivering immunisations directly to the lungs is superior to having a flu jab. “I don’t envision that injections will be a thing of the past; but rather it will be about giving people an alternative method of vaccination.”

She is also very keen on the potential for immunisations to be delivered via inhalation to very premature babies.

“Many premature babies have poor lung development.

This should be a priority so we safeguard them from severe respiratory illnesses quite early on in their life.”

Anushi has become a mother herself since joining the Institute – her children are aged nine months and three.

They have helped guide her research. “Now that I’m a mother I feel very strongly about addressing the needs of premature babies – they are the ones who really need this protection. These children have their whole lives ahead of them and you want to give them the best start to life.”

Autism T

here are a few autism myths Katrina Williams spends a great deal of time dispelling.

At conferences, often with fellow medical practitioners, the paediatrician has found herself emphasising that autism is not rapidly increasing.

Rather, there are other factors which have contributed to the perception of an increase in prevalence; including the fact the criteria used to diagnose autism has broadened over time.

The Murdoch Childrens Honorary Fellow is particularly passionate about stamping out the damaging claims the MMR (measles, mumps, rubella) vaccine causes autism – a theory that has been scientifically disproved – and other more prosaic claims such as heavy metals, gluten, radiowaves or even time spent at the computer contributing to the disorder.

A respected leader in the field, she’s perhaps the best person to ask the intriguing question: What does cause autism?

In other words, she queries whether the hormone oestrogen could be protective while androgen may increase the risk of autism. It’s a question she hopes future research, in collaboration with the gender dysphoria clinic at RCH, will help answer.

“These adolescent patients often display autism symptoms.

“We’re hoping to use that research as a great way of working out what’s the best clinical care, what are the best preventive mental health strategies and also to explore if there’s a causal link that brings the two things – autism and gender dysphoria – together more than in the general population.”

Importantly, the aim of the research will also be to find ways to better support the young people and their families before and after they embark on gender reassignment.

When it comes to autism, you can’t just look down a microscope at the brain and say, ‘Oh, that explains the behaviour,’ Katrina says.

Understanding complex conditions like autism, she says, is “the last frontier of research”.

There’s no straightforward answer, but it’s one of the great mysteries Katrina’s research is trying to unravel.

Adverse events in the womb during pregnancy and the birth process, in combination with genetic factors, may contribute.

“I think autism is a predominantly genetically-driven condition,” Katrina explains. “Then, our genetics create a predisposition so some children are more vulnerable to adverse perinatal, pregnancy and antenatal events.”

Children with autism have difficulties with social communication including trouble maintaining eye contact and understanding body language. They may have highly-focused special interests and have problems coping with change. But how each individual is affected varies.

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More than one in 100 Australian children under six is diagnosed with autism, compared to about four in every 10,000 in earlier studies.

UNIQUE Autism, a pilot study led by Katrina, is exploring differences between identical twins to understand how autism occurs or potentially lead to useful biomarkers to identify individuals at high risk.

While identical twins have mirror-image DNA, researchers are investigating molecular “switches” that turn genes on or off – known as epigenetics.

Gender is also an area increasingly under the microscope in the quest to understand autism. About four boys are diagnosed with autism for every girl.

Very little is known about how hormones affect humans’ brains, Katrina says. She wonders whether the hormone experience could protect girls but put boys at greater risk.

Professor

Katrina Williams

Professor

George Patton

G

eorge Patton and Susan Sawyer believe one critical age in life has been seriously neglected for too long.

Professor

Susan Sawyer

The Murdoch Childrens researchers believe adolescence is enormously pivotal.

“An individual’s health in adolescence reverberates across the rest of their lives,” says Susan, an adolescent physician.

This period, says George, is “absolutely formative”.

“We’re talking about a population that is 50 per cent larger than the population of children aged zero to nine,” the child and adolescent psychiatrist says.

The couple, who are married, are global leaders in adolescent health research and have succeeded in thrusting the health of adolescents and young adults on to the world stage, capturing the attention of many global agencies including the World Health Organisation and the World Bank.

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The Centre of Adolescent Health – a collaboration between the Murdoch Childrens and RCH – was established 25 years ago to investigate the emergence of new health problems including mental health and substance abuse, says Susan, the centre’s director.

At the time, there was an increasing recognition that the onset of puberty was lowering in age and adolescence was lasting longer as more young people took up tertiary education and delayed settling down with a life partner.

Adolescence is now considered to span the ages of 10 to 24 and comes with a range of different health risks to previous generations. Social media has entered the fray, bringing with it problems like cyber bullying and new risks around sexual health.

Adolescence

“We’re talking about the health of about 1.8 billion people – almost 30 per cent of the world’s population currently. It’s the biggest generation of adolescents there will ever be in human history.”

The two researchers have published several world-first studies. A paper George led on the effects of cannabis in adolescents showed early heavy marijuana use compromised young people’s education, employment, relationships and mental health. This work has shifted global debates around cannabis policy.

A recent study led by George has the potential to be equally influential. It found 85 per cent of women who experienced perinatal depression (during and after pregnancy) had a history of similar problems dating back to adolescence. This was based on data from 2000 Victorian adolescents recruited at age 14 and followed for 15 years. It’s a game-changing statistic, Susan says, as the risk was previously thought to be about 25 per cent.

But the game-changer is not just the statistic, says George. “Maternal perinatal depression is one of the clearest predictors of healthy emotional and intellectual development in children – we now know that to address both the mother’s mental health and the child’s future development we need to be intervening in adolescence.”

Their group is working on the particularly neglected, yet pivotal, period of late childhood and puberty. The Child to Adolescent Transitions Study (CATS) focuses on what is a transformative phase of life, says George.

“It’s a time in which the individual really develops a sense of who he or she is. In the evolutionary context it was a time of adaptation for imminent parenthood; in the modern context we still think it’s a sensitive period when physical and emotional changes have lifelong consequences for health,” he says. “It’s been neglected in nearly every study that has happened across the life course.

“It’s also the most important transition in the child’s educational life from primary to secondary school.

“Relationships with friends and teachers change profoundly and a child experiences very different school and peer cultures with the transition. Many

emotional problems begin at this age. Issues related to substance use and abuse commonly emerge. It’s a time when kids often get into trouble. We think it’s a critical transition in a child’s life.”

Meanwhile, much of Susan’s work has informed what quality health care means for adolescents and how to best deliver it. Her research around models of clinical care for young people and their families has changed the way medical services are delivered to this group at RCH and beyond.

One particular area Susan has focused on is anorexia nervosa, involving the RCH eating disorders clinic she established.

“Our group has identified a tremendous upswing in a condition known as atypical anorexia nervosa,” Susan says.

About one quarter of anorexia presentations to the clinic now fall into this category. Patients are not underweight at the time of presentation but have the same severity of mental health and eating disorders as other anorexia patients.

“Rising rates of obesity suggest we can expect many more eating disorders will develop in overweight children who are engaging in extreme behaviours to drop the kilos.”

George and Susan’s unique expertise has prompted The Lancet to commission the pair to lead a Commission on Adolescent Health and Wellbeing which promises to provide a blueprint for future investments to improve adolescent health around the globe.

“We’re talking about the health of about 1.8 billion people – almost 30 per cent of the world’s population currently,” says George. “It’s the biggest generation of adolescents there will ever be in human history.

“Improving their health and wellbeing will change all our futures and transform the lives of the next generation.”

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associate Professor

Yves D’Udekem & Harry After the operation, which redirects blood to the lungs by bypassing the heart, the patients have a ‘functional single ventricle’. This single heart chamber pumps blood with oxygen around the body, while blood – without oxygen – is pumped into the lungs directly via the veins.

While most of these children will live a relatively normal existence well into adulthood, the fear their hearts will suddenly stop is the dark cloud shadowing their lives.

The Registry is giving these patients hope. It has provided more accurate predictions of life expectancy and information to analyse the best medications and management strategies.

Using the large pool of patients, Yves is investigating whether warfarin or aspirin is a more effective bloodthinner. Fontan patients are placed on these drugs after the operation to reduce the risk of blood clots forming. Warfarin has many side effects; aspirin is more benign, so patients are keen for evidence backing the best medicine.

Drugs to lower blood pressure are also prescribed to patients because it is perceived that having a Fontan is akin to heart failure. Yves says there is no evidence for this and his research seeks to clarify the best treatments for patients.

An unexpected but welcome outcome of the registry has been the strong ties forged between Fontan patients, Yves adds.

Y

ves d’Udekem operates on the tiniest patients. Some babies are only a few days old when they have open heart surgery, the first of a number of operations they will undergo before having a procedure known as the Fontan bypass at four or five years of age.

The level of precision required is high so it’s unsurprising Yves considers “super-sophisticated technician” and “artisan” part of his job description.

The Belgian-born surgeon, researcher and selfconfessed adrenalin junkie who has lived in Australia since 2003 leads an internationally-renowned research project known as the Fontan Registry.

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Australia and New Zealand are now recognised as worldleaders in paediatric heart surgery, largely because of the research efforts of cardiac surgeon Yves d’Udekem.

The Registry, established in 2008, has about 1500 Australian and New Zealand patients on its database who underwent a Fontan operation in the first few years of life.

It is expected to double in size over the next 15 years.

“It is the largest database of its kind in the world,” says Yves. “Despite the fact we are a small population, we have a larger database than North America.”

The life-saving Fontan surgery is performed on children with abnormal hearts which cannot effectively pump blood to the body and lungs through two separate chambers.

An active Facebook page and a patient interest group has been established. The registry has given Fontan patients a voice and they are taking control of their condition and care.

“They come up with stuff we did not expect,” says Yves.

“They have health issues we had no idea about.”

No one knew that leg cramps and migraines were so prolific among Fontan patients. The symptoms weren’t described in any textbook or research study but it was a common complaint on the Facebook page and reiterated at regular educational days held for Fontan registry patients, as Yves discovered.

It made sense. Fontan patients have a low amount of blood circulating in their muscles and Murdoch Childrens researchers proved this was the cause behind the leg cramps. The high pressure of blood coursing through the veins – at a rate of 15 to 20 millimetres of mercury instead of the standard zero to five millimetres – might be behind the persistent migraines.

Using the Fontan Registry, Yves and his co-researchers are investigating the impact of these higher vein pressures on the liver and kidneys. The benefits of exercise for Fontan patients, the longevity of patients who may ultimately need a heart transplant and the risks surrounding pregnancy for women who have undergone the operation are also under the microscope.

Heart Surgery

Yves expects 70,000 to 100,000 people will ultimately benefit from the research underway at the Institute.

T

eena Collett knew there was something wrong with one of her identical twin boys at her 12 week ultrasound. At that stage it was too early to pinpoint exactly what the problem was. It wasn’t until 20 weeks the twin was diagnosed with a significant heart problem.

Teena and her husband were told the baby would need heart surgery immediately after birth and several more operations in the first years of life.

After a very stressful pregnancy with frequent monitoring and tests, on top of severe morning sickness, her twin boys Harry and James, were born at 35 weeks.

“The fact we are more in contact with patients means we can improve what they really need. It’s not only about giving them a life, it’s also about patient satisfaction and the pleasure of being alive.”

Outside the operating theatre and when he’s not buried in research, Yves likes to live on the edge – literally. Ice climbing was one of his favourite sports until he decided it didn’t go hand-in-hand with married life. Cave-diving was similarly abandoned when his five children came along and living dangerously was outweighed by the responsibility of parenting.

But it’s the same adrenalin he says drives him in the operating theatre. Whilst he feels more reassured about the job as he grows older, he can still be stricken by panic or fear but it’s a motivator rather than inhibitor.

His love of the outdoors, perhaps combined with the high-pressure environment of heart surgery, drives him to occasionally take some much-needed time out.

“From time to time I need to escape the city and go and build a camp fire in the wild. And the rest of the world stops.”

Recently, he’s taken up surfing and windsurfing. And he hasn’t given up on cave diving completely.

“I will go back into it,” he smiles. “I’m crazy about it.”

Harry was too small for immediate surgery but by six weeks his condition was dire and he was operated on urgently by surgeon and researcher Yves d’Udekem.

Yves has performed all of Harry’s three heart surgeries – the second when Harry was eight months old and the final Fontan operation to redirect the blood flow to bypass the heart was performed when he was five.

“Yves is literally a life-saver,” Teena says. “Without him and his colleagues I would not have my son.”

Harry is now a cheeky, bright, and active eight-year-old who adores his twin brother. The Fontan operation has given him a new lease on life.

“We could never have imagined he would walk around the block before the Fontan operation. But he can do that now,” says Teena.

He hasn’t just walked around the block – Harry has completed a 10km walk, enjoys gymnastics and swimming and has even tried his hand at golf.

He is one of 1500 Australian and New Zealand patients on the Fontan Registry established by Yves. The Registry has allowed Teena and her family to connect with other Fontan patients, stay in touch with surgeons and keep up to date with the latest research.

“The future and quality of life of Fontan patients rely heavily upon Yves’ research,” says Teena, who is keen to know the outcome of the research comparing warfarin to aspirin. Harry takes the blood-thinning medication warfarin, which requires regular pin-prick blood tests – something that would not be needed with aspirin.

“If they find aspirin is as safe and effective as warfarin, then that will make our life easier. We are all desperate to know the answer to that.”

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Acknowledgements We would like to thank the researchers in this book for their time and commitment. They are only a fraction of the talented scientists at Murdoch Childrens Research Institute who work tirelessly to give children around the world healthier lives – to these researchers and all those who have contributed over the years, we thank you.

Thank you to the wonderful families featured for allowing us to share their story, and all the kids and families who have been involved in our research in the last 30 years. You continue to inspire us each day.

Finally, thank you to the donors, supporters and volunteers who continue to support our research – we couldn’t do what we do without your help.

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Photographer Julian Kingma Writer and researcher Michelle Henderson Editors Anna Curran Caitlin Moore Inga Feitsma Simone Edgley Designer Paula Filippone

We kindly thank News Corp Australia for printing for this book. www.mcri.edu.au