Florey Institute Annual Report 2016 by Florey Institute

THE FLOREY ANNUAL

2016

When every minute counts The Florey's role in removing blood clots deep inside the brain. PAGE 19

Mind your metals New tools to help our brains maintain just the right level of copper, zinc and iron. PAGE 4

The cost of binge drinking Could the damage done by long-term alcohol abuse be reversed? PAGE 14

THE FLOREY INSTITUTE OF NEUROSCIENCE AND MENTAL HEALTH Parkville campus 30 Royal Parade Parkville VIC 3052 Australia T +61 3 9035 3000 ABN: 92 124 762 027 Howard Florey laboratories Gate 11, Royal Parade Parkville VIC 3052 Australia Austin campus 245 Burgundy Street Heidelberg VIC 3084 Australia T +61 3 9035 7000

Welcome to the Florey Annual.

Find us online Florey.edu.au Facebook.com/TheFlorey

Report from the Chairman of the Board, Mr Harold Mitchell AC, and the Scientific Director, Professor Geoffrey Donnan AO

From the Chairman

elcome to this, the Florey’s latest Annual. While the science that happens at this extraordinary institute is at the cutting edge of global neuroscience, so is our reporting to our supporters. This journal aims to inspire and surprise with highlights from the last 12 months. As the Chairman, I am constantly amazed by the breadth of research happening at the Florey. More than 600 people work together to delve into the mysteries of the brain. And progress is being made in our efforts to reveal the secrets of the most complex supercomputer on the planet. The Florey Board has excelled and I thank each member for the service they have provided in time, wisdom and expertise. We are on-track to meet our ambitious goals, ensuring the Florey’s robust independence. At the same time, we welcome the opportunity to collaborate with clinical and academic partners. This year we have invested, with the University of Melbourne, to retain several of our world-class researchers. We are determined to ensure great Australian medical researchers are offered a secure future while leading the way from the Florey laboratories. As we move into our 54th year, the Board is undertaking a major fundraising campaign which aims to further strengthen the Florey’s future into the next century. I will be contributing to our campaign and I invite you to join me.

Twitter.com/TheFlorey Instagram: TheFlorey

Diseases of the brain and mind are so common – one in four of us will be directly affected – and for this reason, I can think of no better organisation to support. I spend a lot of time talking to a wide range of people, and one recurring theme is the struggle so many of us face as age-related illnesses impact on individuals and their families. Alzheimer’s disease is particularly common and the cause of so much sadness.

TO DONATE Phone: 1800 063 693 Online: florey.edu.au Post: The Florey Reply Paid 83037 30 Royal Parade, Parkville VIC 3052

Having lost my dearly-loved Dad recently to a stroke, I feel more committed than ever to the task at hand. Thank you for your interest in the work of the Florey and thank you to our researchers who are committed to finding answers to the greatest medical challenge of our time – understanding the brain.

Acknowledgments Editor: Amanda Place Text: Amanda Place, Tom Keeble, Anne Crawford, Nick Place and Brigid O’Connell Design: Blueboat Photography: Chris Hopkins, Mark Chew and Peter Casamento

Our clinical year started with the release of new stroke trial results from the co-head of our stroke division, Professor Vincent Thijs. Vincent’s trial group released new data from the CRYSTAL AF trial which provided two predictors for atrial fibrillation (irregular pulse) in people with stroke. Atrial fibrillation is a major risk factor for stroke, and subsequent strokes, after a transient ischemic attack (TIA/minor stroke). Professor Anthony Hannan continued his laboratory’s very interesting pre-clinical work examining how a father’s environment can affect the behaviour of his offspring, focusing on stress and enrichment. This work will have political and social consequences well beyond the laboratory. Dr Gawain McColl contributed to some exciting work showing that amyloid beta, known to be involved in Alzheimer’s disease, also possesses anti-microbial properties. It may turn out that amyloid production is the brain’s attempt to fight off either a real or perceived infection, opening up new treatment pathways to explore. Returning to the clinic, Professor Graeme Jackson continued his successful work using advanced imaging to diagnose, find and guide the removal of tiny brain lesions causing focal epileptic seizures in young children and teenagers. Also highlighting the real-world potential of our basic research, Dr Tom Oxley’s ‘stentrode’ breakthrough, published early in the year, has continued to attract major support in the hope of helping quadriplegics to walk. Having finished its first round of funding in the US, it has attracted $US10 million to underwrite human trials scheduled to begin next year.

The Florey’s division heads: Professor Seong-Seng Tan, Professor Julie Bernhardt, Professor Robin McAllen, Professor Ross Bathgate, Professor Allan Connelly, Professor Steven Petrou, Professor Geoffrey Donnan, Professor Richard Kanaan, Professor Andrew Lawrence, Associate Professor Amy Brodtmann, Professor Graeme Jackson and Professor Vincent Thijs. Absent: Professor Brian Dean, Professor Colin Masters, Professor Trevor Kilpatrick and Professor Phil Beart.

We were very happy to welcome Florey friend and CEO of the National Health and Medical Research Council, Professor Anne Kelso AO, when she delivered our Women in Science oration recently. L-R: Professor Geoffrey Donnan AO, Professor Anne Kelso AO, Mr Harold Mitchell AC.

For copies of this report and comments, please email amanda.place@florey.edu.au

As I walk the corridors of each of our buildings, I regularly witness the sparks of ingenuity as our scientists work together in the lab and in the clinical setting. The extremely high quality of their science is measured both by publication rates and by the numbers of fellow scientists referencing our work.

Finally, I would like to thank the Chairman and the Florey Board for their support and enormous interest in the scientific endeavour of the Institute. This group of dedicated supporters performs a vital function, ensuring the Florey’s researchers have a stable and dynamic workplace.

Published May 2017 Highlights of the Florey’s laboratory and clinical research can be found by visiting our website at florey.edu.au

am a great optimist and firmly believe that if we provide a rich and fertile environment, great science will flourish and lives of people living with brain diseases will improve. While we are studying some of the most intractable diseases facing medicine today, I am immensely proud of the researchers at the Florey who are chipping away, determinedly contributing to international understanding of the brain. Their work will have profound societal and economic benefits for people around the world.

2016 | The Florey Annual

Proof reading: Margit Simondson and Colleen Buchhorn

From the Director

Florey in a flash

Diabetes insulin breakthrough

Meet Dr Natalia Egorova

hether kids are in Durban or Dubbo, they could soon have access to a much cheaper and longer-lasting form of insulin to manage their juvenile diabetes.

Psychiatrist Amit Lotan has joined Professor Ashley Bush’s laboratory in a quest to improve treatments for people living with psychiatric disorders.

Beyond the bedside

r Amit Lotan is working with Florey researchers while on a two-year sabbatical from Jerusalem, Israel. Under the guidance of Professor Ashley Bush, Amit wants to develop improved drugs for patients living with psychiatric illnesses. As a psychiatrist, Dr Amit Lotan has long been frustrated by the slow evolution of medications for brain disorders. While drugs treating cancers and other major illnesses have progressed dramatically in recent years, drugs for psychiatric conditions haven’t shifted in design for decades.

same mechanism of action as their ancestors which were discovered in the 1950s and ‘60s. Many patients still are very symptomatic, despite the best medical treatment.” Amit travelled from Israel to join the Florey’s Oxidation Biology Unit, led by Professor Ashley Bush, who is a world-leader in the exploration of a potential link between Alzheimer’s disease and metals in the brain (See story page 4). Amit plans to continue collaborating with the Florey after returning to Israel, while also drawing on Israeli expertise at HadassahHebrew University.

“Basically the drugs that we use to treat depression, anxiety and psychosis rely on the

This new type of “thermos-stable” insulin doesn't require an expensive, carefully managed cold-storage chain. The Florey's Dr Akhter Hossain and Dr John Karas developed the new insulin as a by-product of their world-leading research into relaxin. Relaxin has a similar molecular structure to Insulin so while trying to create a stable, active and safe form of the relaxin peptide, Akhter was also able to produce a super-stable form of the insulin peptide. Insulin rapidly degrades if it is left at room temperature which poses immense storage and handling problems for hot and poorer regions. Thermostable Human Insulin

A20-B19 Cystine

A7-B7 Cystine

A6-B11 Cystathionine

She is on a quest. Natalia is trying to determine if the brain’s wider networks go into cognitive decline after a stroke, separate to the localised damage caused when the stroke occurs.

“We tend to think of a stroke as a lesion somewhere in the brain that disrupts your ability to function in a particular way,” she says. “But we also suspect that people experience general degeneration and cognitive decline associated with the stroke.”

Director Professor Geoff Donnan, Carl Dowd, Assoc Prof Chris Reid, Lisa, Wendy and Jason Dowd celebrate at the Florey.

Research Fellowship – a $300,000 fellowship funded by Carl and Wendy Dowd, designed to support extraordinarily talented researchers. We thank Wendy and Carl for their ongoing support of the Florey.

“We are looking at the brains of the stroke patients to see if they eventually develop cognitive decline or dementia,” she says. A major thrust of Natalia’s research is to determine whether depression may be caused by the disruption of a stroke or through general decline of brain networks.

“We’ve found depression in about 30 per cent of stroke patients,” she says. “We’ll need the data at three years or five years to find out if patients get dementia.” “While the motor cortex is directly related to motor function, higher cognitive tasks such as long term memory, attention or decisionmaking are spread around the brain,” she says. “The depression we are talking about is only mild but if we look at our data, already we can see differences in the brain between stroke patients who are mildly depressed and those who are not. There is something physically and biologically present in the brain that drives these depressions or is associated in this decline.”

Fast Facts:

Dr Natalia Egorova, PhD —— Loves languages. She has worked as an interpreter in Russian, English and French, but also speaks German and some Dutch. —— Natalia loves travel, running and cycling. —— Married an Australian, Dr Douglas Brumley, who is a lecturer in mathematics at the University of Melbourne. They met at Cambridge University. —— Her hometown (Komsomolsk-onAmur) is known for manufacturing Russian fighter jets. —— She and her husband make their own cheese, and are particularly proud of their home-made Stilton and a Parmesan that took 12 months to mature. —— She’s heading to Vancouver in late June to a symposium discussing ideas relating to the neuro-degenerative impact of strokes.

to successfully treat patients presenting with similar symptoms but that have distinct genetic causes. Chris is also developing exciting ideas about how to directly target the mechanisms caused by various genetic lesions. Chris’ work has been supported by the Dowd Foundation

Natalia is a member of Associate Professor Amy Brodtmann’s team. They are working on an ambitious longitudinal research program, scanning the brains of stroke patients at defined intervals for the next five years. So far the data is in for one year, post stroke.

“A major thrust of Natalia’s research is to determine whether depression may be caused by the disruption of a stroke or through general decline of brain networks.”

2016 | The Florey Annual

The Florey Annual | 2016

pilepsy is a devastating disease with up to 30 per cent of patients not adequately treated by current anti-epileptic drugs. Historically, epilepsy therapies were based only on the broad syndrome suffered by a patient. However, a rapid rise in our knowledge of the genetics underlying epilepsy syndromes gives hope that we can deliver precision medicine tailored to the needs of each patient.

ow happily ensconced at the Florey’s Heidelberg campus, Natalia is buried in a mountain of rich data, gathered from 175 stroke patients and healthy volunteers.

One syndrome, many causes

Associate Professor Chris Reid wants to answer the question, “Do we treat the syndrome or should we treat the mutation?” Dravet is a devastating epileptic syndrome resulting in childhood cognitive and developmental delays. Chris uses two models of Dravet syndrome caused by mutations in two different genes, SCN1A and SCN2B. His two genetic models of these mutations suggest very distinct cellular mechanisms underlie brain cell excitability causing epileptic seizures. This implies that different therapeutic strategies may be required

Dr Natalia Egorova has travelled a long way to reach the Florey’s Austin campus. Hailing from the Russian town of Komsomolsk-on-Amur (in the far east of Russia, just above Japan), Natalia has come to us via Cambridge in the UK, from the USA and Switzerland.

Mind your metals

The Florey is developing and testing new tools to help our brains maintain just the right levels of three key metals: copper, zinc and iron. The aim: to ensure health and to delay or prevent several diseases associated with ageing.

iometals – copper, iron and zinc – are crucial to ensure our brains operate smoothly. They make sure brain cells talk to one another, produce the energy they require to function properly, remove toxic freeradical waste products and, of course, deliver the oxygen they need to survive. Up to half of all proteins in our bodies interact with biometals to keep our bodies healthy. In a Goldilocks dilemma, too much metal can be harmful, but too little can also mean our brains don’t function properly. Normal learning and our capacity to remember critically depend on these metals existing within the ‘healthy’ range. If metal levels stray outside this range the brain can’t function properly, and it may eventually lead to neurodegenerative diseases like Alzheimer’s, motor neurone or Parkinson’s disease. Our research aims to protect brain health by understanding how metals are involved in neurodegeneration. Zinc: Associate Professor Paul Adlard wants to understand what zinc is doing at the brain’s synapses – the tiny gaps between brain cells across which information is passed from cell to cell.

The Florey Annual | 2016 4

Copper: Although discovered decades ago, a particular class of compounds that deliver copper are now showing great promise in treating neurological diseases. Associate Professor Kevin Barnham works closely with Dr Blaine Roberts, using a molecule called Cu(ATSM) that delivers copper to the motor neurones in the brain and spinal cord, to protect those that would die off in MND. Although the exact cellular mechanisms behind the rapid and devastating death of motor neurones is still unknown, one of the major players is a copper-dependent protein called superoxide dismutase-1 (SOD1). The protein defends against neuronal death by converting damaging free radicals into inert molecules. Mutated versions of the protein inefficiently bind copper, meaning it performs its job poorly, thereby leaving cells vulnerable to free radicals. It may even cause SOD1 to do the reverse, producing excessive free radicals instead of clearing them away. Giving Cu(ATSM), obtained from Associate Professors Anthony White and Paul Donnelly at The University of Melbourne, to an MND mouse model extended the lifespan of the mice by an impressive 25 per cent, while delaying the onset of their movement symptoms.

—— In Australia, approximately 15% of the population is aged 65 and older. This figure is estimated to grow to 21% of the population (8.4 million) by 2050, with global numbers in excess of 1.5 billion. —— 28% of Australians aged over 85 years require assistance with cognitive tasks. —— In the USA, more than 16 million people live with a cognitive impairment.

In collaboration with long-time friend and mentor Professor Jeff Beckman from Oregon State University, Blaine extended this work by giving copper to a mouse model of MND that, along with the mutated human SOD protein, also expressed a protein known as human Copper Chaperone (CCS). It helped the copperdependent protein to properly function by inserting copper, and when this extra copper was delivered using Cu(ATSM), the model mice lived a staggering 18 months (500 per cent) longer than non-treated mice. The results of these experiments were so successful that the new molecule has been fasttracked into MND clinical trials, which have already started in Sydney, and will soon begin in Melbourne.

Dr Dominic Hare, Dr Blaine Roberts and Associate Professor Paul Adlard are trying to understand the role of metals in the brain.

Paul hoped that restoring zinc levels in the hippocampus would result in improved memory in normal aged mice. He used a compound called PBT2, provided by commercial partners Prana Biotechnology, and showed that the aged brain remains capable of performing at a level seen in much younger mice.

Paul’s zinc therapy may also have beneficial effects in seemingly unrelated conditions, like acrodermatitis enteropathica, a congenital disease that results from the body’s inability to absorb zinc. The harmful neurological implications are clear, and Paul’s research offers a glimmer of hope for the families affected by this rare but devastating disease.

Age is the biggest risk factor for cognitive decline.

2016 | The Florey Annual

Synaptic zinc is critical for normal learning and memory. Paul’s group had established that low zinc levels in the hippocampus, a key brain region required for learning and memory, result in a decline in cognitive function regardless of whether it’s normal ageing, or due to the onset of Alzheimer’s.

Paul’s project has been highlighted by the National Health and Medical Research Council as one of its “Top Ten” in Australia, showcasing the high quality and innovative nature of this work.

Mind your metals Iron: What do a baby’s teeth have to do with diagnosing Parkinson’s disease in a 60-year old grandmother? Biometal chemist Dr Dominic Hare plans to find out.

Identifying those at risk: Dominic Hare believes that all life, and all our brain activity, is a chemical reaction. Therefore, it stands to reason that all disease is a chemical reaction – gone wrong.

Around 1300 Australians are diagnosed with Parkinson’s every year, and almost 15 per cent of those are aged under 50. Parkinson’s disease kills the cells in the brain that produce dopamine. A major problem with current approaches to treating the disease is that within a year of someone being diagnosed, more than half of the brain’s dopamine producing cells have died, so therapies given after formal diagnosis are likely to be too late.

Many of the reactions happening in our brains right now depend on the right mix of copper, iron and zinc, and it is important to remember that these reactions do not occur in isolation. Iron-dependent proteins like ferritin, for example, rely on a copper-dependent enzyme to deliver the iron. Disruptions in one or the other could be the underlying cause of several neurodegenerative diseases.

Dominic believes that iron fortification of staple foods like cereals, flour and infant formula, may be responsible for this dramatic rise in iron levels in high-income countries. Iron fortification is a huge public health success story, but with sufficient dietary iron now available we may actually be getting too much of a good thing.

Copper and zinc work together to function properly – meaning that Paul Adlard’s work with zinc therapeutics could have a major impact on motor neurone disease. Paul says: “Teasing out these interactions between metal-dependent proteins is really going to be a major job in the coming decades. By working out these relationships we will be able to develop and deliver therapeutic agents that target the underlying cause, not just treat a by-product of some aspect of the disease we’re working on.”

As Dominic says, “The brain especially isn't very good at getting rid of excess iron. If the brain is given a head start with too much iron and its 'warehouse' is spilling over as it gets older, there may be a risk that the excess iron will interact with dopamine and end up damaging brain cells.“

Professor Ashley Bush, head of the Oxidation Biology unit, says: “We have been working hard over the last couple of years to bring together a multidisciplinary team with a vast array of experience in areas like metal chemistry, advanced mass spectrometry, animal behaviour, the Australian synchrotron, PET and MRI imaging and, of course, patient trials.”

To test this idea, Dominic plans to examine whether ‘growth lines’ of iron deposits in teeth, much like a tree’s growth rings, correlate with dietary iron intake, mapping the source and timing of infant nutrition. Adult teeth begin to calcify at birth, finishing by about age 10. This means they contain a record of dietary iron exposure, which people will carry right into their mid- and old age. These teeth will act as our own ‘iron passport’, documenting the iron environment that a person has been exposed to throughout his or her life.

“I foresee major advances being made in predicting who will come down with Alzheimer’s or Parkinson’s many years before symptoms emerge. We will identify those who need treatment to stave-off these diseases. We are developing technologies, especially MRI, to measure these metals in the brain. At the same time, treatments that correct these metals are being tested, and could complement diagnosis.”

Using teeth, in conjunction with iron imaging in Parkinson’s patients’ brains, Dominic is seeking a connection between iron exposure and the risk of developing Parkinson’s disease. “We need a way to identify those at risk of the disease before it happens. A test that can detect early exposure to excessive iron may be a way of doing that.” Finally, the group will recruit a cohort of middle-aged people deemed to have varying risk levels for developing Parkinson’s disease, then follow them for a number of years while administering an experimental drug called deferiprone, an iron binder which ‘mops up’ excess brain iron. Deferiprone is currently being trialled for Parkinson’s in an end-stage study by a French team. Dominic hopes that by identifying at-risk people early in life, they can be given the drug in time to prevent the neuronal death, and subsequently, the onset of Parkinson’s disease.

Iron build up in neurodegenerative diseases can be visualized in the living brain using advanced magnetic resonance imaging techniques. This image shows high iron concentrations especially in areas deep within the brain. Credit: Dr Jon Cleary, Dr Scott Kolbe, Camille Shanahan, Prof Trevor Kilpatrick, Prof Roger Ordidge.

World Health Organisation data collection begins

In 2001, while Jess was working on her PhD, she read a scientific paper published a few years previously in the journal Nature. It was to define her whole research career. She remembers the excitement as she read about the work of Professor Seth Grant, a leader in the field of synaptic genes and brain function. Synapses are the junctions between neurones where sensory information from the environment is ultimately processed. Disruptions to synapse-regulating genes are linked to more than 130 brain diseases. Seth had worked with Nobel Laureate Dr Eric Kandel in the US, pioneering mouse models with gene mutations. They wanted to understand the impact of genes on learning and memory. He had generated the first mouse model lacking the same synaptic protein that Jess was investigating for her PhD.

She went on to conduct postdoctoral work at the Florey Institute, investigating how gene-environment interactions affected synaptic plasticity (the ability of synapses to change). Soon the call came and she was recruited as a postdoctoral fellow by Seth in 2008 to work at the Wellcome Trust Sanger Institute in Cambridge.

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At this time, Seth had developed more than 100 lines of geneticallyengineered mice with synaptic mutations relevant to various disorders. His team was looking at the way these mutations impacted brain function at the molecular signalling level.

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Dr Dominic Hare has charted the rise of deaths from Parkinson’s disease around the world. Increasing Parkinson’s deaths are most marked in the UK and USA approximately 50–65 years after the introduction of mandatory iron supplementation of grains and milled flour (1980–1995). Japan, with no policy on iron fortification, shows relatively stable mortality rates.

But he wasn’t doing much research on behaviour so Jess stepped in, asking, “How do these mutations impact on complex behaviour and cognition?” Jess forged a collaboration with Professors Tim Bussey and Lisa Saksida at Cambridge University. They were developing a novel behavioural tool – the rodent touchscreen cognitive tests. These touchscreen tests, based on the tests that are routinely used in the clinic with humans, allowed scientists to look more comprehensively at cognitive profiles in mice and rats. Using this technology, the team made some novel insights into the evolution of cognition in a leading paper published in 2013 in the prestigious journal Nature Neuroscience.

“How do these mutations impact on complex behaviour and cognition?” Extending this work, Jess was first author in another paper published in 2015 that showed – for the first time – that identical touchscreen-based cognitive tests could be used in both mice and humans carrying diseaserelated genetic mutations to assess complex learning and problem-solving. This created an important tool and approach to improve the way scientists measure and model cognitive dysfunction in human disorders in animals, and offered a potential way of standardising results between labs around the world. Moreover, it meant that new psychiatric drugs could be tested and validated in mice in the hope they would then also have the same positive effects on cognitive problems in humans – currently a big obstacle for developing effective therapies. In 2014, after a stint at the University of Edinburgh, Jess returned to Melbourne and the Florey to head the Synapse Biology and Cognition laboratory on a coveted Australian Research Council Future Fellowship. Her lab continues to seek the genetic basis of brain disorders, expanding the number of disorders it investigates and creating new tests to tap into complex cognitive processes. The Florey is now the largest site in Australia using the touchscreen technology. Jess has created clinical collaborations in Edinburgh, Netherlands, Adelaide and Melbourne, studying patients with genetic mutations in synaptic genes that increase the risk of psychiatric diseases such as schizophrenia, autism and depression, using genetically engineered mice with the same mutations. She is on the brink of the next phase of this research, and her career, working with the Drug Discovery Biology group at Monash University testing drug compounds for schizophrenia. Now a mother of two-year-old Charlotte, Jess is still fascinated by the play of genes on personality. “She’s my biggest project!”

hen Jess Nithianantharajah was 10 she looked at her siblings and wondered how they could share the same parents yet be so different. Today, Jess’s curiosity about behaviour, environmental influences and genes, and her pioneering work with mice and touchscreens, has taken her to the forefront of behavioural neuroscience and the search for improved medications for psychiatric illnesses.

Jess knew she had to meet Seth. She flew to the UK, exchanged ideas and flagged the idea that they might work together in the future.

Dr Jess Nithianantharajah has always been fascinated by the role of genes.

2016 | The Florey Annual

The Florey Annual | 2016

Age adjusted PD mortality

Tapping into the future

About the Florey

Citations 3854

61,212

622

15.88

Scientific publications published in the 10 years 2006-2016

Cumulative citations 2006-2016

Publications from the Florey in 2016

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All staff and students

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Our team

Our visitors The Florey hosts regular events at our laboratories or out in the field, involving school children and members of the general public. Our researchers and medical specialists share their knowledge of the brain in a variety of ways.

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Our funding

— Credit: Dr Ben Rollo, Epilepsy division.

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This is an image of neurones grown from stem cells taken from children with epilepsy. We are growing these neurones to understand how changes in normal cellular mechanisms can lead to this severe form of epilepsy. Importantly, by growing these neurones in a dish we are able to treat them with next-generation drugs without exposing the children to any potential risks or adverse effects. In this image the cytoskeletal structures of neurones are shown by staining with fluorescent probes. Here green fluorescence represents dendritic structures and red, axons.

2016 | The Florey Annual

The Florey Annual | 2016

The Florey’s income can be broken down into the following:

In the spotlight

Heading-off sepsis in intensive care In a world first, researchers may have found a way to predict a life-threatening condition found in thousands of patients being treated in intensive care units.

r Yugeesh Lankadeva, mentored by senior research leader, Professor Clive May, has developed a technique to provide doctors with an early warning that septic shock (sepsis) is beginning to damage a patient’s kidneys, while there is still time to act. In intensive care units around the world, bacterial infections causing sepsis are the leading cause of death. In Australia each year, an estimated 10,500 people will suffer acute kidney failure because of sepsis or complications during cardiac surgery, and roughly 3000 of those patients will die.

For many years, the Florey has been examining how the brain controls body organs, and it was in this context that Yugeesh began exploring sepsis.

The technique has worked with patients undergoing heart surgery - another patient group at high risk of developing kidney failure. Simultaneously, a pair of successful observational trials at Austin Health validated Yugeesh's initial results in sheep. Florey colleague and Director of Intensive Care at Austin Health, Professor Rinaldo Bellomo, is collaborating. The ramifications of the discovery promise to be enormous, both in terms of lives saved, but also in economic savings for the health care system. “The cost to the health system of dealing with acute kidney failure at the moment is about $400 million,” Yugeesh says.

Sepsis can affect anyone and can be acquired both within our community (70 per cent of cases) and from hospitals and health care facilities (30 per cent). “It is more common among people with weakened immune systems, such as newborn infants and the elderly. “It is also a risk for patients with pre-existing health complications, such as cancer, diabetes, AIDS and kidney or liver disease, who don’t have the ability to fight off these infections.” His work is attracting considerable attention, with politicians from both sides of politics meeting Yugeesh when he visited Canberra recently for an annual “Science meets Parliament” event.

Spends a lot of time as a resident tutor at Janet Clarke Hall at the University of Melbourne, helping first, second and third year students.

Plans to build skills especially in computerised and mathematical research. He has witnessed brilliant thinking when clinicians cross into brain research so wants to be involved.

Started “PhiloSOFI”, a Facebook page for fellow Florey scientists interested in philosophy and neuroscience.

Recently went to MONA and was captivated by the evolutionary origins of art. Why did art happen? What desire motivated early artistic expression? Was it a sexual selection tactic? Do human brains just like patterns and decorations?

“I’d be quite happy if my work ends up helping people or being useful,” Ariel says, “But I just really want to understand how the brain and the mind function.”

When a day isn’t long enough Student, Ariel ZeleznikowJohnston, 24, is undertaking a PhD with Dr Emma Burrows and Professor Anthony Hannan. He’s examining whether brain stimulation helps to prevent or delay neural degeneration.

Has been trying to play the piano for a while. He likes the side effects of music on other parts of the brain.

His work with mouse modelling means he sits in a small room performing the same tasks over and over. He sometimes wonders if he’s secretly part of a larger experiment to see if a lack of environmental enrichment affects a PhD student.

Recently had his first paper published, on the environmental enrichment of rodents with touch screens – the Florey’s first such publication.

Until now, sepsis has been almost impossible to diagnose until it is too late. Doctors could previously only detect severe oxygen loss in the kidneys, leading to irreparable damage, once the acute low blood pressure had become life threatening. By then, patients would be unresponsive to traditional therapy with vasopressors, leading to severe uncontrolled hypotension, reduced organ perfusion, organ failure and death.

Importantly, he adds, techniques have been developed so a catheter can be directed to the bladder. “We’ve added methodology to the new technology.”

All of this has occurred at a time when sepsis is an increasing threat. Yugeesh, a National Heart Foundation fellow, says the incidence of sepsis is rising as our population ages and the number of drug resistant infections increases.

Ariel is from Melbourne but loves travel – so he’s chosen the right career. He spent six months as an exchange student in Montreal where he mastered skiing. He went to Bordeaux for an immersive science workshop last year and revelled in the experience.

2016 | The Florey Annual

The Florey Annual | 2016

Yugeesh says that even those who survive are at long-term risk because their kidneys can be so damaged by the trauma. Secondary kidney failure deaths, long-term dialysis and kidney transplants add to the health and economic impact.

Yugeesh has been able to show that while sepsis is developing, extra blood is sent towards the kidney, but less of this blood makes it to the kidney’s inner zone. As that part of the organ becomes deprived of oxygen, cells stop functioning normally, causing the kidneys to fail. Because urine is produced in the kidneys, Yugeesh suspected that oxygen levels in the kidneys would be the same as those in urine. By testing the urine oxygen levels, imminent kidney damage can be detected and treatment begun more quickly.

Reads fiction and non-fiction. He recently finished an Ian McEwan novel but is also reading a history of Africa. Goal: to eventually read histories of every region around the globe.

An extensive network of neurones lines the gut. This neural tissue is filled with important neurotransmitters, allowing the gut to do a lot more than simply digest food or cause nervous butterflies. The ‘second brain’ in our belly connects to the big one in our skull, helping to determine our mental state, while also contributing to certain diseases.

A NEW PERSPECTIVE:

nflammatory Bowel Disease (IBD) is a chronic and debilitating disorder that can lead to potentially life-threatening complications. Florey Institute researchers are helping to develop a bionic device that could potentially treat IBD and bring relief to more than 75,000 Australians. As they do, they’re pushing at the frontiers of the burgeoning field of “electroceuticals”, the use of bio-electronic implants to stimulate nerves in the body, in this case in the gut. The US Defense Department is funding the team with a $6 million grant.

Currently IBD, which includes Crohn’s disease and ulcerative colitis, is treated with a range of drugs and is moderated by dietary approaches. However, the medications have side-effects and tend to fail over time. Eventually many patients have to undergo surgery but even after surgery, disease, and notably Crohn’s, can recur. A multi-skilled team of five was formed for the project: Florey neurophysiologist Professor Robin McAllen; Director of Biomedical Engineering at University of Melbourne Professor David Grayden; surgeon and Professor of Surgery at the Austin Hospital Professor Bob Jones; and Professors Furness and Shepherd. John is an expert in the field of digestive physiology and nutrition, and is often invited to address conferences here and overseas on these topics. The team successfully bid for funding from the Defense Advanced Research Projects Agency (DARPA) in the US as part of a call for research into electric stimulation to treat disease by modulating the activity of peripheral nerves. The “blue sky” proposal was the only project out of the seven funded by DARPA that was outside the US.

The bionic device is implanted under the skin with a lead to electrodes wrapped around the 2mm wide branches of the vagus nerve in the abdomen. The vagus nerve runs from the brainstem, branching out to many different organs, including the gut. A controller the size of a smart phone outside the body transmits signals to the device. Researchers elsewhere had previously tried stimulating the vagus nerve in the neck to try to manage the inflammation caused by IBD but had encountered side-effects in the heart and larynx. The Florey team decided to use a novel approach to avoid these complications by stimulating the nerve in the abdomen instead. Pre-clinical trials are underway and clinical trials are due to start in 2019. “This is a possible solution to a problem that remains unsolved by drug treatment. Finding another approach to it could be extremely important for IBD. “Crohn’s and ulcerative colitis are terrible conditions because they cause the bowel lining to erode. It may bleed or perforate and the tissue disruption can lead to cancer.” In Crohn’s disease the lining of the digestive system or gut is inflamed. Ulcerative colitis usually occurs in the rectum, lower part of the colon and sometimes the entire large intestine or colon. Similar devices could potentially be used to treat other diseases such as arthritis and respiratory illnesses.

Electrode and implant positioning The implant (receiver) is placed where a cardiac pacemaker is normally positioned. In this illustration, the electrode is on the left vagus. Image courtesy: Bionics Institute.

The project has had an important spin-off. The team has invented a device that measures the effects of inflammation in the colon in real time – a potentially valuable innovation to the field. Currently, inflammatory bowel diseases are difficult to track as they flare up, repair, relapse and go into remission then flare up again. “It’s hard to get a good idea of where you are in the disease process, which is pretty important to treatment and adjusting treatment. “If we can monitor the inflammation successfully we can modify the therapy. Usually you can’t do that, you use indirect ways of understanding the intensity of the disease, such as how the patient is feeling or you have to take invasive measures like biopsies to access what’s going on.” The process will be fully automated, reducing the need for frequent consultations with the clinicians. “This invention is a good diagnostic and monitoring tool. I think it’s going to be pretty important for gastroenterology.” The device, patented last year, has been tested in rats and sheep. It is currently being refined for use in people. The success of this project emphasises the value of multidisciplinary research to produce significant outcomes, according to Professor Rob Shepherd. “In this case clinicians, biomedical scientists and engineers are working in close collaboration to develop new therapies,” Rob says.

Professor John Furness and his collaborators are close to clinical trials of a new device to tackle inflammatory bowel diseases.

“I was fascinated by the challenge,” John says. “Could we develop a way of stimulating nerves to deal with IBD?”

“Treating the stress is helpful but it doesn’t always work,” John says. “Once the disease is established, you’ve got abnormal tissue so removing the stress doesn’t get rid of the disease – you need to find another way,” he says.

2016 | The Florey Annual

The Florey Annual | 2016

Calming the gut

Professor John Furness, the lead researcher on the project, recalls the excitement he shared when the Director of the Bionics Institute, Professor Robert Shepherd, came to him with the idea for the project.

DARPA was interested in the technology’s potential to help the many combat veterans affected by IBD – US veterans have twice the frequency of IBD as the general population, possibly as a side-effect of post traumatic disorder.

The cost of binge drinking

Dr Christina Perry is seeking to repair the brains of heavy drinkers.

Attacking anxiety Dr Despina Ganella asks why “a child is so vulnerable to anxiety peaks and so resistant to ...therapy”.

Could the damage done by long-term alcohol abuse be reversed? The latest work by Christina Perry offers promising results for those wanting to break the cycle of addiction.

r Christina Perry paid her way through university by working behind the bar at a Sydney pub. Night after night, she would see locals come in and drink large quantities of beer and spirits. Over the next decade, years after she had finished working at the pub but still lived nearby, she saw the rapid ageing and deterioration of young men who were now hardened drinkers.

“But long-term binge drinking also causes cognitive decline by affecting the parts of the brain in charge of rational thought and reasoning. Problem drinkers find it hard to abstain because they can’t think their way past a reflexive desire to drink.” Simply walking past a hotel or seeing a beer label can be enough to trigger a problem drinker to break a period of abstinence. Significantly, the passing of time may actually weaken the drinker’s resolve as cravings become more intense. So a question remains – how can our research help alcoholics overcome these triggers? Christina’s research is now exploring whether neurological recovery is possible in the hippocampus and the pre-frontal cortex, once alcohol has done long-term damage.

Working with the rats, Christina is hoping to help people by investigating the effectiveness of exercise, combined with abstinence from alcohol, behavioural therapy and anti-craving drugs. This approach may help a person overcome their addiction and hasten the physical repair required to undo the cognitive damage. “Exercise can lead to neuronal growth and also increase plasticity, which is the ability to learn new things and make new connections. Also in animals and humans, we know that exercise overcomes anhedonia – the inability to feel pleasure – associated with withdrawals. It also helps to deal with some of the mood effects associated with withdrawal and rehabilitation,” she says.

ost parents work out pretty quickly that their teenagers’ brains work very differently to their own. Adolescents are resistant to our wise advice and often seem to have a unique sense of logic.

While the inner life of a teen can be a mystery, researchers at the Florey are trying to work out the role of anxiety – a significant issue with 25 per cent of adolescents struggling with the problem. While we all experience anxiety, and sometimes it is an appropriate survival mechanism, new Florey research suggests adolescents are physically unable to turn off the emotion, or to work through it as an adult may. It all comes down to something called ‘fear extinction’, according to Dr Despina Ganella, a post-doctoral fellow in Dr Jee Hyun Kim’s Developmental Psychobiology laboratory. Fear extinction is a term used to describe the experience of learning that a previously fearful experience is not actually harmful. Repeated exposure helps the brain to match the potentially fearful stimuli with the fact that nothing bad has actually happened or is likely to happen again. In other words, we relax around the issue that once scared us because we realise the original perceived threat no longer exists. Despina says that adolescents do not learn these new associations as well as adults. While exposure therapy remains the most effective treatment for debilitating anxiety – whether it’s being afraid of public speaking, walking into a party or entering a dark room – it is much less effective for adolescent brains. “We are asking: ‘What’s different in an adolescent brain that makes a child so vulnerable to anxiety peaks and also so resistant to exposure therapy?’. “We’ve found that healthy adult and adolescent brains have differences in their activation patterns in brain regions that are important for effective fear extinction.”

“We’ve found that healthy adult and adolescent brains have differences in their activation patterns in brain regions that are important for effective fear extinction.” From the age of 13, adolescents are going through a dynamic period of brain development with fundamental synaptic and structural changes occurring in the ventromedial prefrontal cortex. Despina has found that the prefrontal cortex is unable to calm down, or inhibit, the brain’s fear centre. “Fear memories are really strong,” Despina says. “When they compete with safety memories, they can be very tough to beat. We want to understand the adolescent brain so we can design treatments and more effectively treat anxiety at that age.” If we can treat the cause of anxiety when it occurs in a young person, he or she is more likely to leave it behind and live without the fear in adulthood. If left untreated, it can be very hard to remove.

By exposing rats to high levels of alcohol three times a week, she has replicated the kind of harmful binge drinking found in many cultures, including Australia. Rats and humans share a very similar limbic system, the part of our brain supporting emotional behaviour, motivation and long-term memory. Because our limbic systems are similar, results of experiments on rats are particularly relevant to humans, providing a very useful insight into alcohol’s damage to the human brain. Rats are assessed for cognitive flexibility as they perform tasks on touch screens (think of an iPad for rats). Christina has found that alcohol-exposed rats find it more difficult to process changes and struggle to adjust their behaviour accordingly.

“People with higher cognitive function are more likely to recover and not relapse, as they rationally know the harm they are doing themselves and their family,” she says.

“People with higher cognitive function are more likely to recover and not relapse, as they rationally know the harm they are doing themselves and their family.”

2016 | The Florey Annual

The Florey Annual | 2016

Fast-forward to her lab bench at the Florey in Parkville, and Christina is not only trying to determine exactly how much cognitive deterioration binge drinking may cause, but whether such damage is repairable.

Christina joined the Florey in 2012 to work on addiction with Professor Andrew Lawrence, in the Behavioural Neuroscience division. After exploring why people became addicted to cocaine or alcohol, and studying how often and why they relapsed, she realised a longer term study could be significant.

Nearly 30 per cent of us will experience anxiety at some point in our lives. Dr Despina Ganella is working with a Florey team to uncover why adolescents suffering anxiety are resistant to treatments that usually work for adults.

Focused on stroke

Sixty minutes with... Florey Director, Geoff Donnan, was onto something when he hired statistician extraordinaire, Leonid Churilov. Together, they have published extensively, changing the way stroke is treated in emergency departments around the world.

Professor Geoffrey Donnan

“

I first met Leonid in 2007 when we were recruiting a statistician. Back then, I had a much smaller team and we had researchers doing statistics on a very part-time basis. We were desperate for a statistician to join the team because our clinical stroke research was expanding so quickly.

We work very closely because my main area of research is stroke. Leonid’s involved in all the projects I’m involved in and we see each other regularly at team meetings. He’s been pivotal in designing almost every study we’ve done. We’ve written dozens and dozens of

Leonid has been one of the absolute anchors of the PhD teaching program we started. We have about 150 students at any one time, most doing their PhD. He teaches each new batch of students the groundings of statistics and particularly study design – how to rigorously design their experiments, either in basic or clinical science.

Statistics is an increasingly important discipline. Every research panel in the NHMRC, where all the grant applications go to be assessed, has a statistician to vet the projects and if they’re not statistically up to scratch then they don’t get funded. Needless to say, Leonid is such a key person within this institute, one of the most important cogs in the wheel. My long working relationship with him has been so gratifying. It’s his personality – he’s so enthusiastic, he just loves the science and he’s so easy to work with, it’s just a pleasure. I often refer to him as ‘His Majesty’.”

”

“

Geoff hired me in 2007 to start a new biostats division and to grow analytical capabilities. My original discipline was the science of decision-making – the application of mathematics and statistics for making decisions and for system modelling. I came from the Ukraine and started out in maths. I used to be a university academic here but then decided it was time to jump the divide and apply my analytical skills in clinical and health care systems. I came in at a relatively senior level. For me, it was never a question of whether I would fit at the Florey – it just clicked right from the start. On the first day they gave me an office, an empty room with a desk and chair in it – everything else was being ordered – and two very eager students with burning questions to ask me! It was full-on from the word go, but I loved it. The office was near Geoff’s which was fantastic as it was very easy to talk with Geoff whenever he was around. I look into very, very applied statistics of clinical and pre-clinical studies. Here, it’s the problems that drive the methodology and those problems

are often life and death issues. You can be talking about something in the morning and in the afternoon they’re treating the patients or running vital experiments. It’s really real. It has been a very steep learning curve in terms of moving into clinical science, specifically stroke. I have always felt that if as a statistician I work in a particular neuroscience domain, I need to know about it – in detail. Geoff is immensely helpful. I still have one of the books he wrote on stroke that he gave me on my first day. It has some very kind scribblings on the cover. He’s had an important role as my mentor, teaching me how to go about working with people, bringing together heterogeneous groups, trying to achieve the outcome in a particular way and keeping a strong integrity about it all. Geoff is one, if not ‘the’ person, in stroke internationally – very big in his field – but he never dominates people, he’s a fantastic team player. We have a very close working relationship, it’s completely open, honest and based on trust. It’s probably as close to the ideal set-up

“Geoff’s had an important role as my mentor, teaching me how to go about working with people.” as you can get. Both as a professional and as a person, he’s great. Throughout my life I would probably say it’s the best working relationship I’ve had – and I’ve worked at a number of places. I’ve loved every moment. If there’s a definition of a gentleman, I would imagine that Geoff is it.”

”

Leonid’s role expanded enormously when the Florey amalgamated. Suddenly he became the statistician to 600 people. He now has a number of PhD students working with him.

Even though he’s not a clinician or a scientist, he probably understands as much about stroke as I do – he’s absorbed the information so well. He knows an enormous amount about the field of neuroscience and has an incredible breadth of knowledge. He’s extremely bright but he’s also a brilliant communicator of statistical concepts which he imparts to us and our students – our level of understanding of statistics has gone up immeasurably.

“Leonid has been one of the absolute anchors of a PhD teaching program we started.”

2016 | The Florey Annual

The Florey Annual | 2016

Leonid is an absolute standout – his enthusiasm, his expertise. He is larger than life, a wonderfully warm, jovial personality. People are drawn to him like a magnet. He is a highly regarded academic and had written books and a lot of important articles. When he joined the team, he quickly generated projects in his own right.

papers together. Whenever we sit down at team meetings we say to Leonid, “We’ve got this plan for this study, what do you think? Is it okay statistically?” He then helps us with the sample size, outcome measurements, all those sorts of important parameters. If you don’t do this properly, the study is useless and you’ve wasted a lot of valuable resources.

Professor Leonid Churilov

Focused on stroke

A young life saved

When every minute counts

Caitlyn Liersch: “a walking, talking miracle” of modern medicine

It has been two years since Melbourne stroke experts published their revolutionary advances in stroke care as part of an international trial to physically remove blood clots deep inside the brain. Here, we hear of the latest efforts to push the technique further.

Meet the Victorian Stroke Telemedicine Program’s 1000th patient, 15-year old Caitlyn Liersch.

t first Caitlyn Liersch’s family thought she was playing up when she was lying on the floor one morning last September, complaining of sore feet and acting “silly”. Was there something in her school shoe? Had she been bitten? “Should I call an ambulance, or are you joking around?,” her mother Kathy Liersch wanted to know, not fully understanding what was happening. But within minutes, Caitlyn could no longer stand. Her words were slurred. Only one side of her mouth moved when asked to smile. Her family says she is a walking, talking miracle of modern medicine after their youngest daughter suffered a heart attack and stroke on the same day. The Moama teenager left hospital three weeks later, with some reduced sensitivity in her left hand as her only scar from this against-theodds survival. She is the youngest person — and the 1000th to be treated by the renowned Victorian Stroke Telemedicine Program. The objective: to ensure all Victorians are within one hour of specialist neurological care after stroke.

The Victorian Stroke Telemedicine program offers regional hospitals access to technology and specialist medical advice so a quick diagnosis can be made and a clot-busting treatment can be provided within the critical four-hour window. Within minutes of Caitlyn’s arrival at hospital, Royal Melbourne Hospital neurologist Associate Professor Bruce Campbell assessed

“I just feel very, very lucky.”

Every minute’s delay in seeking medical treatment after stroke costs millions of neurones. These new developments can mean the difference between someone returning to independent life after stroke or being left significantly disabled.

The telemed program, devised and run by the Florey, now covers 16 hospitals to ensure 94 per cent of Victorians are within one hour of expert stroke care. Having now treated more than 1400 patients through the telemedicine service, it continues to set records; clocking up 12 consultations and three thrombolysis cases in one weekend in March.

Geoff says it had long been known that blood clots in a large artery of the brain were the cause of ischemic strokes, which make up 80 per cent of all strokes.

Co-leader of the program, Professor Christopher Bladin says the team is planning to extend the telemedicine service interstate and establish the Australian Telemedicine Network. They are working to end the “postcode lottery” of health care for the 55,000 Australians who have a stroke each year. “The grand aim is that no stroke in Australia goes untreated,” Chris says. “About 5-7 per cent of patients are being treated with thrombolysis. But that should be up around 10-15 per cent.” “Time is brain with stroke. For every minute faster you get stroke care, you save one day of life free of disability. “In Victoria we can now honestly say no matter which postcode you’re in, whether it’s 3km from a metro hospital or 300km from Melbourne, you will get the same international stroke experts treating you.” Caitlyn is now back at school full-time and is still being treated for the cardiac virus that caused her heart attack, which led to the stroke.

esearchers, led by the Florey’s Director Geoffrey Donnan, are preparing to further the success of the minimally invasive clot retrieval procedure to make it safer and more effective. The earlier it is offered, the more precious brain cells are saved.

If the clot can dissolve, then blood flow to the brain can return and compromised brain tissue can be potentially salvaged.

Fast facts Number of stroke patients treated by VST

16 15 11%

1400

Number of Hospitals with the telemed program Number of Telemed neurologists on call Percentage of ischaemic stroke patients who receive tPA Median time to receive tPA: 72 minutes Time saved by the VST program: 30 minutes

While a proportion of clots dissolve on their own – often as patients are mid-flight in the air ambulance on route to the Royal Melbourne Hospital for this endovascular stent thrombectomy – for a large proportion of patients, their clot is too large and the artery remains blocked despite receiving the clot-busting medication tissue plasminogen activator (tPA). A global race began to design a device that would manually remove the clot and restore blood flow safely. Clinical trials started around the world using various models of clot retrieval devices, but were unsuccessful in showing they could advance stroke care. Not only were there problems in the devices’ design, but these studies didn’t use advanced imaging to ensure their enrolled patients even had salvageable brain tissue to begin with, as well as having low rates of reperfusion after retrieval.

“It’s a difficult ask because the device has to completely extract the clot whole, without breaking it up,” Geoff says. “It’s very difficult to design equipment to do that.” A spring-loaded device developed in the US to put coils on aneurysms, similar to a stent used in coronary heart disease, emerged as a promising option. Melbourne was one of five international centres to trial the device in a study with the Royal Melbourne Hospital involving project co-chair Director of Neurology Professor Stephen Davis, neurologist Associate Professor Bruce Campbell and Director of The RMH’s neurointervention program, Professor Peter Mitchell. What set the Melbourne collaboration apart was the strict criteria they use for selecting which patients could receive the experimental procedure. X-ray perfusion imaging has allowed them to select those patients who still had a large portion of surviving brain tissue. This type of advanced imaging uses an automated software program to give clinicians a much more accurate snapshot of the difference between salvable brain tissue and irreversibly damaged regions to select the most appropriate patients. The procedure, known as stent thrombectomy, involves inserting a small tube into an artery in the groin, and threading up the wire-cage stent device to the brain to grab the clot and remove it in one piece. “We were able to demonstrate it was very, very effective,” Geoff says. “It gave patients more than three times the chance of getting up and walking out of hospital, compared to just using the clot-busting drug. It is incredible. “It has changed practice around the world, having a huge effect on how we deliver patient care.”

The results were published in early 2015 in the prestigious New England Journal of Medicine. In just the past 12 months, the RMH has performed this procedure on more than 200 people. Inspired by the results, there was a collective team brainstorm: how could they bring this life-changing procedure to a broader range of people, faster and with fewer complications? They are now considering whether endovascular clot retrieval can be used as the first-line treatment, bypassing the need for tPA. This means patients could have their clot retrieved at least 30 minutes earlier, as well as removing the need for tPA which increases the risk of post-stroke bleeding. The team is now combing patient data from all the five international trials to uncover if there are clues in patient histories and outcomes that can indicate which patients will benefit. “It might be that we could look at patients with a slightly longer time window.” “Theoretically we might be able to operate up to six hours after the stroke, but we’re not quite sure yet. Perhaps we can offer it to patients who have less surviving brain tissue and they still might benefit. “We’re planning that trial right now.” With RMH and Monash Medical Centre now equipped to perform the procedure, Geoff predicts it will not take long before the technique is offered more broadly at major hospitals thanks to the pioneering work that has established the safety and efficacy of this treatment. “Every minute counts with stroke. We lose about two million brain cells per minute once the process has started. This is all about getting people treated as quickly as possible, so more people are walking out of hospital doors, going home after a stroke.”

Just two years earlier, the same event would have left Caitlyn with lifelong and severe disabilities.

He also arranged her urgent transfer to Melbourne for endovascular clot retrieval – a procedure to manually remove the clot. Fortunately, this was not required as the drug dissolved the blockage en route.

“I’ve got a little bit of rehabilitation to go on my hands, like I couldn’t tell if I was holding something fluffy or something rough, but I’m nearly there,” she said.

2016 | The Florey Annual

The Florey Annual | 2016

“She’s our little miracle. We’re so grateful this telemedicine service was there,” Kathy says.

her via videolink and reviewed her brain scans to give her the go-ahead to receive a thrombolysis injection to help dissolve the clot in her brain.

Focused on stroke

Tracking every stroke

Pushing the limits

You can’t improve what you don’t measure. It is a simple concept, but it’s a grand objective. A team, led by the Florey, aims to track the quality of hospital care and outcome of every stroke patient in Australia with the intention of improving patient care.

There are few situations more heartbreaking than learning there is a proven, readily available treatment for stroke, but it’s a life-line out of reach because doctors don’t know the time the stroke occurred. A Florey-led study hopes to change international guidelines.

iven how inextricably a person’s survival and recovery from stroke is linked to the acute health care they receive, stroke experts – including those at the Florey – recognised early that hospitals must take regular stock of their performance. For the past eight years, the Australian Stroke Clinical Registry (AuSCR) has enabled the collection and publication of patient outcomes from acute stroke and “mini strokes”, or transient ischemic attacks. The register, which is managed by the Florey as one of four partners in the national project, has the aim of assessing stroke treatment and rehabilitation to ensure patients have the best possible chance of recovery, no matter where they are treated. Head of Public Health at the Florey, Associate Professor Dominique Cadilhac says that while previous audits showed there was significant variability in best practice care across Australia, clinicians have struggled to access data to gauge whether they are meeting standards.

Patients also undertake a survey three months after discharge, to rate their degree of disability, quality of life, readmission to hospital and recurrent strokes. Importantly, hospitals can regularly download their own data to measure their performance over time. The results also act as a checklist

cause of death and disability worldwide

STROKES EACH YEAR in Australia: 1000 a week or 1:6



“If there’s a problem they can identify it and act on it.

Stroke survivors with physical or mental impairment

“We’ve found that if hospitals contribute to the registry over a number of years, there’s a shift in their practice. They are improving.”

 

Practical changes have been made. For example, after analysing their data, some hospitals have increased speech pathology for patients to address swallowing difficulties.

ISCHAEMIC VS. HAEMORRHAGIC STROKE

Other hospitals were able to increase access to their specialist stroke units and improve communication between patients and staff.

10%

After starting as a pilot program in 2009 with six hospitals contributing, 45 services are now involved. The registry’s grand aim is to include data from all 50,000 strokes that occur across Australia each year.

% OF STROKES IN PEOPLE UNDER 65

“Stroke is a complex condition and there is now greater recognition that access to recommended care is essential to achieve better outcomes. “For the first time, the registry gives clinicians important information for understanding the influence of the care they provide and patient outcomes after they have left hospital.”

The earlier you can reopen the blood vessel and get blood flowing again to the affected part of the brain, the more likely that tissue can be saved.

An international trial is being led by the Florey to test whether tPA is still safe and effective up to nine hours after stroke onset.

The protein tissue plasminogen activator (tPA) has been the most potent therapy for doing just that since it was first trialed in Melbourne in 1999.

If successful, the biggest beneficiaries of this new research will be the “wake up stroke” population; the 20-30 per cent of ischemic stroke patients who have the event at some stage overnight but don’t know when.

A patient’s chance of getting up and walking out of hospital increases by 30 per cent if they are treated with tPA, but on average only 11 per cent of patients currently receive the drug. Florey Director Professor Geoffrey Donnan says the other 89 per cent of patients do not make it to hospital in time to receive the intravenous infusion within the designated 4.5 hours that the drug is proven to work.

DEVELOP DEMENTIA AFTER STROKE

30% after subsequent strokes



REDUCED RISK OF DEATH AFTER 180 DAYS IF TREATED IN A STROKE UNIT: 59%

“To give them the drug and to see them hop up off the bed, to walk out of hospital – it’s quite emotional.”

In major metropolitan hospitals across Australia, 20 per cent of eligible patients receive tPA. But because of the time pressures involved in busy emergency departments, many units struggle to treat even five per cent of eligible patients. “To give them the drug and to see them hop up off the bed, to walk out of hospital - it’s quite emotional when you realise what you can do for them.” But consensus is growing among the global stroke community. tPA may be useful beyond 4.5 hours. Advanced brain imaging is revealing that many patients have salvageable brain tissue well beyond this small window. “We know there is viable brain tissue in some people for as long as 48 hours after the stroke onset. How the stroke plays out depends on how much circulation they’re getting from other arteries, how old they are, and other factors.”

This could see between 2000 and 4000 extra Australians access tPA treatment each year, and between 500,000 and two million people worldwide. “Even though we keep emphasising that patients must come to hospital as early as possible, if for some reason they’re unable to - and if the results of this trial are positive - then we’ll be able to treat them up to nine hours after the stroke.” The international trial involving 23 centres in Australia, 12 in Taiwan and one in New Zealand has recruited 189 patients. Patients initially receive advanced brain scans to determine if there is still salvageable brain tissue before they are randomly allocated the tPA treatment up to nine hours, or given the standard treatment of aspirin. Patients have follow-up brain scans 24 hours after the treatment, and again three months later to determine their level of disability. They hope to reach 200 patients within the next three months. At this point they will analyse the interim results of the randomised, blinded study to determine if they need to expand or abandon the trial. “For all of these trials, the eyes of the world are upon us,” he says.

Notes EVERY TEN MINUTES someone in Australia will suffer a stroke

TWO THIRDS of survivors will be disabled close to

440,000 Australians are

living with the impact of stroke

By 2032 it will be 700,000 ECONOMIC COST TO AUSTRALIA EACH YEAR > $5 BILLION $3 billion in lost productivity $1 billion in lost wages

Risk factors Australians most at risk of a stroke include:

6.1 MILLION people living with high cholesterol 4.1 MILLION with high blood pressure 434,000

with atrial fibrillation

The AuSCR records various aspects of patient care including whether they received clotbusting medication, their mobility, if they were discharged on blood pressure lowering medication, and given a discharge care plan.

to see if they’re meeting national benchmarks, and how they’re rating against the best performing hospitals.

Stroke statistics for Australia and the world

lorey researchers are trying to improve the chance of recovery for the thousands of Australians who suffer a stroke each year and can’t say when it happened, often because they were asleep. A ground-breaking international trial aims to extend the time that clot-busting medication can be administered after ischemic stroke.

2016 | The Florey Annual

The Florey Annual | 2016

Dominique believes the registry’s success lies in the way it gathers clinically relevant processes of care and outcomes, not routinely gathered by other data collections.

“We’ve found that if hospitals contribute to the registry over a number of years, there’s a shift in their practice. They are improving.”

PHIL BEART

Driven by curiosity

Phil Beart has made a significant contribution to the world’s understanding of brain injury. He has modelled the way neurones can suddenly burst or die slowly – in disease and as we age. These days, however, he is investigating how we might protect our neurones in a most unexpected way.

Florey Institute stalwart, Professor Philip Beart, is supposed to be slowing down. The problem is, his ever-creative, constantly curious brain is yet to register that it can begin working at a walking pace.

A pioneering paper that he co-authored in 2005 established that naturally occurring antioxidants found in soy beans, red wine and tea could prevent brain cells from dying in cellular models of Parkinson’s disease.

As he reluctantly acknowledges he is semiretiring, Phil continues to discover new directions for his research involving chemistry, molecular assemblies, super foods, and cell death.

“I don’t really work in that area but this paper has been cited more than 200 times,” he says.

Phil has enjoyed a fascinating career and has contributed to medical research for more than 40 years. He has published more than 250 publications and been cited more than 8000 times. Phil has been central to at least 10 pharmaceutical patents in a career that has taken him from England to Boston, Paris, Copenhagen and other international science hubs.

The Florey Annual | 2016 22

Phil takes resveratrol every day, and eats walnuts, sunflower seeds and pumpkin seeds as part of his breakfast, drawing on his neuronutraceutical research for his own health. It appears to be working in this admittedly small sample. Phil is sharp, agile and energetic, even though he is recovering from back surgery that has briefly halted his basketball and surfing and modified his yoga practice.

Looking back, Phil considers himself lucky to have started his career when he did, finding grant money easy to come by when he returned to Australia with Cambridge and Harvard on his curriculum vitae. “The path to research, and winning grant funding, is getting tougher and tougher,” he says. Luckily for the Florey’s mid-career researchers, Phil Beart is likely to still be around (most of the time) to guide and encourage.

Professor Beart will deliver a public lecture on the benefits of neuro-nutraceuticals on 1 November 2017. For more details, please visit florey.edu.au

It is hard to imagine how Phil will leave his office as he prepares to “semi-retire”.

The term “nutraceutical” was invented in 1989, to categorise foods that are healthy, but Phil has gone further, personally creating the word “neuro-nutraceutical” to define the naturallyoccurring molecules that might play a role in arresting or reversing major brain disorders ranging from autism to Parkinson’s disease.

In another of his many projects, with an Italian colleague, Phil is enthusiastic about the power of molecules found in the skin of red grapes. They would appear to enhance the function of ageing brains and muscle. The problem, however, is that Phil estimates we would need to drink 300 glasses of red wine to achieve the benefit. Luckily, it is now found in pill form, as resveratrol, available over the counter.

His colleagues cannot see any sign of Phil slowing down. He’s involved in several grant submissions heading into the new financial year; he’s a mentor to younger Florey scientists and is the historian for the International Society of Neurochemistry.

2016 | The Florey Annual

This superfit 69 year old is a passionate advocate of a healthy diet and regular exercise regime. This partially explains his ongoing interest in so-called super foods. Could they really be good for the brain? While Phil is never going to simply throw kale into a morning smoothie and not consider why, he is delving into his background as a chemist to try and isolate the exact molecules that might have a positive impact on neurones.

In a recent turn of events, Phil, along with other members of his Friday afternoon science club at the Florey, discovered that an existing drug, Rilmenidine, may be useful in reversing the acute toxic effects of an MDMA (“ecstasy”) overdose, as Narcan is used for heroin overdose. The result? Yet another publication for this prodigiously curious mind.

Phil has published more than 250 publications and been cited more than 8000 times.

Revealing the intangible Conversion disorder is a psychiatric condition deserving much more attention, according to psychiatrist, Professor Richard Kanaan. Imagine one day your legs refuse to move, or you can no longer see. Sadly, a significant number of patients are dismissed as imagining their conditions when conventional medical tests fail to find a cause.

elcome to the mysterious and perplexing world of a neurological condition known as conversion disorder. It has been written about for centuries but is only now being unlocked by psychiatrists including the co-head of the Florey Institute’s Biological Psychiatry and Mental Health division, Professor Richard Kanaan.

“A lot of the symptoms can appear to be voluntary,” Richard says. “This has puzzled people. Are the patients doing it on purpose? Is there some other reason? Is it an evil spirit? Can they control it?

“But for the first time, we can say we understand what’s going on and we know why a patient can’t walk,” Richard says. “Lots of people recover and not every person is paralysed. All patients could be cured, we think.” The research is so new that Richard says published papers by him and other leaders in the field have not yet been formally replicated and confirmed, to be accepted scientifically. “We haven’t had one particular breakthrough but the incremental breakthroughs are happening,” he says. “The next 10 years will be significant in our understanding of this, I believe.” However, patients are starting to see the benefits.

Professor Richard Kanaan is seeking to understand one of the brain’s most mysterious, under-diagnosed illnesses.

“People may be suffering paralysis or fits yet doctors are repeatedly saying: ‘I can’t find anything wrong on the scans. Everything is normal’.” “We are evaluating treatments that are working very well. With fits or seizures, due to conversion disorder, we would expect most people to recover. Evidence also tells us that most people will improve with a short course of physiotherapy.” Another question still being considered is the role anxiety plays in the disease. While high levels of anxiety are naturally present in most sufferers, Richard believes researchers are still trying to unravel whether anxiety is embedded in the cause of the disease, or is an understandable by-product of it. There’s a lot of work still to be done, but the mystery is beginning to unravel.

ts size, the folds and troughs on the brain’s surface, and sometimes what is noticeably missing from its surface, mean she can make astute judgments about this individual’s health — and their ultimate demise — long before she picks up a knife. Conducted behind a locked cage door in the bowels of the Florey, this is detective work like no other. As leader of Victoria’s Brain Bank, the busiest and one of the largest in the country, Catriona and her collection of 1500 brains are helping researchers around the world unlock the secrets of head trauma and degenerative brain diseases. The 60-70 annual donations provide crucial pieces to the puzzle of brain diseases that cannot be adequately and ethically studied until after death. Catriona and her small team are helping researchers wanting to improve diagnosis and treatments to prevent progressive brain diseases. Under the microscope the brain, when removed from its bony helmet, reveals its secrets. An Alzheimer’s brain, for example, is much smaller than a healthy brain. For more than 25 years, the bank has existed for two main reasons: to provide a diagnosis for the family, who may also be at risk of developing the disease; and to provide samples of brain tissue and spinal cord for research purposes. While it conjures images of something out of a sci-fi movie — with rows of illuminated brains in vats — the bank is a compact filing system that houses neatly packed rows of plastic containers.

Each shelf is labelled: trauma, Parkinson’s disease and Alzheimer’s sit alongside motor neurone disease, bipolar and schizophrenia. Some are healthy “controls”. Inside each container is half a brain, sliced into pieces, wrapped and topped with formaldehyde. This half is used for a diagnosis — to confirm if the condition is hereditary, and, if the person was receiving treatment in a clinical trial, to confirm that they actually had the condition the trial was testing. The other half of the brain is sliced and then frozen in the freezers of the upstairs laboratory, ready to be shipped to researchers around the world.

It is in this upstairs laboratory that McLean and her colleagues lay the brain on a plastic kitchen chopping board and use a knife — with no serrated teeth but as big as a breadknife — to strategically cut each brain into more than 100 slices. A brain is soft like jelly to cut through, except when you reach an area affected by a neurodegenerative condition, and then it’s softer, like butter. Catriona is keen to expand the service to allow analysis of new neurological diseases and head traumas such as football-related concussion. She also wants to train the next cohort of neuropathologists to continue this highly specialised detective work.

Last year about 3500 samples were sent to researchers in Melbourne, New South Wales, Korea, Germany and Sweden.

“There is an ongoing need for this work,” says Catriona, who is part of an international project studying a degenerative brain disease that has never been described before.

The youngest brain is from a 22-year-old with an early onset dementia.

“We still don’t understand the process of disease.

The oldest are samples taken from the Papua New Guinea cannibal tribe that ate their dead as a funeral rite, leading to kuru, the first human-transmitted form of the rare and deadly brain disease transmissible spongiform encephalopathy. “The tissue is invaluable for research work into neurodegenerative diseases, otherwise you’re studying a mouse model or cells,” Catriona says. “To me, if you’ve got the tissue, that’s the real disease you’re studying. You’ve got the end point, you can study that disease process.”

“Research is about trying to find out exactly what’s happening, so in diseases like Alzheimer’s we can flick the right switch to stop it happening or delay it. “When we understand what’s happening in motor neurone disease, Parkinson’s and Alzheimer’s, and with all the new diseases still coming on board in 2016; when we can diagnose them all in life, correctly every time, there will be no need for us. But we’re not there yet. The brain still has some mysteries.” With thanks to Brigid O’Connell and News Limited.

In some parts of the world, conversion disorder has been blamed on witchcraft, or deemed to be some kind of possession by evil spirits. Western general practitioners may not even think of it as a possible diagnosis. Among the many presentations, patients may have symptoms of epilepsy, stroke or paraplegia.

Conversion disorder was originally brought into the light by the famous Austrian neurologist Sigmund Freud, who believed it was the result of trauma, but then his theories faded from view as his work lost favour within academia. But in the last two decades, psychiatrists like Richard have started to use a variety of tools and modern scanning to research the disorder, even by a process of elimination, through MRI scans or, for example, by clearing a patient of epilepsy through an EEG scan. “Scanning is not a clinical tool,” he says. “It’s for research.”

From the moment the renowned and passionate neuropathologist Professor Catriona McLean picks up a donated human brain, she is busy diagnosing the disease within.

Professor Catriona McLean in the Victorian Brain Bank. IMAGE: News Ltd.

2016 | The Florey Annual

The Florey Annual | 2016

Originally from Scotland, and having spent 11 years working at the Institute of Psychiatry in London, Professor Kanaan has been in Australia for four years. Treating patients with conversion disorder is his passion, as he seeks to determine the causes of this misunderstood and under-diagnosed ailment. Until recently there were no patient support groups or official acknowledgement. In fact, a major study in Scotland found it to be the most common condition referred to psychiatrists by doctors in that country, more than headaches, strokes or epilepsy. In his first two years at Austin Health, Richard has seen about 100 cases of conversion disorder and says referrals are increasing.

“It’s hard for doctors and patients alike. Lots of people stray off the path to saying things people find difficult to accept. ‘Your problems are not real; there’s nothing wrong with you’. People may be suffering paralysis or fits yet doctors are repeatedly saying: ‘I can’t find anything wrong on the scans. Everything is normal’.”

Brain mysteries exposed

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2016 | The Florey Annual

The Florey Annual | 2016

During 2016, the pace and potential of lifesaving research has vastly accelerated at the Florey. Contributions by generous benefactors provide essential support, alongside government grants. Backing from donors, corporations, foundations and organisations act as a catalyst for our scientists, funding new ideas and innovations as they emerge — driving our ability to chase discoveries and to improve lives. We are grateful for the generous investment from all of our supporters in our relentless pursuit to improve the prevention, detection and treatment of brain diseases and mind disorders.

Financial snapshot 2016 $m INCOME Grants 39.5 Philanthropy 6.7 Other 21.3 Total Income

Perhaps you would like to help us cure one of the many serious brain diseases affecting one in four people, young and old.

FLOREY INCOME 2014-2016

67.5

EXPENSES Salary and wages Other research expenditure Depreciation and amortisation Other items (non-cash accounting entries)

(39.4) (23.1) (4.8) (8.4)

60 50

Your gift could help us reveal the causes of brain diseases affecting so many people; conditions like stroke, Alzheimer’s disease and schizophrenia.

Total Expenses

(75.7)

Our research aims to transform lives for patients in Australia and around the world.

DEFICIT (8.2)

2014

2015

2016

FINANCIAL POSITION Current assets 40.5 Non-current assets 66.6 Total assets 107.1 Liabilities (10.6) NET ASSETS

— Give today.

96.5

•

There are many ways you can help to fund our research.

— Pledge over time - join our Brains Trust.

•

Government

— Plan for the future - make a gift in your will.

Non-Government

Phone: 1800 063 693 Email: info@florey.edu.au Online: florey.edu.au

SOURCES OF INCOME

• • • • • •

Post: The Florey Reply Paid 83037 30 Royal Parade, Parkville VIC 3052

2016 $m

Government

34.9

Commercial

12.6

Private donors

6.7

Peer review

4.6

Investment

1.2

Other

7.5

SOURCES OF INCOME – 2016

Thank you for backing our great researchers.

TOTAL 67.5

2016

The Florey Annual | 2016

ENDOWMENT INVESTMENTS

• • • •

Term deposits

16.7

Managed funds

5.5

Cash-at-bank

0.9

Other

0.2

TOTAL 23.3

After 1 July 2017 visit the Australian Charities and Not-For-Profits Commission website for detailed financial reports of the Florey’s 2016 year.

Donations to the Florey Institute of Neuroscience and Mental Health of $2 or more are fully tax deductible.

ENDOWMENT INVESTMENTS AT DEC 2016

he Florey Institute of Neuroscience and Mental Health is one of the largest brain research centres in the world and the biggest in Australia. Our scientists share a common goal – to improve people’s lives through brain research and, ultimately, to influence global wellbeing and health economics. Neuroscience is an area of medical research attracting enormous attention as our understanding of the brain rapidly evolves. Internationally, populations are ageing and there is a sense of urgency to find causes, treatments and cures for conditions affecting the brain and mind. We are addressing these conditions to avoid suffering and to contain health-related expenditure. The Florey is a world leader in imaging technology, genetics, stroke rehabilitation and epidemiological studies. Mental health research is a growing focus with psychotic illnesses and neurodegenerative diseases demanding attention.

We study: — Addiction

— Huntington’s disease

— Alzheimer’s disease

— Motor neurone disease

— Autism

— Multiple sclerosis

— Cardiovascular disease

— Parkinson’s disease

— Mental illness including anxiety, schizophrenia, bipolar disorder and major depression

— Stroke

— Epilepsy

— Sudden infant death syndrome — Traumatic brain and spinal cord injury

To keep up to date with Florey events, news and research, visit florey.edu.au or email: info@florey.edu.au

The Florey Institute of Neuroscience and Mental Health acknowledges the traditional owners of this land, the people of the Wurundjeri people and the Kulin Nations. We pay our respects to their elders, past and present. We would like to acknowledge that our three sites rest on this precious land.