Retraining brain and body communication underpins novel pain treatment
People challenged with chronic back pain have been given hope thanks to a first of its kind pain treatment, trialled by researchers at Neuroscience Research Australia (NeuRA), UNSW Sydney and collaborating universities, that retrains how the back and the brain communicate.
A novel approach to chronic back pain
The new treatment, known as ‘graded sensorimotor retraining’, challenges traditional treatments for chronic back pain, such as drugs, spinal manipulation, injections, surgery and spinal cord stimulators, by viewing long-standing back pain as a modifiable problem of the nervous system rather than a disc, bone or muscle problem.
Professor James McAuley from NeuRA and UNSW’s School of Health Sciences explained that people with back pain are often told their back is vulnerable and needs protecting.
“This changes how we filter and interpret information from our back and how we move our back. Over time, the back becomes less fit, and the way the back and brain communicate is disrupted in ways that seem to reinforce the notion that the back is vulnerable and needs protecting. The treatment we devised aims to break this self-sustaining cycle,” he said.
“Sensorimotor retraining alters how people think about their body in pain, how they process sensory information from their back and how they move their back during activities.”
Professor James McAuley
What the trial found
The trial, carried out at NeuRA, divided 276 participants into two groups: one undertook a 12-week course of sensorimotor retraining and the other received a 12-week course of sham treatments designed to control for placebo effects, which are common in low back pain trials.
“What we observed in our trial was a clinically meaningful effect on pain intensity and a clinically meaningful effect on disability. People were happier, they reported their backs felt better and their quality of life was better. It also looks like these effects were sustained over the long term; twice as many people were completely recovered. Very few treatments for low back pain show long-term benefits, but participants in the trial reported improved quality of life one year later,” Prof. McAuley said.
The study authors say that more research is needed to replicate these results and test the treatment in different settings, populations and in other chronic pain states that show similar disruption within the nervous system. They are optimistic about rolling out a training package to bring this new treatment to clinics and have enlisted partner organisations to start that process.
Once the new treatment is available via trained physiotherapists, exercise physiologists and other clinicians, which Prof. McAuley hopes to occur in the next six to nine months, people with chronic back pain should be able to access it at a similar cost to other therapies offered by those practitioners.
Improved treatments for debilitating mental health conditions is the challenge being embraced by researchers at QIMR Berghofer, aiming to tap into genetic discoveries from the last decade to deliver a new era of precision psychiatry.
Answers lie within our genetic blueprint
Scientists have discovered hundreds, and in some cases, thousands of genes linked to the full range of mental health conditions, including anxiety, depression, anorexia nervosa, schizophrenia, bipolar disorder, autism spectrum disorder, and ADHD. This has been made possible thanks to new genetic data sets of DNA donated by millions of people, and advancements in supercomputing technology.
She has co-led a new study, published in Nature Genetics, identifying 10 key challenges in overcoming clinical translation of these genetic discoveries.
“We’ve had an era of genetic discovery and now we’re on the threshold of a new era of precision psychiatry which could offer more effective drugs for patients, and could help clinicians to better diagnose and treat these complex conditions.
“The challenges we’ve identified are not simple to solve but with a creative, collaborative, and co-ordinated research approach, and investment that supports scientists to do this work, we could make this new era a reality. We owe it to the people who have generously donated their DNA and to those living with a mental illness,” Professor Derks said.
The opportunity is great, the necessity for progress is even greater
Two in five Australians have experienced mental illness at some point in their life. Anxiety and depression are the most common, with the COVID-19 pandemic triggering a 25 per cent increase in cases according to the World Health Organisation (WHO). Mental illnesses can significantly impact patients’ quality of life, and cost the Australian economy around $70 billion every year.
Dr Zachary Gerring, who co-led the study, said there is a tremendous opportunity to use genetic data to find more effective treatments.
“For decades, there has been little progress in developing new drugs for mental health conditions. It can be a long process of trial and error for patients to find a treatment.
“We can integrate the genetic data with drug databases to identify potential new drug candidates that can be repurposed, meaning we could get treatments to patients more quickly and cheaply,” Dr Gerring said.
QIMR Berghofer PhD candidate and co-lead author, Jackson Thorp, said there is huge potential to use genetic discoveries to work out the biological mechanisms of mental illnesses.
“By better understanding the biological processes, we could find the causes of mental health diseases which could lead to identification of high risk groups of people, more tailored interventions, and more accurate tools for diagnosis
“I’m extremely hopeful that we can use this genetic information to improve the lives of people living with mental illness, underpinned by further funding to do this work,” Mr Thorp said.
World-first heart transplant technology giving hope to patients
World-first heart transplant technology giving hope to patients
World-first technology pioneered by researchers at the Victor Chang Cardiac Research Institute and St Vincent’s Hospital, Sydney, is allowing surgeons to transplant donor hearts that have stopped beating after death – setting a new global precedent in organ transplant techniques and reducing wait times on heart transplant lists for patients.
Known as ‘Heart in a Box’ this novel technology has seen the number of successful transplants of hearts that have stopped beating after death (called DCD hearts) soar by a quarter at St Vincent’s Hospital, Sydney, since its introduction. New research revealing the technique has been published in the journal Transplantation.
A paradigm shift in organ donation
Before the first DCD heart transplant was performed in 2014, patients relied solely on donor hearts from brain-dead patients whose hearts were still beating at the time of retrieval.
Dr Yashutosh Joshi, St Vincent’s Hospital cardiothoracic registrar and lead author of the paper, said he expects the number of transplants to increase even further after research revealed survival outcomes were just as successful for those who received DCD hearts as those who received hearts from traditional brain-dead donors.
“Previously, donor hearts from a DCD pathway were not able to be used. In the last eight years we have now been able to retrieve these hearts and increase the donor pool which has had a positive impact on our waitlists with more heart transplants being performed than before,” explained Dr Joshi, who is also a recipient of a Heart Foundation PhD Scholarship.
Since 2014, 74 DCD transplants have been performed by the team at St Vincent’s.
How ‘Heart in a Box’ works
DCD transplants allow hearts to be donated from patients who have died after withdrawal of life support and in whom death is declared only after the heart has stopped beating. This is achieved by using a defined preservation fluid developed in the laboratory and a machine that allows the heart to beat outside the body which allows the organ to be reanimated and assessed.
Professor Peter Macdonald, from the Victor Chang Cardiac Research Institute and senior cardiologist at St Vincent’s Hospital, led the team that pioneered DCD heart transplant surgery.
“Since 2014 our team of scientists and surgeons have worked tirelessly to ensure outcomes are every bit as successful with this new technology. Now that this has been achieved and proved, we expect many more heart transplant teams around the world to embrace this technology,” he said.
“Around the world, there are now hundreds of people who have received DCD hearts. Our discovery has been life-changing and lifesaving for so many patients.”
Professor Peter Macdonald
Initially, it was found that hearts retrieved from DCD donors took a lot longer to recover after transplantation. Around a third of patients had to be placed on a machine similar to heart-lung bypass for a short period of time to allow the newly transplanted heart to recover. However, the team from the Institute and the hospital has since worked out how to better protect DCD hearts during retrieval and transport, drastically reducing the need for this with only a small percentage now requiring temporary bypass.
Going forward, the team is now looking at ways to extend the period of time hearts can survive without circulation prior to transplantation.
Whilst the team at St Vincent’s Hospital in Sydney is the only one in Australia which can perform DCD transplants, its transplant team travels the country to retrieve suitable donor hearts by using the ‘Heart in a Box’ machine.
DCD Heart transplantation is now being carried out in the US, Spain, Belgium, the Netherlands, and the UK, where close to half of all transplants are now with DCD hearts.
Community-led approach reducing rheumatic fever
Members of the research team: (L-R) Vicki Wade, Valerina Mungatopi and Angela Kelly
A community-based research project in the Northern Territory is providing hope to remote communities in reducing rheumatic fever cases and the bacterial infections that trigger the condition.
Rheumatic fever, caused by household crowding and high rates of untreated streptococcal infections in children, can have devastating consequences, such as causing heart disease at a young age.
Community-driven activities key to success
The study – part of a 4-year collaboration with Menzies School of Health Research, Telethon Kids Institute, Sunrise Health Service and NT Health – focused on reducing household health risks through community-based activities led by Aboriginal Community Workers, in a bid to curb infection rates.
Housing and environmental health support – such as fixing showerheads, broken pipes and other health hardware – as well as information-sharing about rheumatic fever and assisting families to navigate healthcare, made up the focus of the activities.
This helped people gain the knowledge needed to seek medical treatment, which initially increased the number of reported infections. Because those infections were then able to be properly treated, rates of infection decreased to below baseline levels, especially in children.
Study co-author and Chairperson of the Board for Sunrise Health Service, Anne-Marie Lee, said the findings suggested the community-led activities translated into a reduction of the types of infection that drive rheumatic fever. The number of new cases of rheumatic fever also decreased during the study.
“Indigenous people working on the ground from that community, it works well. It doesn’t work if an outsider thinks that they can come in. You have to get local people on the ground to do the job,” Ms Lee said.
Director of RHDAustralia and Aboriginal advisor for the study, Ms Vicki Wade, agreed.
“It is so important for rheumatic fever control to be community-led. Rheumatic fever is fuelled by the socio-economic determinants of health, so that’s what we need to tackle, using scientifically based approaches that are co-designed in partnership with communities,” Ms Wade said.
First of its kind study in Australia
Study lead and Senior Clinical Research Fellow at Menzies School of Health Research, Professor Anna Ralph, said rheumatic fever had declined in southern parts of Australia and globally in high income countries in the mid-1900s as standards of living improved – otherwise known as primordial prevention.
“Translating the key components of primordial prevention into tropical and central Australia requires innovation and strong partnerships,” Professor Ralph said.
“This is the first time Australian data has been published on the health impacts of community-led rheumatic fever primordial prevention. These findings are promising but need to be scaled up to whole communities.”
A genetic variant linked to the most common form of motor neurone disease, which holds potential as a genetic marker to better treat the neurological disease, has been discovered by researchers at the Perron Institute and Murdoch University.
The study represents a step forward in the quest to find new genetic markers to understand and advance new approaches to treat the complexities of motor neurone disease (MND).
MND is a neurodegenerative disease resulting in progressive paralysis. An estimated five to ten percent of cases are familial (hereditary), but most are sporadic.
Study marks first genetic association of its kind in MND research to be published
The collaborative research investigated the Stathmin-2 gene, which is necessary for neuron growth and regeneration. The team uncovered a structural variant within this gene that is linked to sporadic amyotrophic lateral sclerosis (ALS), the most common form of MND.
Results indicate that the variation is a risk factor and may affect the progression of the disease in some patients.
Professor Anthony Akkari, senior author of the study who heads the Motor Neurone Disease Genetics and Therapeutics Research team at the Perron Institute and Centre for Molecular Medicine and Innovative Therapeutics at Murdoch University explained.
“Identifying variations in genetic makeup is a key element in improving approaches to preventing, diagnosing and treating diseases such as MND.
“Overall, in this area of unmet need, the aim is to discover what therapies would work best for specific patient groups. Our research is aimed at filling in genetic pieces of the puzzle.
“As well as giving us a better understanding of disease mechanism, knowledge of this variant could improve outcomes of clinical trials. Grouping participants by this genetic marker would enable researchers to investigate whether the sub-group responds differently to a particular therapy.”
Frances Theunissen was lead investigator of the study, a research assistant and PhD candidate at the Perron Institute and Murdoch University.
“This newly discovered genetic variant has the potential to be a disease marker and tool for cohort enrichment in future MND clinical trials and this strategy should become standard practice,” she said.
“It’s a step towards developing new, personalised treatments for motor neurone disease.”
The collaborative study involved renowned local researchers and international collaborators, including Professors Don Cleveland, John Ravits and Dr Ze’ev Melamed (University of California, San Diego), Professor Richard Bedlack (Duke University, North Carolina) and Professor Alan Mackay Sim (Griffith University, Queensland).
The research was made possible thanks to funding from the Perron Institute, the Giumelli Foundation, Ian Potter Foundation, Racing for MNDi Foundation and the Pierce Armstrong Foundation.
Undercovering link between cardiovascular disease and sleep apnoea
Undercovering link between cardiovascular disease and sleep apnoea
With an increasing number of people losing their lives to heart disease each year, researchers from the Kolling Institute have launched a first of its kind study using MRI technology to broaden scientific understanding of the link between cardiovascular disease and sleep apnoea.
The new study follows latest figures showing cardiovascular disease is the leading cause of death worldwide, killing one Australian every 12 minutes.
This makes the research important and timely, especially given that obstructive sleep apnoea is also increasing and now affects around one billion people. Known as the silent killer, this chronic disease causes low oxygen levels, sleep disturbance and dangerous pressure inside the chest.
Meet the team searching for answers
Royal North Shore Hospital respiratory and sleep medicine specialist Professor Peter Cistulli will lead the study, collaborating with RNSH Head of Respiratory and Sleep Medicine Dr Ben Harris, and Kolling Institute researchers Professor Martin Ugander and Dr Rebecca Kozor, who are experts in cardiac imaging.
Professor Cistulli said obstructive sleep apnoea has been linked to the development of cardiovascular disease, including hypertension, heart attack, atrial fibrillation and stroke – but there have been no randomised controlled trials confirming a causal link between the two.
“We hope our project will provide definitive evidence of the relationship between sleep apnoea and cardiovascular disease, closing our existing gaps in knowledge and informing future treatment approaches,” he said.
Nina Sarkissian, Director of Research Development for the Sleep Research Group across the Charles Perkins Centre and Royal North Shore Hospital, plays a key role in developing such cross-disciplinary collaborative research programs.
She said “Our CardioSleep Program will be unique, uniting three major disciplines of cardiology, respiratory and sleep medicine, and radiology to develop a precision medicine approach. This will help define which patients are at greatest risk and require personalised treatment.”
“We would like to see this valuable research program drive a new approach, and one which will dramatically reduce the number of people who lose their lives prematurely with a combination of sleep apnoea and cardiovascular disease.”
The project has been made possible following funding from the Ramsay Research Grant Program.
Protecting children receiving chemotherapy from hearing loss
Protecting children receiving chemotherapy from hearing loss
Researchers at Ear Science Institute Australia have developed a novel nano-gel therapy to protect children receiving chemotherapy from hearing loss – a common side effect of the cancer treatment.
The project which involves testing the nano-gel in a new study is led out of Ear Science Institute Australia and supported by funding from the Channel 7 Telethon Trust.
A much-needed preventative approach
Lead researcher, Associate Professor Hani Al-Salami, said about half of children who go through chemotherapy will have some degree of permanent hearing loss due to toxicity of the drugs.
“There is currently no proven prevention or cure for this hearing loss, so this new research will test the effectiveness of a nano-gel that is injected into the ear before chemotherapy to prevent the possible side effect of cancer treatment among children,” Associate Professor Al-Salami explained.
“The nano-gel has been developed in partnership with Curtin University by a group of clinicians, pharmaceutical scientists, ENT (ear, nose and throat) surgeons, cochlea physiologists and synthetic chemists using cutting-edge technologies.
“Human bile extract is put through specialised systems to produce a gel, which is capable of being injected into the human ear. It can potentially protect children from the side effects of chemotherapy, which targets and destroys cancer tissues and can also kill other healthy tissues resulting in problems including hearing loss.”
Ear Science Institute Australia CEO, Sandra Bellekom, said it was a very exciting time for ear and hearing medical research in Western Australia.
“The Telethon grant will allow Ear Science to further develop an established and proven nano-gel, improving efficacy and making it safer for use in our children,” Ms Bellekom said.
The Channel 7 Telethon Trust’s support of Ear Science Institute Australia also includes funding for the procurement of a newly developed scanning electron microscope for use in the research, which is capable of micro and nano scale visualisation of critical features of the nano-gel.
SAHMRI researchers are the first in the world to develop a ground-breaking new blood test to measure autophagy, the body’s process of recycling unwanted or damaged cells to stay healthy.
The research study, which sheds light on autophagy in humans like never before, has been published in the journal Autophagy.
A peek into biological aging
Dr Tim Sargeant, Neurobiologist at the South Australian Health and Medical Research Institute (SAHMRI), said the effectiveness of autophagy in an individual is the strongest indicator of how well they will age.
“Previous studies have shown that the better autophagy is, the less prone the individual will be to cancer and chronic disease.”
“We think the higher you score on this blood test, the longer you’re likely to live and live well.”
Researchers are confident autophagy holds the key to improving outcomes for those with incurable neurological diseases like dementia by signalling risk factors for the condition earlier.
“If we can learn more about what causes the process of autophagy to stop and start, we can work towards creating life-changing interventions.”
Findings significant in other health fields
The research development is also greatly significant to the future of nutrition and dieting.
It’s widely held that factors such as food and fasting influence autophagy in the body, but science hasn’t been able to prove it in humans, until now.
“This will lead to us being able to point definitively to what kind of fasting is most effective for people and exactly how much exercise they need to do to increase their autophagy,” explained Dr Sargeant.
“In our view, this is the new frontier of health research and our blood test is really the first step that opens the door to a new world.”
How the test works
The test involves taking a person’s blood and splitting it into two tubes.
The chemical chloroquine is then added to one of the tubes to stop the autophagy process and by comparing this to the other sample, it’s possible to gage how efficiently autophagy is working.
The test is currently in the early stages of development and requires further investigation into its viability for use with patients.
Researchers are optimistic that autophagy measurement will eventually be included in the standard health check-up, like blood pressure and cholesterol tests.
“Our aim is for the blood test to provide clinicians with a baseline from which to experiment with preventative strategies to increase autophagy in their patients; including everything from lifestyle adjustments to drugs.”
The research was carried out in partnership with collaborators at SAHMRI and the University of Adelaide.
The team are currently undertaking investigations that focus on using the test to measure autophagy in those living with a wide range of diseases, with the aim of understanding how this impacts the disease process.
Pioneering endocrine hypertension research to be fast-tracked into hospitals
Pioneering endocrine hypertension research to be fast-tracked into hospitals
After identifying Primary Aldosteronism (PA) as a significant cause of high blood pressure in Australia, Dr Jun Yang is now leading a multi-state program to equip hospitals to treat this form of endocrine hypertension, which until recently has had a low rate of diagnosis.
As Head of the Endocrine Hypertension Group at Hudson Institute of Medical Research and a Consultant Endocrinologist, Dr Yang heads a project designed to work collaboratively with major hospitals for an expected influx of patients with PA.
The project entitled EQUIPPA aims to equip tertiary care for the optimal diagnosis of PA, and thanks to funding from the Medical Research Future Fund in the recent Federal budget, it’s about to be rolled out in four states over the next three years.
The project was awarded $2,993,294 to be distributed through centres in Victoria, New South Wales, Queensland and Western Australia.
It is also a tribute to Professor Michael Stowasser from the University of Queensland, whose research over the past three decades highlighted primary aldosteronism as an important secondary cause of high blood pressure in Australia.
Prevalence of endocrine hypertension
It comes on the back of the recent study, led by PhD student Dr Renata Libianto, in which GPs tested patients newly diagnosed with hypertension for PA and found that its prevalence was much higher than previously thought.
Dr Yang says it is important to ensure the health system is set up to manage these cases appropriately.
“Before our study, Australian GPs reported less than one in every thousand of their patients had PA, but once they started testing for it, the figure jumped to an astounding one in seven or 14 per cent.”
More cases of PA
“If we’re identifying more patients with PA, we need our hospitals and pathology labs equipped to properly diagnose it in a timely, efficient and cost-effective way.”
“We want to prevent the health system from being unable to cope with newly-identified demands,” she said.
This multi-state project is made possible by the work of NSW Health Pathology, Metro South Hospital and Health Service, Qld, PathWest, WA and South East Sydney Local Health District, NSW.
The team encompasses endocrinologists, hypertension specialists, nephrologists, chemical pathologists, radiologists, health economist and Implementation scientists.
As well as the institutions listed above, the EQUIPPA project relies on the work of Hudson Institute of Medical Research, Monash Health, Monash University, University of NSW, University of Qld and University of WA.
In PA the adrenal glands produce too much aldosterone, a salt retaining hormone.
As well as high blood pressure, PA increases the risk of stroke, heart attack and kidney disease, despite being rarely diagnosed.
PA is frequently undiagnosed and a simple blood test could save more than half a million Australians from unnecessary illness, medication and expense.
An Australian-first study led by Hudson Institute of Medical Research, published in the Medical Journal of Australia, found that of the one-in-three Australian adults with high blood pressure (hypertension), at least ten percent have PA.
This equates to approximately 600,000 people in Australia.
This month is May Measurement Month, drawing attention to high blood pressure, which is the number one cause of preventable death worldwide.
Australian first gene therapy for childhood blindness
Australian first gene therapy for childhood blindness
Two Sydney siblings have become the first patients in the country to receive a novel gene therapy that has rescued their vision and holds hope for preventing them from going blind.
The ocular gene therapy, LUXTURNA, is the world’s first approved gene replacement therapy for an inherited blinding eye condition and one of the first gene replacements for any human disease. Approved by the Therapeutic Goods Administration, LUXTURNA is used to treat children and adults with biallelic pathological mutations in RPE65, a rare mutation that leads to vision loss and blindness. It is being distributed in Australia by Novartis.
Therapy has stopped progressive vision loss
Seventeen-year-old Rylee and 15-year-old Saman were both diagnosed with Leber congenital amaurosis, a severe form of retinal dystrophy, in their first year of life. They received the life-changing therapy at The Children’s Hospital at Westmead in late 2020 and early 2021. The therapy has stopped their progressive vision loss and led to some improvements in their vision.
The therapy was delivered as part of Ocular Gene and Cell Therapies Australia (OGCTA), a new collaboration involving the Genetic Eye Clinic at Sydney Children’s Hospitals Network (SCHN), the Eye Genetics Research Unit and Stem Cell Medicine Group at the Children’s Medical Research Institute (CMRI), and the Save Sight Institute at Sydney Eye Hospital and University of Sydney.
CMRI was represented on this project by Professor Frank Martin who is CMRI’s Board President, Professor Robyn Jamieson, Head of the Eye Genetics Research Unit at CMRI and SCHN and Dr Anai Gonzalez Cordero, Head of the Stem Cell Medicine Group and Professor Ian Alexander, Head of the Gene Therapy Research Unit and their teams.
Professor Jamieson is also lead of OGCTA and Head, Specialty of Genomic Medicine, University of Sydney. She said the therapy was revolutionary and would lead to transformation of care for patients with blinding eye diseases.
“Inherited retinal disease is a devastating diagnosis. Up until now, these patients suffered progressive vision loss that led to blindness and there was no therapy for them at all.”
“But through new genomic diagnostics and the use of ocular gene therapy, we are finding that we have the ability to not only stop this ongoing progression but also help to improve vision for people who have RPE65-related retinal vision loss.”
Children and adults born with a mutation in both copies of the RPE65 gene can suffer from a range of symptoms, including night blindness (nyctalopia), loss of light sensitivity, loss of peripheral vision, loss of sharpness or clarity of vision and potentially total blindness.
Replacing faulty genes
Ocular gene therapy works by injecting LUXTURNA under the retina and carrying a functioning RPE65 gene to replace the faulty one, thereby preventing some of these devastating symptoms.
“The real-world improvements in visual function has been quite remarkable bringing to life the rather dry clinical trials outcome measures,” said Professor John Grigg, Head of Specialty of Ophthalmology, Save Sight Institute, University of Sydney and lead inherited retinal disease specialist in OGTCA said.
“It is tremendously heartening to see the changes in vision capabilities for these first patients treated with LUXTURNA.”
“As an ophthalmologist who has been caring for patients with Leber’s amaurosis for many years and unable to offer any treatment, it is incredibly rewarding to now have the opportunity to not only give families hope but also be involved in improving their child’s vision,” said Frank Martin, Clinical Professor in the Specialties of Paediatrics and Child Health and Ophthalmology at the University of Sydney said.
Associate Professor Matthew Simunovic, Vitreoretinal Surgeon, Sydney Eye Hospital and SCHN and Associate Professor at the Save Sight Institute, University of Sydney performed the first surgery and said the benefits of treatment should extend well into the future.
“This is incredibly delicate surgery in which LUXTURNA is injected under the retina, which in some patients can be as thin as a sheet of copy paper. Riley and Saman have had profound improvements in their vision, which mirror the results seen in the pivotal clinical trials.”
“Importantly, such benefits appear to be sustained for many years – in fact, for as long as patients have been followed up. Successfully delivering the first approved gene therapy has been a fantastic team effort, and it underscores Australia’s capability in this field.”
To date, this treatment has been used to treat four patients and while it can only be used to treat this specific form of retinal disease, it does provide significant hope that similar treatments will be able to be applied to other retinal disease genes in the future.
“This heralds a new era in transforming the lives of these people who otherwise have a life of blindness ahead of them and provides hope for more than 15,000 other affected Australians who live with some form of inherited retinal disease,” Professor Grigg said.
Hunt for facial deformity gene ends after 20-year search
A new disease gene discovery began with a Perth PhD student and the world’s largest known family affected by the facial congenital disease, hemifacial microsomia. The research laid the foundation for a match to be found two decades on, in work involving researchers from Yale University U.S.A and affected families in America.
Hunting for disease genes is like putting together an international jigsaw puzzle. The DNA of families across the globe often contributes to the necessary process of cross-referencing discoveries of tiny segments of genetic code to see if they match.
One of the world’s best, Professor Nigel Laing AO at Perth’s Harry Perkins Institute of Medical Research says it’s a Eureka moment whenever a discovery is made.
“In that moment you know you are looking at something no-one else has ever seen, the precise genetic mutation causing a disease that’s affecting families around the world. When you make that discovery you know those families will finally get the answer that they have longed for,” he said.
Families with hemifacial microsomia, a condition where one side of the face is underdeveloped and does not grow normally, have just joined that rarefied group.
Their disease gene has been found.
For the first time families affected by the condition will be able to find out if they are passing it on to the next generation.
Hemifacial microsomia is the second most common facial congenital disability after cleft palate. It affects one in every 3,500 to 4,000 births.
In a very small number of cases, hemifacial microsomia is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. For an adult with the affected gene, each of their children has a 50 percent chance of inheriting the condition.
The disease develops in utero and babies born with facial deformities can need breathing support or a tracheostomy soon after birth if the jaw is severely affected. The condition does not improve with growth. In fact, deformities can get worse.
Children with hemifacial microsomia have an increased risk of hearing loss, speech impairment and feeding problems and, unsurprisingly, can experience psycho-social challenges in childhood.
The hunt begins
Twenty years ago, a hunt for the disease gene began in Perth, Western Australia.
PhD student, now Dr David Chandler, started working with the biggest known family with the condition.
Nine members of the same family were affected. They had been seen by Genetic Services WA, the Department of Health’s clinical genetics service, which works with families to diagnose their condition if possible and provide genetic counselling if wanted.
David Chandler commenced the arduous process of analysing the family’s DNA for clues about what might be causing this genetic disease to see if a diagnosis could be made.
His PhD was supported by a UWA PhD Scholarship and by the National Health and Medical Research Council (NHMRC) Project Grant associated with the NHMRC Fellowship that Professor Laing held at the time.
Internationally renowned geneticist Professor Nigel Laing AO, Head of the Genetic Disease Group at the Harry Perkins Institute of Medical Research, jointly supervised the PhD.
At the time, the technology available limited the search.
“We could narrow down the hunt from three billion base pairs of DNA to 14 million.”
Professor Nigel Laing AO
“We were looking for DNA markers shared by everyone who had the disease and David Chandler found that on a region on a particular chromosome, but without the genetic sequencing technology available today, it wasn’t possible to refine the search further.
“We also needed to cross reference our findings with other families with the condition. We knew of research in Germany but it looked like that family’s condition was on a different chromosome,” he said.
Despite not being able to take the research further the proposed chromosome region of the gene was published in 2001.
Two decades later
Dr David Chandler was awarded his PhD and now works at the Australian Genome Research Facility at Royal Perth Hospital.
Professor Laing is Head of the Preventive Genetics Group at the Harry Perkins Institute of Medical Research where his lab has been involved in the discovery of more than 30 disease genes including one that bears his name, Laing distal myopathy, a condition that causes progressive muscle weakness from childhood.
Professor Laing’s team variously receives support from the NHMRC through Fellowship, Project and Ideas Grants and the Medical Research Future Fund.
In recent years, the team has also been generously supported by The Fred Liuzzi Foundation in Melbourne, The Zac Pearson Legacy in Perth and the family of the late Dr Patricia Kailis AM, OBE, FTSE who conducted world leading genetic research before the mapping of the human genome had occurred. Dr Kailis recorded the world’s first decrease in the incidence of an inherited disease as a result of genetic counselling.
Her family has established the Patricia Kailis Fellowship in her honour to provide funding for mid-career researchers focused on unlocking the secrets and providing treatments for rare genetic diseases.
The link with America
Last year, the senior authors on the West Australian 2001 paper were contacted by Professor Andrew Timberlake at Yale University, U.S.A.
His laboratory had been analysing the genetic code of six other families with hemifacial microsomia, mostly from the USA.
“He said he had identified a possible gene for hemifacial microsomia in the region on the chromosome that matched the region identified 20 years before in our research,” said Professor Laing.
“Professor Timberlake found variants which knocked out the function of a particular gene affecting the growth patterning that influences facial development.
“He’d scoured the published literature and found our 20-year-old research and contacted us.”
The Yale University group were very keen to know whether the Perth family’s DNA had been kept and could be again accessed. They were still believed to be the largest affected family in the world.
The answer was yes.
“We still had DNA of members of the Perth family and Genetic Services WA recontacted the family and updated the family tree which now had 12 affected family members.
“Collaborating with Diagnostic Genomics in Pathwest, we discovered that the Perth family also had the function of the gene knocked out.
“Finally, we could say that the gene causing hemifacial microsomia had been found.”
Dr Chandler was delighted that his research as a young student had resulted in an international discovery.
“It is incredibly exciting to have a genetic search that commenced such a long time ago resolved for families around the world,” Dr Chandler said.
Professor Laing said the discovery gives couples with a history of the disease in their family reproductive choices.
The 2021 research has been published in Nature Communications
Professor Nigel Laing and Dr David Chandler discuss finding the hemifacial microsomia gene
Looking towards better patient outcomes in schizophrenia
Improving antipsychotic drug treatments for schizophrenia patients
Looking towards better patient outcomes in schizophrenia
Researchers at the Illawarra Health and Medical Research Institute are looking to improve antipsychotic drug treatments for schizophrenia patients.
Schizophrenia is a developmental brain disorder, which develops in late adolescence, and affects the perception of reality and thoughts. It is a widely stigmatised and misunderstood condition often associated with unpredictable or violent behaviour. The chronic mental health condition affects 1 in 100 Australians and approximately 20 million people worldwide.
IHMRI’s Distinguished Professor Xu-Feng Huang has dedicated the past 20 years to studying schizophrenia, looking at better ways to treat the condition and improve patient outcomes.
Improving current treatments
Antipsychotic drugs are the most widely used method for treating schizophrenia and are used for a range of other conditions, including bipolar, Alzheimer’s Disease, and Parkinson’s Disease. Figures from the Australian Institute of Health and Welfare show prescriptions for antipsychotic drugs under the Pharmaceutical Benefits Scheme (PBS) increased by 359 percent over a 24-year period from 1992 to 2016.
Despite the wide use of antipsychotic drugs, they come with a host of side effects that can create other health issues for patients. In 2019, Professor Huang secured $1.5 million to support his research into the side effects of antipsychotic drugs used in schizophrenia. The funding formed part of the Federal Government’s $440 million investment in world leading health and medical research projects under the National Health and Medical Research Council’s (NHMRC) grant program.
Professor Huang’s research program investigates neuropathology and side effects of antipsychotics in schizophrenia. Current treatment mainly relies on drug therapy, which does not directly address the fundamental neurite and spine deficits. Drug treatment can cause cortical thinning of the brain, which leads to cognitive impairment, as well as severe metabolic side-effects such as obesity.
“I have a huge concern about the widely used antipsychotic drugs without considering the side effects. It has been prescribed to not only the elderly but to teenagers and even young children.”
Addressing the root cause of negative side effects
Metabolic related side effects impact around 45% of users of antipsychotic drugs with the fat primarily stored around the visceral organs like the heart, liver, and gut.
“The problem with this type of fat is that it is bad fat around the inside of the body, and it can happen within two to three months, so it is rapid. On average, in one year, it can cause up to seven kilograms of visceral fat, which is huge,” said Professor Huang.
Professor Huang explained that because of this fat, the number one killer for patients with schizophrenia is not the disease itself, but a heart attack caused by the metabolic related side effects.
The second research program from Professor Huang’s team, aims to prevent and treat antipsychotic drug-induced obesity and cortical thinning by looking at the pharmaceutics. The aim is to keep the therapeutic side of the drug and remove the negative side effects by reviewing its clinical structure. Researchers hope that by addressing the root cause of these side effects, the use of the drug will be safer long-term for schizophrenia patients.”
A disease like schizophrenia – it’s not like a cold where it lasts for a week – it lasts a lifetime. Therefore, you must be on antipsychotic drugs, and if not, it can get much worse. This is why improving antipsychotic therapy and reducing the side effects is important,” Professor Huang added.