Why does Western Australia have such an international reputation for neuromuscular disease research?
History
A personal view by Emeritus Professor Nigel Laing May 2024
Western Australia has a more than 60-year and four generation of researchers’ history and reputation of pioneering neuromuscular and neurological disorder research and diagnosis and development of treatments. My aim is to recount the history in terms of the four generations of neuromuscular and neurological disorders researchers, starting with the first generation where most are no longer with us and ending with the fourth generation who are just starting to emerge. Will there be a fifth generation?
GENERATION I
Professor Byron Kakulas AO
The history of neuromuscular and neurological research and multiple generations of neuromuscular and neurological disorder researchers in Western Australia can, in reality, largely be traced back to one person, the late and remarkable Professor Byron Kakulas.
Professor Kakulas to me epitomises the pioneering spirit of immigrants, or the children of immigrants who had the courage to leave everything behind and start a new life in a country far away. In the case of Western Australia, very far away.
Western Australia is so remote from anywhere else, that there has to be a degree of self reliance, of being willing to tackle the job in hand no matter how hard it is. There is also a freedom to see things differently and see different solutions. In sport this produced world leaders such as Herb Elliot who was winning Olympic gold in Rome in 1960 - around the same time Professor Kakulas was launching his career in medical and fundamental research.
Ultimately in medical research, the West Australian attitude of tackling and seeing things differently culminated in the 2005 Nobel Prize in Medicine or Physiology awarded to Barry Marshall and Robin Warren for showing ulcers were caused by Helicobacter pylori not stress.
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Professor Kakulas had his first single author paper in Nature in 1961. It showed regeneration of muscle in the Quokka, a marsupial endemic to Western Australia (Kakulas 1961). By the mid 1960s he had had two more. It is worthwhile remembering he only received his medical degree in 1956.
Later he would establish a world-class neuropathology department in Royal Perth Hospital and, in 1982, the Australian Neuromuscular Research Institute at QEII Medical Centre which 1 concentrated together neuromuscular and neurological researchers in one location and developed an interwoven team of clinical researchers and fundamental biologists.
Dr Patricia Kailis, AM OBE
Dr Patricia Kailis invented genetic counselling for neuromuscular disorders in Western Australia in the 1960s. In partnership with Professor Kakulas, they developed a battery of test to predict which females in known Duchenne muscular dystrophy families were carriers and which were not. The tests included measuring CK, muscle biopsy and light and electron microscopy. Identifying women with a high likelihood of being a carrier led to a reduction in the incidence of Duchenne muscular dystrophy in Western Australia through their actions creating what would now be called “cascade testing”. Western Australia therefore has a long history of carrier testing and of allowing couples to avoid having a child affected with a severe genetic condition – if that is what they wanted to do.
Professor Frank Mastaglia AM
Professor Frank Mastaglia obtained his medical degree from the University of Western Australia in 1964 and thus his career has run about 10-years after Professor Kakulas. Professor Mastaglia did further training at the Institute of Neurology, Queen Square, London and the Muscular Dystrophy Association Laboratories in Newcastle-upon-Tyne. Although 10years apart, Professors Kakulas and Mastaglia worked hand in glove over decades, with joint publications from 1966 to 2003. Professor Mastaglia has an illustrious history in research into inclusion body myositis. He continues to publish in 2024.
Professor John McHowell AO
Also in the first generation was Professor John McHowell who was the inaugural professor of veterinary pathology at Murdoch University and thus the equivalent in animal research to Professor Kakulas in human neuropathology research. Professor Howell pioneered gene therapy in large animal models of genetic muscle diseases including the golden retriever model of Duchenne muscular dystrophy and McArdle disease in sheep.
GENERATION II
Alan Lamb was a West Australian medical graduate and primary physician. He did his PhD in developmental neurobiology with Dr Martin Prestige at Edinburgh University and then returned to Western Australia to continue his research into motor neuron survival in the spinal cord of Xenopus. Alan was one of the lead fundamental biologists in the Australian Neuromuscular Research Institute in the early 1980s. In later years he became a composer of Aeolian harp music.
Dr Alan Lamb
Emeritus Professor Nigel Laing AO
Dr Teepu Siddique
Dr Allen Roses
Emeritus Professor Nigel Laing gained his PhD in developmental neurobiology with Dr Martin Prestige at Edinburgh University (the same supervisor as Alan Lamb) in 1979. Martin Prestige passed away from his post-polio syndrome during Professor Laing’s PhD. Following a one-year post-doc with Professor Jan Jansen at the University of Oslo, Professor Laing came to Western Australia in 1981 at the invitation of Alan Lamb to join Alan Lamb’s laboratory and knowing Alan Lamb’s Group was scheduled to move into the Australian Neuromuscular Research Institute that Professor Byron Kakulas was establishing.
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Professor Laing studied developmental neurobiology in the chick embryo from 1976 to 1987. Between July 1987 and June 1988, through spending 12 months with Teepu Siddique in Allen Roses’ group at Duke University, Professor Laing transitioned from being a developmental neurobiologist to being a human molecular geneticist. At Duke, he trained in the then revolutionary techniques of linkage analysis through which, for the first time ever, genes causing human genetic diseases could be localized in the human genome and then identified.
Professor Miranda Grounds
Clinical Professor Phillipa Lamont
Returning to Perth, in 1988, Professor Laing was tasked by Professor Kakulas with creating a research neurogenetic laboratory in the University of Western Australia Centre for Neuromuscular and Neurological Disorders within the Australian Neuromuscular Research Institute, and a diagnostic neurogenetic laboratory in the Department of Neuropathology at Royal Perth Hospital.
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In 1988, only one genetic muscle disease gene had been identified, the gene for Duchenne muscular dystrophy. It was only the “new genetics” as it was called, that finally, more than 120 years after Duchenne described the muscle disease that bears his name, identified its cause. While only being able to analyse the DMD gene, the new diagnostic laboratory could f inally provide accurate diagnosis for Duchenne and Becker muscular dystrophy and accurately identify carriers in known families. The RPH Neurogenetic Unit also performed the f irst ever prenatal diagnosis using DNA technology for an unborn boy at risk of Duchenne muscular dystrophy, determined he did not have the family deletion variant and he was born healthy.
At the same time as the RPH diagnostic laboratory was pioneering molecular diagnostics in Western Australia, the research laboratory embarked on establishing human disease gene discovery in the State. The first family the laboratory researched was a very large family with 4 inherited motor neuron disease. Working with Dr Patricia Kailis on this family, the laboratory contributed to the first linkage of a gene for inherited motor neuron disease in the human genome in 1991 (Siddique et al. 1991) and then the identification of the first gene for inherited motor neuron disease as SOD1 in 1993 (Rosen et al. 1993). Identification of SOD1 as the first inherited motor neuron disease was a significant landmark in the history of human genetics, since it was one of the first genes identified for a genetic neurogenetic disorder. The Huntington’s disease causal variant was published a month later.
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There were other large families like the motor neuron disease family in Western Australia and elsewhere in Australia, with dominantly inherited genetic neuromuscular or neurological disorders, because of founder effects of one person emigrating to Australia and then having many descendants who inherited the disease. Professor Laing, working with Dr Kailis and other geneticists around Australia and such families linked and identified the first gene for nemaline myopathy (Laing et al. 1995) and later the first gene for distal myopathy, which became known as Laing distal myopathy (Meredith et al. 2004). Professor Laing was thus one of the pioneers of human disease gene discovery in Australia.
By the early 2010s hundreds of genes had been identified for neuromuscular and neurological conditions and the WA diagnostic neurogenetic laboratory pioneered the use of next generation sequencing targeted gene panels for diagnosing these conditions. The WA diagnostic Neurogenetic Laboratory became and remains an Australasian reference laboratory for diagnosis of these conditions.
The research laboratory continued, and continues, to identify new disease genes not only for neurological and neuromuscular disorders but also for any large dominant families in West Australia including skeletal disorders craniometaphyseal dysplasia in collaboration with a group in Germany (Nurnberg et al. 2001) (which involved the German group exhuming deceased members of the family) and hemifacial microsomia ultimately with a group in the USA (Timberlake et al. 2021) twenty years apart.
In 2003, Professor Laing moved his research group into the West Australian Institute of Medical Research (WAIMR). WAIMR was established to bring together research groups from different fields of research to facilitate building bridges between the Groups and enabling the groups, working collaboratively, to tackle larger issues.
In 2014, WAIMR transformed into the Harry Perkins Institute of Medical Research, where Professor Laing’s Preventive Genetics Group remains based.
Reproductive genetic carrier screening.
As long ago as 1988 Professor Allen Roses proposed that it would be better to find the carriers of Duchenne muscular dystrophy before they had a boy with Duchenne rather than them f inding out they were carriers by having an affected son (Roses 1988). Theoretically, this is a logical thing to do. However, the problem at the time was that there was no technology available that could deliver carrier detection for Duchenne muscular dystrophy at scale. Professor Laing, over his years of working in genetic diseases, came to the conclusion that Professor Roses had been correct and that it was better to find carriers of recessive diseases rather than diagnosing affected children. This conviction came from three directions. 1. From his experiences in identifying genes associated with early onset and severe genetic muscle diseases. 2. From time and again identifying carriers of Duchenne muscular dystrophy and autosomal recessive diseases after they had had an affected child. 3. The overall lack of 5 effective treatments for genetic diseases. In a 2012 review of genetic neuromuscular disorders (Laing 2012), Professor Laing suggested that next generation sequencing could be used to provide carrier screening at scale, taking into account the then recent publication of Stephen Kingsmore’s group doing targeted sequencing of 437 genes associated with severe genetic disease.
Professor Laing then co-organised and chaired an international workshop on reproductive carrier screening as a satellite meeting of the European Society of Human Genetics annual meeting in Glasgow in 2015. This workshop included clinicians and researchers from multiple countries along with patient representatives and reached a workable consensus by the end of the Workshop (Molster et al. 2017). He next co-organised and chaired a meeting in the Perkins in 2016 of clinicians and researchers in Australasia interested in researching the implementation of reproductive carrier screening in Australia. This workshop too reached a consensus on three projects to initiate in Australia.
In May 2018, thanks in large part to the activism of Rachael and Jonathan Casella and other patient advocacy groups, the Federal Government announced in the annual budget that Mackenzie’s Mission, the Australian Reproductive Carrier Screening Project, would be the first project to be funded by the Australian Genomics Health Futures Mission with $20m. Mackenzie’s Mission was run and completed recruiting by the end of June 2022. Mackenzie’s Mission provided the research evidence by which Australia can move towards a national government funded reproductive genetic carrier screening program. If such a program is eventually put in place, it will fundamentally change forever the relationship between Australians and their genetics. Australians will no longer be at the mercy of severe recessive diseases, but have the opportunity if they want to use it to be in more in control of their genetics.
Professor Grounds obtained her first degree from the University of Western Australia but did her PhD with Terry Partridge in London 1978. Professor Grounds first publication was in 1978 and she is still publishing. She therefore has a 46-year history of research into muscle disease and muscle disease treatments. Professor Grounds has had wide-ranging interests in myoblast therapy, regeneration and sarcopenia. She is another West Australian with a worldwide reputation for her neuromuscular disease research.
Professor Phillipa Lamont obtained her medical degree from the University of Western Australia. She completed a PhD with Professor Roger Pamphlett in Sydney and then did further training at Great Ormond Street Hospital in London. Upo n her return to Perth in 1996, she trained in Adult Neurology, mainly at Royal Perth Hospital. In response to the enormous effect the emerging field of molecular genetics was beginning to have in the field of neurology, Professor Lamont established the Western Australian Neurogenetics service, which she continues to lead. Throughout that time, she has also acted as a clinical consultant to the Diagnostic Genomics laboratory, Pathwest. She also leads the Neuromuscular service and clinic at Perth Children’s Hospital. The population of Western Australia in 2024 is only 2.9m people. This is not a large population. However, most patients families in Western Australia with a known or suspected neurogenetic condition will end up being seen in Professor Lamont’s Neurogenetic Service. This generates it seems a never-ending series of undiagnosed patients and families that are enrolled into research projects and result in participation in discovering and publishing many new disease genes – from Laing (MYH7) distal myopathy in 2004 (Meredith et al. 2004) to the FGF14 repeat in 2023 (Pellerin et al. 2023) with others in the pipeline. The research also frequently identifies variants in known disease genes that could only be found through application of new technologies or bioinformatic tools. This extremely successful symbiotic collaboration between Professor Lamont’s Neurogenetic Service and the research Group has been running now for nearly thirty years.
​Professor Steve Wilton AO and Professor Sue Fletcher AO
In the 1990s Steve Wilton became fascinated by the very small numbers of revertant muscle fibres in in the muscle biopsies of boys with Duchenne muscular dystrophy. These revertant fibres are dystrophin positive in an ocean of dystrophin negative fibres. They had somehow managed to cure themselves. Steve managed to show these fibres had alternatively spliced RNAs in the mdx mouse model that bypassed the nonsense mutation in exon 23 (Wilton et al. 1997). From this eventually, working with Professor Sue Fletcher came the exon-skipping 7 oligonucleotide therapy for Duchenne muscular dystrophy that achieved FDA approval. Not many researchers take a fundamental discovery all the way to therapy. This is an outstanding achievement.
Professor Merrilee Needham
Professor Merrilee Needham is the Foundation Chair in Neurology – a joint position between Murdoch and Notre Dame Universities and Fiona Stanley Hospital. Professor Needham obtained her medical degree from Sydney University but did her PhD with Professor Frank Mastaglia which was awarded in 2009 researching, following in Professor Mastaglia’s footsteps, inclusion body myositis. Professors Needham and Mastaglia continue to publish together on the HLA-based genetic predisposition to inclusion body myositis.
Professor Colin Masters FAA AO
Professor Colin Masters is a West Australian neuropathologist who obtained his medical degree from the University of Western Australia in 1970. He then had further training at the Massachusetts General Hospital, National Institutes of Health, USA and Heidelberg. His major field of research has been Alzheimer’s disease. Working in the Australian Neuromuscular Research Institute in the early 1980s his group, in collaboration with Konrad Beyreuther isolated and identified the beta amyloid protein that forms the plaques in the brains of Alzheimer’s patients and Down syndrome patients (Masters et al. 1985). This was a world-leading discovery. Masters, C.L. et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82, 4245-9 (1985).
Generation II – reflection
Looking back, with four members of generation II, Sue Fletcher, Nigel Laing, Colin Masters and Steve Wilton, now made Officers of the Order of Australia, the 1980s and 1990s in the Australian Neuromuscular Research Institute were extraordinary. They began with Colin Masters’ identification of the amyloid protein in the early 1980s. In the late 1980s was the start of disease gene discovery in Western Australia and then in the 1990s came Sue Fletcher and Steve Wilton with their antisense oligonucleotide therapy for Duchenne muscular dystrophy. A small group of researchers in Perth Western Australia took turns in leading the world.
GENERATION III
Selected PhD Students of Professor Nigel Laing
PhD students of Professor Nigel Laing with continuing roles in genetics
Professor Anthony Akkari completed his PhD in 1995. His PhD research included researching and participating in identifying a variant in slow alpha-tropomyosin (TPM3) as the first known cause of nemaline myopathy. Post PhD he worked for years with Allen Roses at Glaxo-SmithKline in North Carolina. He has now returned to Perth and is the inaugural professor of Industrial Pharmacogenetics at Murdoch University. His current research includes research into the genetics and therapies for motor neuron disease.
Professor Anthony Akkari – Murdoch University and Perron Institute
Adjunct Associate Professor Mark Davis – Senior Scientist in Charge, Neurogenetic Unit, Department of Diagnostic Genomics, PathWest Laboratory Medicine, Department of Health, Western Australia.
Associate Profesor Mark Davis completed his PhD, with Distinction, in 2003 on core diseases of muscle including ryanodine receptor (RYR1) diseases. Mark completed his PhD while continuing to work in the diagnostic neurogenetic laboratory at Royal Perth Hospital. Mark has built the diagnostic laboratory into the national referral centre for molecular diagnosis of neuromuscular and neurological disorders that it is. This has included the introduction of next generation sequencing diagnostics for neuromuscular and neurological disorders and successfully applying for a Medicare rebate for genetic testing for these disorders so molecular testing for these diseases is government-funded and can be free for patients. Mark has an international reputation for molecular diagnostics for neuromuscular disorders.
Adjunct Associate Professor Kristen Nowak OAM – Director of the Office of Population Health Genomics, Health Department of Western Australia.
Dr William Wallefeld – Neurologist
Kristen Nowak completed her PhD in 2002. During her PhD, she identified variants in ACTA1, the gene encoding skeletal muscle alpha-actin as a cause of nemaline myopathy (Nowak et al. 1999). She spent two postdoctoral years with Professor Dame Kay Davies in Oxford generating transgenic mice that expressed heart actin in their skeletal muscles. Back in Australia, Kristen crossed these Oxford mice with the skeletal muscle actin knock out mice generated by Jim Lessard’s group in the US. The Lessard Group mice are a model of human recessive skeletal muscle actin disease in having no skeletal muscle actin in their muscles and all died by 9 days post birth. Crossed with the Oxford mice so that they had cardiac actin 9 in their skeletal muscle, the Lessard mice lived as long as two years (Nowak et al. 2007). The experiment demonstrated that heart actin could cure the skeletal muscle actin knock out mice and was therefore a target for therapeutic intervention. Adjunct Associate Professor Nowak was the World Muscle Society Young Myologist of the Year (best early to mid-career muscle disease researcher in the world) in 2012. Adjunct Associate Professor Nowak sought new challenges in the mid to late 2010s and is now Director Office of Population Health Genomics – leading integration of genomics into health department policy in Western Australia and nationally including in newborn screening and carrier screening.
Dr William Wallefeld obtained his PhD in 2011 researching the genetics and pathobiology of Laing distal myopathy. On completing his PhD, Dr Wallefeld retrained in medicine. He is now one step from being a consultant neurologist. He will then be approaching neurogenetic diseases from the clinician’s viewpoint.
Associate Professor Ravenscroft obtained her PhD in 2009. During her PhD she worked on the mouse models of skeletal muscle actin disease, including rescuing the skeletal muscle actin knock out mice. This was greatly facilitated by her background in muscle physiology. Later, she was first author on the publication demonstrating that transgenic cardiac actin could ameliorate the phenotype of dominant mouse models of skeletal muscle actin disease (Ravenscroft, McNamara, et al. 2013). During her PhD, Associate Professor Ravenscroft also worked in disease gene discovery. In the early 2010s, she pioneered the use of next generation sequencing in disease gene discovery, resulting in leading or participating in identifying multiple genes associated with recessive foetal akinesia eg (Ravenscroft, Miyatake, et al. 2013). She has continued disease gene discovery research to the present day. Associate Professor Ravenscroft has also led implementation of new technologies into the diagnostic space in the PathWest Neurogenetic Unit and continues to research therapies for genetic muscle diseases. She is internationally renowned for her research. Associate Professor Ravenscroft was the World Muscle Society Young Myologist of the Year (best early to midcareer muscle disease researcher in the world) in 2017. She is an elected member of the Executive Board of the World Muscle Society. She is President of the Australian Association of Research Fellows. Associate Professor Ravenscroft is currently funded by her third consecutive Australian National Health and Medical Research Council Fellowship.
Associate Professor Gina Ravenscroft – Group Leader Rare Disease Genetics and Functional Genomics Group, Harry Perkins Institute of Medical Research
Dr Royston Ong
Dr Macarena Cabrera-Serrano – Neurologist and genetics researcher Seville, Spain and Perth
Dr Macarena Cabrera-Serrano is a consultant neurologist from Seville in Spain, who carried out the research Part of her University of Seville in Professor Laing’s research Group in Perth. She completed her PhD in 2015. During her PhD, she learned how to apply next generation sequencing techniques to neuromuscular and neurogenetic disorders. She continues multiple, highly successful collaborative projects with Associate Professor Ravenscroft, spending time in Perth and Seville each year.
PhD awarded 2021. Dr Ong during his PhD was instrumental in completing the West Australian pilot study of preconception carrier screening which recruited from a limited number of sites in the Perth metropolitan area and the regional town of Busselton. Dr Ong also performed a survey of the attitude of West Australians to reproductive carrier screening, which showed a significant appetite for carrier screening (Ong et al. 2018). Dr Ong’s successful completion of the WA pilot study was a significant stepping stone towards Mackenzie’s Mission, the $20m Medical Research Future Fund nationwide reproductive carrier screening project. Dr Ong later left research to use his skills in more secure employment.
Sam Edwards – Genetic counsellor, PhD student
Sam Edwards was the genetic counsellor on the West Australian pilot study of reproductive carrier screening and the West Australian, Queensland and South Australia project officer for Mackenzie’s Mission. She is now working on a PhD on the genetic counselling needs for nationwide carrier screening programs.
references
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Masters, C. L., G. Simms, N. A. Weinman, G. Multhaup, B. L. McDonald, and K. Beyreuther. 1985. 'Amyloid plaque core protein in Alzheimer disease and Down syndrome', Proc Natl Acad Sci U S A, 82: 4245-9.
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