Dr. Matt Farrer earned degrees in Biochemistry (BSc 1991) at King’s College and Human Genetics (PhD 1996) at St. Mary’s, Imperial College, London. His early research focused on the human genome draft and contributed to the first genetic and physical maps of chromosome 21. His doctoral thesis was in statistical and molecular genetics applied to complex (sporadic) traits. Dr. Farrer did postdoctoral training in Medical Genetics (Kennedy-Galton Centre, UK) and Neurogenetics (Mayo Clinic, USA). His independence came with a Faculty appointment in Molecular Neuroscience at Mayo Clinic in 2000. He relocated to Vancouver, Canada and The University of British Columbia in 2010 where he is currently the Rix Chair in Genetic Medicine and a Canada Excellence Research Laureate. Dr. Farrer is the Specialty Editor for Frontiers of Neurology, in Neurogenetics. Dr. Farrer has played a pioneering role in the genetic epidemiology of Parkinson’s disease (PD) and its molecular neuroscience. His original contributions include several mutant gene discoveries in late-onset parkinsonism, for example, alpha-synuclein (SNCA) triplication/duplications, LRRK2 including p.G2019S, VPS35 p.D620N and RME-8 p.N855S, and discoveries in early-onset/atypical parkinsonism, including DCTN1 Cap-Gly and DNAJC12 null mutations. Dr. Farrer has generalized many of those discoveries by candidate gene association to idiopathic PD in worldwide populations, including SNCA, LRRK2, MAPT and GBA. He also co-authored the first genome-wide association studies in PD and progressive supranuclear palsy. In parallel, and always upon a genetic foundation, Dr. Farrer creates and characterizes models of mutant gene dysfunction. These include SNCA overexpression, LRRK2 p.G2019S and VPS35 p.D620N knock-out and knock-in animals. Dr. Farrer’s neuroscience largely focuses on the dopaminergic system in these mice, where phenotypes relevant to the human condition are subtle and require physiologic approaches to study.
Parkinson’s, penetrance and the development of precision medicine
Parkinson’s disease (PD) is a multifaceted, age-associated syndrome best known for movement disorder but also affects autonomic, cognitive, psychiatric, sensory and sleep systems. Progressive loss of dopaminergic neurons disrupts cortical and thalamic neurotransmission, and the ability to modulate striatal outputs necessary to initiate and control motor function. Compensation is profound, the symptoms insidiously emerging as it fails. Mid-brain Lewy body pathology is typically noted at post-mortem but its relationship with respect to clinical symptoms remains enigmatic. In the past 20 years the genetic analysis of Parkinson’s disease has challenged and helped re-defined its epidemiology, clinical subtypes and pathologic criteria. Monogenic discoveries, in particular, provide a wonderful framework for translational biology and for pathogenesis, though they currently highlight more gaps in our molecular knowledge of dopaminergic function, synaptic-endosomal recycling, chaperone activity, mitochondria, microautophagy and immunity than they solve. Nevertheless, on this genetic background specialty Pharma have begun to invest in disease-modification (neuroprotection) trials, to slow or prevent parkinsonism in genetically-defined patients (precision medicine). Symptom onset and progression in such patients remains challenging to predict, penetrance is variable and incomplete. My seminar will illustrate how clinical presentations and penetrance were just as challenging to the research that nominated those genetic targets, and will re-consider missed (future) opportunities.