The tight efficacy study, with outcome data of which the basic pharmacologist would be proud and economy in sample size, is a hallmark of our Clinical Pharmacology and Therapeutics core team [Dr R John Dobbs DCH MD FRCP & Sylvia M Dobbs MSc MD FRCP (Clinical Pharmacologists/Hon Consultant Physicians, Dr André Charlett MSc PhD (Statistician/Head of Statistics, Modelling and Economics, Centre for Infectious Disease Surveillance and Control, PHE, London) & Dr Clive Weller DIC PhD MIEE CEng (Biomedical Engineer)]. Work on the aetiopathogenesis of Parkinson’s disease grew from developing methodology to answer fundamental therapeutic questions, such as tolerance to anti-parkinsonian treatment. Growing collaboration across clinical and academic boundaries is crucial to the problem solving. Conventional approached may have limited potential: major advances are not made on bandwagons, but by thinking the unthinkable, not accepting dogma, and reviewing the obvious. Since the shaking palsy (a syndrome of poverty and slowness of movement and muscle rigidity, with a characteristic tremor and stooped posture) was described in 1817, there have been few therapeutic milestones. Indeed, the only major advance, dopamine-substitution therapy, dates back to description of dopamine deficiency in basal ganglia in 1960. No medicines are currently licenced for disease-modification. Therapies targeting processes (e.g. ant-oxidants and non-steroidal anti-inflammatory agents) have been unsuccessful. Manufacturer-led trails targeting the characteristic proteinopathy are predicted 0n prion-like replication being the primary process. Targeting aetiopathogenesis, rather than just phenotypic descriptors of disease, has the potential to open doors on cost-effective screening, prophylaxis, amelioration of the underlying processes and cure. This is our motivation and excitement, intervention in a pre-clinical state the goal. Definition of pre-presentation states in functional and pathophysiological terms is a cornerstone, longitudinal, objective follow-up a must. This is the story behind our research programme.