Parkinson’s researcher burns bright
As a teenager in Devon, England, Dr. Matthew Farrer spent much of his summers working with children, teenagers and adults with neurologic and psychiatric illnesses. All were cared for in institutionalized settings. He had fun playing with children with Down syndrome and found it humbling to feed a teenager of his own age with cerebral palsy. But working with patients suffering from Alzheimer’s disease, Parkinson’s disease and different forms of dementia was another matter.
It was tragic, recalls Farrer, now Professor in the Department of Medical Genetics, Canada Excellence Research Chair in Neurogenetics & Translational Neuroscience and Don Rix BC Leadership Chair in Genetic Medicine at the University of British Columbia. Patients had no meaningful therapy and little hope. Patients who recognized their plight often sought escape on the train tracks nearby.
He vowed that, one day, he would find a way to help people with debilitating brain diseases – and he has kept that promise in a spectacular way.
His groundbreaking work in molecular genetics is unravelling the mysteries of degenerative brain disorders, especially Parkinson’s disease (PD). Where no hope existed, he has furthered our understanding of PD, identifying many of the defective genes that cause this disease. He is confident that, in less than 10 years, possibly even 5, this research will lead to effective treatments.
Farrer began his revolutionary work in PD at a time when physicians believed that the disease was not inheritable. After earning a PhD in human genetics at St. Mary’s Hospital Medical School, London, UK, he came to the Mayo Clinic, USA, to pursue postdoctoral studies in dementia. The retiring chair of neurology, Dr. Manfred Meunter, sent his unpublished manuscript on parkinsonism-dementia to Farrer – a story that began in 1924 with an Iowa farm family, several generations of which had fallen victim to PD. No one had found the cause.
“It was a wonderful pathological, biochemical and neurotransmitter description of three brains of people from the same family with Parkinson’s,” he says. “That started me off.”
He spent many years looking for family members who had fled the family farm after physicians and neuroscientists alike had attributed their illness to environmental causes.
Although at least five generations had been afflicted with PD, every doctor whom they consulted had told them that PD was not an inheritable condition, because that’s what medical textbooks taught at the time.
“I’m a geneticist, so I believe that everything in biology has a heritable component, even a predilection to chocolate,” Farrer jokes. “When they said to me, there are no genetics in PD, I was steadfast in my conviction that they were incorrect.”
He remembers arriving on the doorstep of a Seattle home on rainy night to meet family members with Katrina Gwinn, formerly a movement disorders neurologist at Mayo Clinic. As he approached the house, he heard crying and wailing. He knocked on the door and a Hell’s Angel answered. The man demanded why he was there.
“I’m here for your blood,” he replied.
The crying came from the man’s grieving mother. She had lost her husband to PD, and one of her sons in his thirties was severely affected with the disorder. His young family played at his feet. Another son was later found to be a carrier.
Several teams of Mayo clinic researchers had visited the family over the years, but none had reported back any results or performed any genetic analysis.
“I’ve had so many humbling experiences with patients and families affected by this condition. I promised myself I’d do better, and I’d let them know” he states. “I’m all about accountability. Transparency and accountability are part of my core values.”
He spent six years performing genetic linkage analysis to find the culprit gene and discovered the molecular mechanism underlying the family’s disease. He and his team published their findings in Science in 2003. Now, at least a half dozen pharmaceutical companies have been inspired to push targeted drugs into clinical trials.
Mapping PD genes
Farrer has made some of the most significant contributions to genetic research into PD in the past two decades. His influential discoveries have led to paradigm shifts in the way that researchers regard the disease. His work is showing how and why PD occurs.
Based on his gene-mapping studies, researchers now know that PD is not triggered by a single mutation, but that it is a complex disease with multiple genetic causes.
Farrer and his team are chasing down PD-related mutations in populations around the world. In Norwegian fishing villages, they discovered Lrrk2 G2019S, now appreciated as the most common genetic cause of PD. Its ancestral origin is in the Berbers of North Africa, where it explains disease in 30% of all patients. They found a far more frequent albeit lower risk variant in the same gene in 6% to 8% of all patients throughout Asia, from Taiwan to Korea. Closer to home, they have discovered a different gene and pathogenic mutation for PD in Mennonite families spread across five Canadian Provinces.
He and his UBC team have recently helped to discover at least two more new genes for PD, one recessive and one dominant, yet to be published. “They’re pieces of the puzzle that tell us what the disease is really about, at a human molecular and physiologic level,” he says. “We now have the corners and most the edges. It’s connecting the rest, the blue sky, that remains.”
Finding a genetic mutation is the first step to effective therapy. The second step is to investigate how that mutation leads to PD and test how various drug compounds might correct that problem.
Functional neuroscience needs animal models in order to do that work. So, Farrer and his team used subtle genome engineering to create mouse models of genes that are dysfunctional in PD. “The brain is complex. Even a mouse has about a trillion synapses (functional connections between brain neurons), and a person has about 1500 times as many,” he explains.
“Parkinson’s is a very subtle disease. It takes about 70 years to manifest motor symptoms and, because of that, I don’t expect a mouse to develop overt pathology or debilitating movement disorder in its lifetime.
“Our models are designed to recapitulate the human genetics of PD, to see consequent effects on brain physiology. Then we must use sensitive techniques like electrophysiology to see subtle changes in neurotransmission.”
They have modelled many genes implicated in PD and have made innovative strides in exploring areas of the brain that control movement. “It’s initiation and fine motor precision that’s are problematic in PD,” he says.
Fire in the brain
But PD is more than a simple movement disorder, he maintains. It also affects the peripheral nervous system leading to autonomic, cognitive, psychiatric, sleep and sensory problems.
In Lrrk2 G2019S, a dysregulation of synaptic communication occurs early in the development of disease. Neuronal firing goes awry. “There’s a leaky neurotransmission and it’s happening at a network level – not just with one type of chemical messenger or one neurotransmitter system or one set of neurons,” he explains.
“In brain function, tremendous compensation occurs. It’s all about balance. The brain basically manages that balance by up regulating some parts and down regulating others, to control this blazing fire of neuronal activity, but that ability to compensate fails over time with age, and then symptoms start to manifest.”
In other words, the candle burns too brightly and doesn’t last as long. Lrrk2 G2019 speeds synaptic senescence (aging). The question now is what can be done about it? Farrer thinks that precision medicine is the way to go, targeting the underlying problem in mutation carriers to prevent PD from manifesting.
“In this case, those drugs have already been developed but clinical trials must be cautiously designed to prove efficacy and long-term safety” he says.
Refractory epilepsy in newborns and more
Some of most gratifying translational neurogenetics and neuroscience that keeps Farrer going every day is making a difference for children and families with refractory epilepsy – from newborns to infants whose seizures are not controlled by two or more medications. Their prognosis is extremely poor. Survivors become developmentally incapacitated, because seizure activity interferes with normal brain growth.
His laboratory has been performing rapid diagnostic DNA testing for these infants as a clinical service for some years. While provincial agencies deliberate to fund the work, Farrer explains, “I couldn’t say no.” Admittedly, there are relatively few labs in the world with the expertise in genetics and bioinformatics. “We sequence the whole coding genome. In about 30% of children, we find the cause; in 16%, we change care.”
Frustrated by the translational gap between advances in neurogenetic research and clinical care, Farrer has begun a new enterprise, a company called Neurocode Laboratories Inc. It’s an ethical and social partnership to make and mine sequencing data related to brain disorders, make that data useful and accessible worldwide, and drive advances in diagnosis and treatment.
“Parkinson’s is my love,” Farrer admits. “It has taken time to discover the genes and to model that biology, but clinical trials have begun.” While his accomplishments should be enough for one career, Farrer is driven by his beginnings, the devastated lives of patients and families, and the promises that he’s made along the way.
“Precision medicine, based on genetic insight, is where we’re going” he says. “But to predict and prevent brain disorders are paradigm shifts for the medical profession, which diagnoses and treats symptoms but seldom causes. Another challenge is whether pharmaceutical companies will invest in personalized, genetically informed treatments.”
Farrer says, “Healthcare authorities and big Pharma must react to this revolutionary change, as most expect them to lead the way.”
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