Using human genetics to help understand and treat neurological disorders
Neurological disorders affect the nervous system and can be challenging for individuals and their families. They contribute to an estimated 7% of the total global burden of disease, and there is often a lack of effective treatment options.
Fortunately, by studying our DNA, we can identify the causes of many neurological disorders and learn how to better manage or treat them. New advancements in gene technologies allow us to understand the human genome in ways that were not previously possible. My research group (Wright Lab Neurogenomics Research) at the University of Manitoba started in 2020, and we use human genetics to advance our understanding of neurological diseases and improve their management and treatment. We use a hybrid approach that combines traditional wet lab (or bench science) with computational approaches like machine learning (known as the dry lab) to understand the function of human genes in both health and disease.
How can human genetics identify the causes of rare neurological disorders?
Genes are passed from generation to generation and play an essential role in neurological disorders. Many rare neurological disorders occur from a change or changes in a single gene, but many individuals do not receive an official diagnosis. My research lab is studying a local group of undiagnosed individuals, including children, who are affected by rare neurological disorders using high-throughput sequencing. High throughput sequencing is a method that allows scientists to identify the changes in DNA sequence and understand how genes are regulated (when, where, and how much genes are expressed). This allows us to identify where genes have undergone a change that may be affecting neurologic function. For the first time in Manitoba, we are using an advanced DNA sequencing technology (long-read whole genome sequencing), along with other genetic information from disease-affected tissues, to find genetic variants in genes that are known to be related to certain conditions or diseases. These genetic findings can help end the search for a genetic diagnosis (also known as the ‘diagnostic odyssey’) faced by affected individuals and their families. A genetic diagnosis can be a crucial next step in the effort to improve disease management.
How can human genetics help us find new drugs to treat neurological disorders?
Human genetics holds the key to improving our understanding why the same rare neurological disorder can look different from person to person; for example people affected by the same rare neurological disorder may experience the first symptoms of the disorder at different ages, or may experience differences in symptom severity. These differences occur because of genetic modifiers that modify or change the disease outcomes but do not actually cause the disease itself. Identifying genetic modifiers is helpful because they can potentially be targeted with drugs to alter disease course and ultimately improve health outcomes. In my lab, we are currently studying genetic modifiers in Rett syndrome, which is a rare neurodevelopmental disorder that primarily affects girls and causes loss of motor skills. We use a gene editing system called CRISPR and differentiate human stem cells into three-dimensional brain organoids, which are essentially tiny, simplified versions of the human brain. These techniques allow us to understand the underlying genetic modifiers and determine how they can be targeted with drugs or medications.
What are the future directions for this work?
We aim to expand our rare disease sequencing and genetic modifier work to investigate additional neurodevelopmental disorders. We also plan to continue working with ENRRICH investigators to accomplish this. Finally, in collaboration with other researchers at the University of Manitoba, Drs. Drögemöller and Kowalec, we now have funding to develop local single-cell and spatial genomics infrastructure which we will be applying in our studies. This will allow us to study individual brain cells and gene activity in different brain areas and learn more about brain development in terms of both health and disease.
A note of thanks
I want to thank the team members (undergraduate/graduate students and technicians) from my lab and my network of collaborators for enabling this work. I would also like to thank the following organizations for supporting our work (Brain Canada, Canada Research Chairs Initiative, Canada Foundation for Innovation, CHRIM/ENRRICH, CIHR, HSCF Winnipeg, NSERC, Ontario Rett Syndrome Association, Research Manitoba, University of Manitoba and the Winnipeg Foundation for Innovation).
About the Author
Dr. Galen Wright is an Assistant Professor and Canada Research Chair in Neurogenomics in the Department of Pharmacology and Therapeutics at the University of Manitoba. He is also a Principal Investigator in the Neuroscience Research Program at the Kleysen Institute for Advanced Medicine. Dr. Wright’s research interests lie in the fields of precision medicine, neurology, and DNA repair in the brain. He completed his Ph.D. in Genetics at Stellenbosch University and received additional training in computational biology at the South African National Bioinformatics Institute. Dr. Wright moved to Canada in 2014 and completed a postdoctoral fellowship at the University of British Columbia (UBC). His work at UBC led to the identification of highly predictive genetic biomarkers for various adverse drug reactions, including drug-induced neurotoxicities in pediatric individuals. His precision medicine research includes the investigation of genetic modifiers in neurological disorders, including the neurodevelopmental disorder, Rett syndrome