Research and Labs
The overarching goal of the Institute of Genomic Medicine (IGM) laboratory research is to create an ecosystem that begins with clinical gene discovery, moves onto the bench, and then to bedside— all with the aim of improving the prognosis of individuals with genetic disease. IGM laboratory research is intricately connected to IGM’s human genetics and genomics efforts and to Columbia’s Precision Medicine Initiative. Current research focuses most heavily in the area of neurodevelopmental disease, including intractable seizure disorders of childhood and the equally refractory accompanying cognitive and neurosensory features.
Genetics is fundamental to the applied research at IGM. Genetic abnormalities—either inherited or arising during fetal development (so-called de novo mutations)—account for an appreciable amount of human disease. Disease genes and interactions between the encoded mRNA and/or proteins represent new opportunities for targeted therapeutic discovery and development.
There are two facets of genetics research at IGM. First, our human genetics and genomics team leads local and international partnerships with clinicians and industry leaders to facilitate gene and pathogenic variant discovery across a number of diseases. To this end, IGM is developing and optimizing novel approaches to analyzing exome and whole genome sequencing data.
Second, our applied research arm then combines genetic engineering and a multi-modal approach in animal and cellular disease models to understand the functional and molecular etiology of gene mutations. It is our conviction that the unique integration of clinical genetics and functional studies is essential for the mechanistic insight necessary for the development of effective new therapies.
IGM’s applied research group largely focuses on neurodevelopmental disorders. Our primary emphasis is on rare, often intractable, pediatric epilepsy for two important reasons: The genetic bases of epilepsy are more securely understood than for other neurodevelopmental disorders, and epilepsy is often co-morbid with sleep disturbances, intellectual disability, and autism. Much of our research involves identifying mutation-specific defects as well as common mechanistic insights into the molecular etiology of various epilepsies with an aim to develop targeted treatments.
For functional insight into genetic disease, it is critical to understand how genes behave or misbehave. At IGM, we place particular emphasis on genetic disease models that recapitulate patient genotypes. No disease model is flawless, which is why it is important to examine the effects of mutations in different species and at varying levels of biological complexity. Currently, we have more than 10 genetic mouse models and more than seven human stem cell models of genes that cause a range of neurological phenotypes. We use both rodent and human stem cell models engineered with patient-equivalent mutations identified in clinical studies to study a mutation’s effects at the organism and cellular levels, offering the opportunity to explore different biological functions, including:
- Activity propagation
- Synaptic vesicle release
- Synaptic transmission
- Postsynaptic scaffolding
- Cell signaling
- mRNA metabolism
- Cytoskeletal dynamics
Human Stem Cell Models
|Gene||Variant Genotype||hPSC Type||Derivation|
|ATP1A3||Homozygous KO||ESC (WA09)||Edited|
Genetic mouse models are crucial for understanding a given mutation’s effects on behavior, brain morphology and function. Functional characterization of primary neuronal networks from mutant mice affords a greater level of detail into pathobiology and represents a more tractable model for initial drug screening efforts. Recognizing that there are significant species differences between mice and humans at the organism and cellular level, we also employ neuronal and neural network models derived from human pluripotent stem cells, which can be studied in 2D as monolayer cultures or in 3D as organoids, to identify mutation-specific effects on neurodevelopment and activity.
|Gene||Variant Genotype||Seizure Activity||Aberrant|
|GNB1||D76G||(in progress)||(in progress)|
|SZT2||KO, cKO||Low seizure threshold||(in progress)|
|ARFGEF1||KO||Low seizure threshold||Yes|
|HNRNPU||KO||Low seizure threshold||Yes|
|STXBP1||KO||Spike-wave discharges||(in progress)|
The powerful combination of studying the same pathogenic mutations in clinically relevant human cell populations and in mice provides important scientific rigor to design more effective therapeutics.