Transport Biology
How molecules reach their destination and what happens when they don't
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Disease Mechanisms
Identifying hidden biological defects in genetic disease
Precise Measurement
Mass spectrometry to define molecular fingerprints
Translation
From molecular fingerprints to mechanism and therapy
Transport Biology: How molecules reach their destination and what happens when they don't
A vitamin cannot support metabolism if it cannot reach the cellular compartment where it is needed. Our laboratory studies the transporters that move vitamins, cofactors, and metabolites across biological membranes, and how defects in these pathways cause disease.
Using genome-wide CRISPR screening and metabolomics, we identified SLC25A38 as the transporter required for mitochondrial accumulation of PLP, the active form of vitamin B6 (Pena et al, 2025, Nature Communications), providing a mechanistic explanation for congenital sideroblastic anemia. We are now extending this work to other transport pathways, including SLC52A2 in riboflavin transporter deficiency and SLC19A1 in folate metabolism and acute myeloid leukemia.
By defining how vitamins and cofactors move between cells, organelles, and metabolic pathways, we aim to uncover fundamental principles of human metabolism and identify new opportunities for therapeutic intervention.
Disease Mechanisms: Reading the Biochemical Fingerprint of a Gene Defect
Finding the gene behind a rare disease is only the first step. The next, and perhaps harder question is what that gene's loss does to a cell, and why that harms a child.
Every rare disease leaves a unique molecular fingerprint: a characteristic pattern of changes in metabolites, proteins, organelles and cell features. We model patient variants in cells and animals and read these fingerprints by combining metabolomics, proteomics, organelle profiling, functional genomics and cellular imaging. These signatures reveal what a gene does, which pathways fail, and which molecular changes come first. We are applying these approaches to mucopolysaccharidosis type I (MPS-I), pyridoxine-dependent epilepsy (PDE), and other rare diseases through collaborations within Care4Rare.
They can also help families still waiting for a diagnosis. When genetic testing finds a variant of uncertain significance, we test whether it produces the same fingerprint as a known disease-causing mutation. A match gives clinicians the functional evidence they need.
Precise Measurement: From Molecules to Mechanisms
Understanding disease begins with precise molecular measurements. Many of the molecules disrupted in rare metabolic disorders are difficult to detect because they are present at low abundance, chemically unstable, or confined to specific cellular compartments.
Dr. Pena established the CHEO-RI Mass Spectrometry Unit, which combines a Thermo Scientific Orbitrap Exploris 240 for discovery-based metabolomics with a Waters Xevo TQ-S platform for highly sensitive targeted analysis. Together, these instruments allow us to quantify vitamins, cofactors, drugs and metabolites across cells, tissues, biofluids, and purified organelles.
To understand how genetic variation alters cellular function, we integrate mass spectrometry with CRISPR-based genome engineering, high-content imaging, organelle profiling, and disease models ranging from patient-derived cells to induced pluripotent stem cells (iPSCs) and mice. These complementary approaches enable the generation of molecular fingerprints that reveal gene function, disease mechanisms, biomarkers, and opportunities for therapeutic intervention.
Beyond supporting our own research, the CHEO-RI Mass Spectrometry Unit will provide metabolomics, and targeted analytical tools to investigators across CHEO-RI and the University of Ottawa, expanding access to advanced analytical technologies.
Translation: From Mechanism to Intervention
Understanding disease mechanisms creates opportunities for intervention. Our laboratory searches for biomarkers for diagnosis and disease monitoring, investigates metabolic and gene-directed therapies, and works closely with clinicians to translate molecular discoveries into improved patient care. We also partner with families, rare disease foundations and patient organizations (CureRTD, CurePDE) to ensure that our research addresses questions that matter most to affected communities.
Current efforts include therapeutic development for congenital sideroblastic anemia, studies of metabolic rescue in riboflavin transporter deficiency, and biomarker discovery and disease stratification in mucopolysaccharidosis type I.
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