A systems-based approach to schizophrenia: integrating patient-derived olfactory neural stem cells and multi-omics for personalised therapy
Alexandre S. Cristino(1)
(1) Neurogenomics and Systems Biology Lab, Institute for Biomedicine and Glycomics, School of Environment and Science, Griffith University, Nathan, QLD, 4111
Schizophrenia is a highly polygenic disorder in which hundreds of risk variants, predominantly located in non-coding regulatory regions, collectively disrupt gene regulatory networks and core cellular processes. Moving beyond neurotransmitter-centric models, there is growing recognition that disease mechanisms operate at the level of systems biology, affecting subcellular organisation, cell dynamics, and gene network architecture.
Here, we present a systems-based strategy that leverages patient-derived olfactory neural stem (ONS) cells to identify personalised therapeutic interventions for schizophrenia. We generated a comprehensive phenotype/multi-omics dataset from schizophrenia patient-derived ONS cell lines and unaffected controls integrating whole-genome sequencing, transcriptomics including long, small, and circular RNAs, proteomics, and quantitative high-content imaging.
Our analytical framework combines genome-wide association study (GWAS) signals, Connectivity Map (CMap) drug-induced transcriptional signatures, cell-specific expression profiles, and regulatory elements to identify disease-relevant gene networks and candidate therapeutic compounds. Using this integrative approach, we map molecular perturbations onto quantifiable cellular phenotypes.
We demonstrate that schizophrenia-derived ONS cells exhibit reproducible alterations in cell architecture and dynamics, including changes in cell area and morphology, mitochondrial and endoplasmic reticulum organisation, and cell motility parameters. These phenotypes are linked to dysregulated gene networks involved in cell adhesion and migration, which show convergence with GWAS loci and drug-response signatures.
Importantly, our framework enables the prioritisation of FDA-approved drugs predicted to reverse patient-specific gene expression patterns and cellular phenotypes. We also exploring small RNA treatment to reverse dysregulated genetic programs. This study establishes a scalable platform for linking genetic risk to functional cellular readouts and therapeutic response, advancing precision medicine strategies for schizophrenia.
Bio
Dr Alexandre Cristino is a molecular biologist and bioinformatician specialising in systems biology and functional neurogenomics. He leads a multidisciplinary research program integrating multi-omics, high-content imaging, and computational modelling to elucidate gene regulatory networks in neurological disorders.
He has established a systems-level framework linking genetic variation to cellular phenotypes in patient-derived stem cell models, with a strong focus on schizophrenia and neurodegeneration. His work has contributed to high-impact publications in leading journals including Nature, Science, Molecular Psychiatry, Nature Communications, and Blood, with a sustained track record of influential first, corresponding, and senior author papers.
Dr Cristino has secured over $9M in competitive research funding as a lead or co-investigator, including major awards from NHMRC, MRFF, and ARC. He has supervised 20 higher degree research students and built collaborative programs spanning bioinformatics, molecular biology, and translational neuroscience.
His research aims to advance precision medicine by integrating multi-omics data with functional cellular assays to identify disease mechanisms and prioritise targeted therapeutic interventions.
