Columbia systems biologists have developed unique, leading methods for ‘omics data analysis, resulting in elucidation of key genomic events and regulatory mechanisms driving disease initiation, progression, and drug sensitivity in cancer, neurodegenerative, and neurobehavioral disease. These methodologies have produced novel approaches for the study of pharmacologically actionable disease dependencies, whether functional or genomic based, leading to highly innovative clinical trials, including studies for the selection of therapeutic approaches in individual patients targeting non-genetic vulnerabilities of the tumor (N of 1 studies), with very promising initial results.
Disease initiation and maintenance results from aberrant activity of key proteins working in concert to induce pathological cell states. This results either from their genetic/epigenetic (genomic) alteration or, more frequently, from alterations in their upstream regulators. Indeed, except for a small number of high-penetrance alterations, most common diseases, including cancer, result from additive or epistatic convergence of multiple DNA sequence variants, each one presenting extremely low penetrance. Systematic elucidation and pharmacological modulation of the mechanisms by which these diverse alteration patterns converge to induce virtually indistinguishable disease in individual patients, represents perhaps the ultimate and most formidable challenge we intend to tackle through precision medicine. Systems biology promises to address this challenge by systematically reconstructing and interrogating the cell’s mutational landscape and the regulatory/signaling logic responsible for its pathogenic integration.