Cell fitness is an omniphenotype

ABSTRACT Moore’s law states that computers get faster and less expensive over time. In contrast in biopharma, there is the reverse spelling, Eroom’s law, which states that drug discovery is getting slower and costing more money every year. Herein, we propose a solution to this problem. We put forth a consensus algorithm for inexpensively and rapidly prioritizing new factors of interest (e.g., a gene or drug) in human disease research. Specifically, we argue for synthetic interaction testing in mammalian cells using cell fitness – which reflect changes in cell number that could be due many effects – as a readout to judge the potential of the new factor. That is, if we combine perturbing a known factor with perturbing an unknown factor and they produce a synergistic, i.e., multiplicative rather than additive cell fitness phenotype, this justifies proceeding with the unknown gene/drug in more complex models where the known perturbation is already validated. This recommendation is backed by the following evidence we demonstrate herein: 1) human genes currently known to be important to cell fitness involve nearly all classifications of cellular and molecular processes; 2) Nearly all human genes important in cancer – a disease defined by altered cell number – are also important in other common diseases; 3) Many drugs affect a patient’s condition and the fitness of their cells comparably. We provide proof of concept of the Omniphenotype model using the widely used osteoporosis drug, bisphosphonates, implicating its mechanism of action (MoA) genes, ATRAID, SLC37A3, and FDPS, as potential gerotargets for neurodegenerative conditions. Taken together, these findings suggest cell fitness could be a broadly applicable phenotype for understanding gene, disease, and drug function. Measuring cell fitness is robust and requires little time and money. These are features that have long been capitalized on by pioneers using model organisms that we hope more mammalian biologists will recognize. Short summary Cell fitness is a biological hash function that enables interoperability of biomedical data.