Grant: Project Grant

This project aims to exploit a new technology that will enable drug and toxin mechanism of action to be determined directly and systematically in human cells. This approach, called chemogenomic profiling, is based on a revolutionary new method called CRISPR/Cas9 genome editing, which allows all genes in the human genome to be simultaneously assessed in a single experiment. Large pools of human cells in which every gene has been individually disrupted in a targeted manner by CRISPR/Cas9 are grown in the presence of a drug, toxin or any other chemical to reveal the genes whose loss confers either sensitivity or resistance to the drug when compared to a non-treated control pool. Analysis of such chemogenomic profiles provides direct genetic evidence for how a drug or toxin affects the cell. We propose here to apply this method to 1000 drugs and toxins of high priority to Health Canada. The type of information revealed by this technology has never been available previously and will transform our ability to establish specificity in early stages of drug development and assess the absence of unintended side effects for approved drugs. The technology will enable the cost-effective and rapid determination of toxin mechanism of action without the need for expensive animal studies. This information will enable extensive current lists of known or suspected toxins to be triaged for more detailed toxicological studies, and thereby save a great deal of time and cost in the assessment of chemical exposure, both to the general public and within specific industries. The retrospective investigation of established toxins will also suggest future means to mitigate the risks of exposure. The ability to rapidly assess drug and toxin effects by chemogenomic profiling will facilitate the development of new drugs and improve environmental safety for the benefit of all Canadians.