Experimental genetics provides a powerful window into complex biological processes. Recently we have developed an entirely novel genetic model system to expand the toolbox for genetics in human cells. This method enables efficient inactivation of human genes by a single mutation using insertional mutagenesis in cells that are haploid or near-haploid. We have used haploid genetic screens to identify genes that play a role in human disease. This led to the identification of the lysosomal cholesterol transporter NPC1 as the long-sought intracellular receptor for Ebola virus, the first cellular entry receptor used by a Clostridium difficile toxin and numerous host factors needed for construction of the Lassa virus entry receptor. Beyond its application in infectious disease we use haploid genetics to identify genes important for drug-action or to search for cancer cell vulnerabilities.
In parallel, we are also interested in understanding the mechanisms that control organ size. How tissues stop growing upon reaching a certain size remains a mystery in biology. This is likely relevant for tumorigenesis because tumor cells are able to bypass normal growth control and continue to proliferate unabated. Drosophila genetics has increased our understanding of the biology of organ size control, and the Hippo signaling pathway has emerged as a key regulator. Interestingly, all the components of the Hippo pathway are conserved in mammals and some have been implicated in cancer. We use genetic mouse models and biochemical methods to address how this signaling pathway regulates tissue size in mammals and how it contributes to tumorigenesis.