Decoding cellular circuits to identify therapeutic targets

Employing the Cell-seq technology, the Brummelkamp laboratory (inventor of Cell-seq) and Scenic Biotech BV (exclusive license holder of Cell-seq) have already established Phenosaurus, a database containing about 100 haploid screens. Each screen reveals whether the inactivation of a particular gene results in changes in expression or activity status of a specific protein. As the latter are the workhorses of the cell, playing important roles in cellular processes such as repairing DNA damage or cell division, Phenosaurus contains millions of links between genes and cellular processes. In this project the Brummelkamp laboratory, Scenic Biotech BV and the Wessels laboratory will further expand Phenosaurus and employ it to perform advanced computational analyses to reconstruct the cellular circuits that describe how genes control cellular processes.

Societal and economic impact: A more complete understanding of the cellular circuits that control important processes in the cell will reveal ways in which we can safely interfere therapeutically in abnormal processes, with the aim to rebalance disease. More than 7,000 distinct types of rare disease exist and 80% of the rare diseases are caused by genes that do not function well. Only 5% of rare diseases have an FDA approved treatment. In 2018 drug sales for rare disease are expected to reach 138 

Achieved results:

1. The generation of a large genotype-phenotype database that enables researchers to connect genes to multidimensional cellular phenotypes. This will enable clinicians to better understand the consequences of genetic mutations, such as those that cause genetic disorders. This also provides companies involved in drug discovery with a view on which genes to target and which ones to avoid in order to prevent unwanted toxicity.

2. The identification of genes that act together to control cellular behavior and the identification of genes with new functions.

Example 1: Completely new insight into the mechanism of action of chemotherapeutics. Whereas it is commonly known that DNA damage induces cell death through the p53 pathway, oncologists know that this paradigm cannot explain how chemotherapy works: the majority of tumors has no functional p53 gene and are still treated using chemotherapy. Thus, a different and clinically-relevant pathway must exist to explain the action of chemotherapeutics. This pathway was identified which involved ribosome-stalling as a critical event (Boon et al, Science, 2024). Understanding better how cells respond to chemotherapy may later enable the selection of patients that benefit most from such treatments. Besides, the selection of targeted modulation of the identified pathway may also be beneficial from a therapeutic point of view. We hypothesize that inhibition of this pathway can reduce the side effects of chemotherapy. At the Netherlands Cancer Institute, we are developing the new mouse models to test this hypothesis in a new project and will, if successful in animal models, expand this project to include patient data and later on early phase clinical trials.

Example 2: The identification of a new cellular master regulator complex as a new coactivator for zinc finger transcription factors. This master regulator controls the activity of a particular class of transcription factors and is crucial for normal brain development. These findings are relevant for a better understanding of neurological disease. Various academic groups in the Netherlands will continue on the function of this new master regulator, a publication is expected to come out in the scientific journal Science (as indicated in 5a) and a grant proposal will be written together with structural biologist Anastassis Perrrakis for ZonMW to elucidate the composition of the master regulator complexes.