Research
For precision medicine to realize its potential, we must map the connection between genotypes and phenotypes. With the advent of CRISPR-mediated genome editing and high-throughput sequencing, we can systematically perturb the genome and quantitatively measure their phenotypic effects. In the Hess lab, we are broadly interested in both the development and application of these and other functional genomics technologies to address critical biological questions and improve human health.
Mammalian DNA Damage & Genome Stability
Numerous chemotherapies use DNA damaging agents or target DNA repair machinery to induce cytotoxicity, however, the response can vary greatly from patient to patient. Identifying the genetic factors that predict this response will greatly improve pateint outcomes. Furthermore, in the genome-editing field, there is growing interest in manipulating these DNA repair pathways to improve the efficiency and fidelity of editing. Therefore, annotating and understanding the effect of genes, variants, and recruited proteins on DNA repair is essential. We employ genetic screening methods with an array of phenotypic readouts (drug selection, fluorescent reporters, high-throughput sequencing, etc.) to quantify the effects of these genetic perturbations. We use these findings to dissect the molecular mechanisms that regulate DNA repair and translate these findings to improve genome editing and understand differential responses to cancer therapies.
Pathogenic Effectors
Microbial and viral pathogens have a significant impact on global human health. These pathogens have evolved efficient methods to survive and proliferate in mammalian hosts by manipulating endogenous machinery. In some cancers, these alterations have an oncogenic role, either promoting tumor growth or developing drug resistance. With current efforts to mine microbial and viral genomes, the list of potential effectors is ever-growing, so the development of tools to systematically characterize these effectors is critical. In the Hess lab, we dissect how these effectors hijack the host machinery using high-throughput functional genomics. In particular, we are focused on effectors that can modulate DNA repair, epigenetic states, and immune response. These findings will uncover new host-pathogen interactions and novel therapeutic strategies and targets.
Therapeutic Response
We want to improve patient treatment by understanding the genetics behind our therapeutics. To achieve this goal, we use high-throughput screening strategies to identify genetic factors and biomarkers that predict therapeutic response, dissect modes of resistance and mechanism of action, and uncover potential combination therapies. Through the investigation of the underlying biology of these therapeutics, we can improve patient outcomes.
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Retro-2 protects cells from ricin toxicity by inhibiting ASNA1-mediated ER targeting and insertion of tail-anchored proteins. eLife. (2019).
Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nature Biotech. (2017).
Directed evolution using dCas9-targeted somatic hypermutation machinery. Nature Methods. (2016).
Technology Development
In the Hess lab, we develop high-throughput screening technologies to answer critical questions in biology and health. We have expertise with CRISPR/Cas genetic screening tools (CRISPR cutting/knockout, CRISPRi/a, base editing, and prime editing) and screening protein libraries in a mammalian cellular context. We are interested in improving these technologies, including library construction, novel genome-editing tools, and high-throughput selection strategies. In addition to our interests in DNA repair and pathogenic effectors, we are excited to apply these technologies to a broad set of questions.
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High-throughput discovery and characterization of human transcriptional factors. Cell. (2020).
Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nature Biotech. (2017).
Directed evolution using dCas9-targeted somatic hypermutation machinery. Nature Methods. (2016).
