Research
For precision medicine to realize its potential, we need to understand the connection between genotypes and phenotypes to assess a patient’s disease risk and prescribe optimal treatments. Additionally, we need potent and targeted therapeutic strategies that take advantage or correct the genetic susceptibilities in afflicted tissue (e.g., tumors). In the Hess Lab, we use high-throughput functional genomics and genome engineering tools (e.g., CRISPR) to answer these questions to advance the goals of precision medicine and improve human health.
Defining genetic factors that regulate disease risk and therapeutic response
Genome Stability and DNA repair
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 patient 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.
Genome Editing and 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).
Biomolecule discovery for engineering and manipulating mammalian cells
Identifying potent effectors that can manipulate mammalian cells is a major benefit as potential targeted therapies or powerful research tools. While nature has evolved many potential molecules for these purposes, identifying and characterizing these biomolecules is challenging and labor-intensive. Therefore, we leverage high-throughput approaches to interrogate biomolecules derived from the human genome or pathogens across a spectrum of phenotypes (e.g, cell proliferation, DNA repair, transcriptional regulation). These studies have identified biomolecules with therapeutic potential and expanded the genome engineering toolbox.
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A high-throughput screen for antiproliferative peptides in mammalian cells identifies key transcription factor families. ACS Synthetic Biology. (2024).
Development of compact transcriptional effectors using high-throughput measurements in diverse contexts. Nature Biotechnology. (2024).
High-throughput discovery and characterization of human transcriptional factors. Cell. (2020).
Development of functional genomics technologies
We develop methods for the high-throughput study of mammalian cell models to answer critical questions in biology and health. These methods include novel tools for programmable engineering of the genome (e.g., CRISPR-X and DivA-BE). Additionally, we establish approaches for high-throughput assays using emerging sequencing technologies (long read sequencing and single-cell techniques).
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Towards optimizing diversifying base editors for high-throughput studies of single-nucleotide variants. bioRxiv (2024).
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).
