Research

Overview

Research in the Corn Lab seeks to understand the intersection between human DNA repair and genome engineering tools and to develop new approaches to cure human diseases. We also use advanced genome editing to uncover the mechanisms by which cells accomplish amazing feats of quality control such as the the targeted degradation of individual proteins within the complex proteome or stimulus-dependent destruction of entire organelles. We take a multidisciplinary approach to tackle these problems that includes genome-wide functional genomics, computational modeling, in vitro biochemistry and biophysics, and mechanistic cellular biochemistry.

The intersection of DNA repair and genome editing

Cells encode the instructions for life within their genomes. But this DNA is under constant assault from a variety of sources. Going outside without sunblock, drinking alcohol, smoking, and exposure to radiation are particularly serious stresses. But even just copying the genome can cause multiple forms of DNA damage. Failure to detect and reverse DNA damage can lead to errors that affect functional sequences and perpetuate from generation to generation. A wide variety of debilitating conditions have their origins in improper DNA repair, ranging from cancer to genetic disorders such as sickle cell disease.

But there is a bright side to DNA damage. Genome engineering systems, from nucleases to prime editors, work by targeting DNA damage and influencing repair to achieve a desired outcome. Genome engineering has already revolutionized approaches to fundamental biological discovery and begun to yield cell-based therapies and cures for debilitating genetic disorders. DNA damage therefore represents both the cause and potential cure for a wide range of human diseases.

But the majority of genome editing is still a guess-and-check exercise. Researchers and clinicians most often iteratively try to install an edit into a cell, tissue, or organism of interest, testing various technologies and tricks and hoping for an improvement. Genome engineering is unpredictable in part because of fundamental gaps in our understanding of heterogeneous DNA repair in diverse backgrounds of cell state and genotype. The Corn Lab works to determine the molecular mechanisms by which cells process DNA damage, such as that which is incurred during genome engineering, with the goal of furthering fundamental understanding of DNA repair and finding routes to high efficiency gene editing.

You can read even more about one of our projects on DNA repair, an ERC-funded collaboration at http://www.ddreamm.org.

Deciphering quality control with genome engineering

Cells keep a close eye on their contents. Misfolded proteins are marked by ubiquitin ligases and sent for destruction by the lysosome or proteasome. But proteins can be damaged in many other ways, and misfolding is not the only signal for protein degradation. We use study “unusual” stresses and responses that go beyond classic ubiquitin-mediated degradation. We seek to understand how cells make decisions about myriad forms of damage to their complex proteomes and attempt to overcome these insults.

Much like proteins, entire organelles can be damaged by stressful conditions. For example, the mitochondria and endoplasmic reticulum can be marked for autophagic destruction in the lysosome. An inability to clear damaged proteins and/or organelles underlies a host of human disorders, including Alzheimer’s and Parkinson’s Disease. Organelle autophagy is also a hallmark of dramatic cellular differentiation, such as the loss of all organelles during the production of the lens or red blood cells.  We are using next-generation genome engineering technologies to discover new players in the homeostasis of targets ranging from proteins to organelles. For example, using unbiased screens with complex phenotypes, we are decoding novel effectors and signaling logic that code for the destruction of each organelle. Endogenous tagging and editing approaches enable us to gain a deep understanding of the mechanisms by which these effectors operate and how they mis-fire in human disease.

Real world translational impact

Better understanding of DNA repair and protein/organelle quality control, coupled with advanced genome editing, holds great promise to uncover the root causes of human diseases and develop new treatments. In the case of inherited genetic disorders, genome editing can even be used to reverse the causative mutations, yielding a lasting cure. The Corn Lab always keeps an open eye to translational opportunities arising from our fundamental discoveries. These can include collaboration with clinical academic or industry groups, as well as spinning out companies from our own lab.

For example, our lab frequently collaborates with clinicians to translate genome editing approaches towards real world applications. We use genome editing to explore the mechanisms by which genomic variation causes or modifies disease, for example by introducing disease-associated mutations into human cells and measuring exact phenotypic outcomes. And we develop reagents aimed at curing genetic disorders via precision sequence replacement, for example reversing sickle cell disease or Fanconi Anemia mutations in human hematopoietic stem cells.

The Corn Lab is part of the Swiss National Centre of Competence in Research on Childhood Cancer (NCCR Children & Cancer), a national initiative that brings together researchers, clinicians, patients, and advocacy organisations to accelerate discoveries and improve outcomes and quality of life for children and adolescents with cancer.

Partnering with GEML at ETH Zurich, the Corn Lab is engaged in international EU-Horizon and EIC-Pathfinder projects. This collaborative effort involves close cooperation with European partners to select, design, and refine safe and efficient next-generation genome editing technologies for the development of Gene and Cell Therapy Products. For additional information on these projects, please visit: EDITSCD, geneTIGA, and T-Fitness.