Research

Research Overview

Cells must maintain the integrity of their genomes or risk permanent damage to functional sequences. Eukaryotes have evolved a wide variety of integrated pathways to sense and repair multiple types of DNA damage, from bulky lesions to double strand breaks. Deficiencies in these pathways can cause cells to accumulate genomic errors that lead to human diseases, including somatic cancers and Mendelian inherited genetic disorders. Harnessing DNA repair through the development of programmable nucleases such as ZFNs, TALENs, and recently CRISPR-Cas effectors is revolutionizing approaches to fundamental biological discovery and holds great promise for the cure of genetic diseases.

Next-generation gene editing tools, exemplified by CRISPR-Cas effectors such as Cas9, are fundamentally DNA damaging agents that introduce double strand breaks (or nicks if so engineered). Hence, they are inextricably linked to DNA repair in that they represent new opportunities to study DNA repair in human cells and intensify the urgency of studying these processes.

Research in the Corn lab seeks to understand the intersection between human DNA repair and genome editing tools and to develop new approaches to cure human diseases using genome editing. We furthermore use advanced genome editing to uncover the mechanisms by which cells use ubiquitin-based signals to encode information, including the stimulus-dependent destruction of entire organelles. We take a multidisciplinary approach to tackle these problems that includes computational modeling, in vitro biochemistry and biophysics, genome-wide screening, and mechanistic cellular biochemistry.

The intersection of DNA repair and genome editing

annealingflapThe development of CRISPR-Cas9 for genome editing and regulation is transforming biological research and has opened up potential therapeutic avenues. However there are still many problems that we lack the tools to tackle. For example, while Cas9 can be used to “knock out” genes through error-prone sequence disruption, methods to precisely insert or replace sequences are still in their infancy. Gene editing outcomes are currently unpredictable in part because we have fundamental gaps in our understanding of DNA repair. As a programmable nuclease, CRISPR-Cas9 represents both a powerful tool to edit the genome through the controlled introduction of DNA damage, and also an exciting new opportunity to study the ways in which human cells keep their genomes intact. We are working to determine the molecular mechanisms by which cells process DNA damage, such as that which is incurred during genome editing, with the goal of furthering fundamental understanding of DNA repair and finding routes to high efficiency gene correction.

Using genome editing to decipher quality control signals

autophagyif2Cells keep a close eye on their contents. Misfolded proteins are marked by ubiquitin ligases and sent for destruction in the proteasome. Similarly, entire damaged organelles such as 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.

Translational impact in the real world

sicklecd750-600x400Genome editing holds great promise to uncover the root causes of human diseases and even to reverse mutations that cause inherited genetic disorders. We collaborate with clinicians and industry groups to translate genome editing approaches towards real world applications. We have recently determined how certain cancer cells resist cutting-edge targeted oncology therapies and are developing strategies to bring them back under control. We also use genome editing to explore the mechanisms by which genomic variation causes or modifies disease, for example by introducing disease-associated noncoding SNPs into human cells. Finally, we develop reagents aimed at curing genetic disorders via precision sequence replacement, for example by correcting the sickle cell disease mutation in human hematopoietic stem cells.

Contact Us

Questions and/or comments about Corn Lab and its activities may be addressed to:

JACOB.CORN@BIOL.ETHZ.CH

Share: