The Schwank Lab is part of the Institute of Pharmacology and Toxicology of the University Zurich. Our mission is to develop transformative technologies for the treatment of genetic disorders. Much of our work involves the generation of novel genome editing technologies, and their testing in animal models and human organoids. Current research in our lab can be divided into two major areas:
• The development of CRISPR-based genome editing approaches to correct monogenetic disorders of the liver and brain
• The application of functional genomics approaches to develop targeted and personalized treatments for colorectal- and pancreatic cancer
Development of gene editing therapies for monogenetic disorders of the liver and brain
There is a large number of severe genetic diseases in the liver and brain that are currently not treatable. The CRISPR/Cas9 genome editing tool is a powerful system that promises cure for these genetic disorders. In its initial version, the CRISPR/Cas9 complex generates a DNA double-strand break at a desired locus, which requires repair by homologous recombination (HR) from template DNA for precise editing. In most cells of adult tissues, however, the HR pathway is not active and targeted nucleases predominantly lead to stochastic mutations, rendering them unsuitable for gene editing therapies. In our lab we exclusively focus on 2nd and 3rd generation CRISPR/Cas9-based genome editing tools, which directly convert DNA bases without the generation of DNA double strand breaks and the need for homologous recombination (base-editing; PRIME-editing). These systems consist of catalytically impaired Cas9 proteins that are either fused to deaminases, allowing direct conversion of C-G into T-A base pairs and vice versa, or to a reverse transcriptase, allowing the insertion or deletion of specific sequences from template RNA.
Our major goal is to develop clinically viable in vivo gene editing approaches that in the future could be applied in patients with monogenetic disorders. Examples for current research projects in the lab are:
• Establishment of viral and non-viral in vivo delivery strategies for genome editing components in mouse models for monogenetic liver diseases.
• Development of tools that allow us to assess the occurrence of undesired off-target mutations during in vivo therapies.
• Developing of novel editing tools with additional features by rational protein engineering and molecular evolution approaches.
Functional genomics approaches to develop targeted and personalized cancer treatments
Understanding how epithelial cells in healthy tissues transform into premalignant adenomas and further progress into aggressive adenocarcinomas is a requirement for the development of targeted cancer therapies. In our lab we apply CRISPR/Cas9 genome editing in organoids and mice to study these mechanisms in colorectal- and pancreatic cancer. Below are two examples for current research projects in this area.
In the recent years CRISPR screening has already been excessively used in 2D cancer cell lines to study the function of thousands of genes in a single experiment, leading for example to a better understanding of evolving resistances to anti-cancer drugs. In our lab we have developed a protocol for genome-wide CRISPR screening in 3D organoid models. Currently we exploit this technology in order to identify the genetic components that render cancer stem cells independent of niche signals during tumor progression.
In another project we have established a pancreatic cancer organoid biobank from over 30 tumors. The biobank was carefully analyzed by RNA-seq and whole exome sequencing, and widely reflects the phenotypic and mutational spectrum of primary pancreatic cancers. We are currently using the organoid biobank to perform large-scale drug screens, and apply genome editing to study drug-gene interactions. The goal of these studies is to identify novel effective compounds for the treatment of pancreatic cancer, and to personalize pancreatic cancer treatments to individual patients.