RESEARCH
1. Develop Specialized CRISPR Technologies for Genome Diversification
While there is a significant emphasis on enhancing genome editors for the precise introduction of specific mutations, CRISPR can also be utilized to create targeted genetic diversity. In this process, CRISPR generates a wide array of different alleles at a specified location in the genome. These diversity-generating technologies enable us to identify de novo mutations and alleles with tailored activities, even without prior knowledge of the beneficial allele. In the realm of biomedical research, these technologies can aid functional genomics studies to identify and comprehend mutations in key proteins that cause diseases.
In pursuit of this goal, we are working on the development of novel base editors with an expanded mutagenic scope. We employ various protein engineering strategies to maximize their mutagenic potential, particularly in mammalian cells.
2. Accelerate Agricultural Crop Breeding with CRISPR
For the first time in history, we have the ability to modify the genomes of living organisms at will. This is largely attributed to advancements in the CRISPR-Cas system. Fundamentally, CRISPR enables us to target any arbitrary sequence in the genome with specificity and ease. This is a monumental achievement, especially considering the vast number of DNA base pairs in the human genome, which is approximately 3.2 billion.
Initially, CRISPR technologies depended on creating double-stranded DNA breaks and utilizing error-prone DNA repair mechanisms to alter sequences. This approach often resulted in imprecise editing outcomes, limiting its utility. In contrast, base editing, a more recent genome editing technology, offers greater precision and does not require creating breaks in the DNA. It employs nucleotide deaminases to convert single bases with high accuracy, acting more like a molecular scalpel than a sledgehammer.
We aim to apply these base editing techniques to enhance key traits in agricultural crops. This is vital for sustaining Canadian agricultural productivity amidst global climate change. In partnership with the National Research Council (NRC) of Canada, we are employing genome editing to expedite the development of several traits in major row crops that are crucial for Canadian agriculture. Our primary focus is on developing disease-resistant crops and enhancing their nutritional value.
3. Develop New Methods for Spatial and Temporal Control of Genome Editing Proteins
In recent years, we have witnessed an explosion of CRISPR technologies capable of reprogramming biology at both DNA and RNA levels. To successfully translate this progress into effective therapeutics for patients, we must minimize potential side effects. Off-target editing represents one significant concern, where genome editing proteins induce unintended mutations at sites unrelated to the target modification. To ensure patient safety in genome editing therapies, these off-target effects must be minimized. Controlling the exposure of genome editors within the cellular environment is critical for achieving this goal. Our laboratory is developing novel methods for precisely regulating the spatial and temporal activity of state-of-the-art genome editing systems, enhancing both their safety and therapeutic potential.
4. Engineering Enhanced Stability of Macromolecules in Mammalian Cells
Engineered macromolecules, including RNAs and proteins, are increasingly becoming a vital component of human therapeutics. They provide an unparalleled capability to modulate biological processes such as protein-protein interactions. However, RNAs and proteins must navigate a hostile cellular environment where they are constantly recognized and degraded. This makes it challenging for functional macromolecules to accumulate at a concentration high enough in the cell to yield therapeutic benefits.
Recent advancements in proteomics, genomics, and epigenomics have significantly enhanced our understanding of the factors that influence the intracellular stability of biomolecules. However, we have yet to effectively integrate these insights to create more potent functional biomolecules. To address this challenge, we are employing high-throughput strategies to create custom-stabilized RNAs and proteins and demonstrate their effectiveness in various biological contexts. Progress in this research area will lead to the establishment of general biomolecule design principles that will drive the development of the next generation of macromolecular therapeutics.
Funding Sources
