Revolutionizing CRISPR: Quantum Biology and AI Merge to Enhance Genome Editing

“Revolutionizing CRISPR: Oak Ridge National Laboratory Breaks New Ground in Genome Editing with Quantum Biology and Explainable AI”

Researchers at Oak Ridge National Laboratory (ORNL) have achieved a significant breakthrough in CRISPR Cas9 technology, particularly in microbial genome editing. By harnessing the power of quantum biology and explainable artificial intelligence, they have elevated the precision of genetic modifications in microorganisms, thereby expanding the potential for renewable fuel and chemical production.

ORNL, renowned for its expertise in quantum biology, artificial intelligence, and bioengineering, has successfully enhanced the efficiency of CRISPR Cas9 genome editing techniques, particularly in the context of renewable energy development.

CRISPR, a revolutionary tool in bioengineering, is employed to manipulate genetic codes, either to enhance an organism’s performance or to rectify mutations. The CRISPR Cas9 tool relies on a unique guide RNA that directs the Cas9 enzyme to bind with and cleave a specific targeted site within the genome. However, existing computational models for predicting effective guide RNAs for CRISPR tools were primarily based on data from a limited number of model species, leading to inconsistent efficiency when applied to microorganisms.

Microbe-Centric CRISPR Research

Carrie Eckert, leader of the Synthetic Biology group at ORNL, noted that most CRISPR tools were originally developed for model species such as mammalian cells or fruit flies, with limited focus on microbes, which have distinct chromosomal structures and sizes. Eckert observed that the behavior of CRISPR Cas9 machinery differs when working with microbes, a realization supported by this research.

To enhance the modeling and design of guide RNA, ORNL researchers delved into the fundamental processes occurring within cell nuclei, where genetic material is stored. They employed quantum biology, an interdisciplinary field bridging molecular biology and quantum chemistry, to investigate how the electronic structure of nucleotides, the building blocks of DNA and RNA, influences their chemical properties and interactions.

Erica Prates, computational systems biologist at ORNL, explained that the distribution of electrons within molecules impacts reactivity and conformational stability, including the effectiveness of the Cas9 enzyme-guide RNA complex in binding with the microbe’s DNA.

Leveraging Explainable AI in CRISPR Research

The scientists developed an explainable artificial intelligence model known as the “iterative random forest.” This model was trained on a dataset comprising approximately 50,000 guide RNAs that target the genome of E. coli bacteria. Importantly, it also considered quantum chemical properties. This approach, documented in the journal Nucleic Acids Research, unveiled critical insights into nucleotides, aiding in the selection of improved guide RNAs.

Jaclyn Noshay, a former ORNL computational systems biologist and first author of the paper, highlighted that using explainable AI provided a clear understanding of the biological mechanisms driving the results, as opposed to relying on a “black box” algorithm with limited interpretability.

The explainable AI model, with its thousands of features and iterative nature, was trained using the powerful Summit supercomputer at ORNL’s Oak Ridge Leadership Computer Facility (OLCF), a Department of Energy (DOE) Office of Science user facility.

Expanding CRISPR Cas9 Tools for Diverse Species

Consideration of quantum properties in genome editing offers the potential for enhancing Cas9 guide design for all species, including humans. This research carries implications beyond microbial applications and can impact fields such as drug development, where precise targeting of specific genome regions is essential.

Carrie Eckert emphasized that refining CRISPR Cas9 models enhances the predictive capacity for linking genotype to phenotype, a crucial aspect of functional genomics. This research has direct relevance to the work of the ORNL-led Center for Bioenergy Innovation (CBI), which aims to improve bioenergy feedstock plants and bacterial fermentation of biomass.

In conclusion, this research marks a significant advancement in understanding and improving CRISPR technology. By comprehending the underlying biological processes and incorporating a wealth of data into predictions, scientists aim to enhance the precision and efficiency of genome editing, reducing costly errors in an organism’s genetic code. This work is supported by the DOE Genomic Science Program’s Secure Ecosystem Engineering and Design Science Focus Area (SEED SFA) and has the potential to further evolve with additional training data and continued reliance on explainable AI modeling.

Reference: “Quantum biological insights into CRISPR-Cas9 sgRNA efficiency from explainable-AI driven feature engineering” by Jaclyn M Noshay, Tyler Walker, William G Alexander, Dawn M Klingeman, Jonathon Romero, Angelica M Walker, Erica Prates, Carrie Eckert, Stephan Irle, David Kainer and Daniel A Jacobson, 20 September 2023, Nucleic Acids Research.
DOI: 10.1093/nar/gkad736

Co-authors on the publication included ORNL’s William Alexander, Dawn Klingeman, Erica Prates, Carrie Eckert, Stephan Irle, and Daniel Jacobson; Tyler Walker, Jonathan Romero, and Angelica Walker of the Bredesen Center for Interdisciplinary Research and Graduate Education at the University of Tennessee, Knoxville; and Jaclyn Noshay and David Kainer, who were formerly with ORNL and now with Bayer and the University of Queensland, respectively.

Funding for the project was provided by the SEED SFA and CBI, both part of the DOE Office of Science Biological and Environmental Research Program, by ORNL’s Lab-Directed Research and Development program, and by the high-performance computing resources of the OLCF and Compute and Data Environment for Science, both also supported by the Office of Science.

Frequently Asked Questions (FAQs) about CRISPR Advancements

More about CRISPR Advancements

• Oak Ridge National Laboratory
• Nucleic Acids Research Journal
• CRISPR Cas9 Technology
• Quantum Biology
• Explainable Artificial Intelligence
• Summit Supercomputer
• DOE Genomic Science Program
• Center for Bioenergy Innovation
• ORNL’s Lab-Directed Research and Development Program