Research Overview
Embedded Files
CRISPR-Cas is an RNA-guided, genetic interference pathway in prokaryotes that enables acquired immunity against invasive nucleic acids. Nowadays, CRISPRs also provide formidable tools for facile, programmable genome engineering in eukaryotes. Cas9 proteins are the “effector” endonucleases for CRISPR interference; and have recently begun to be also recognized as important players in other aspects of bacterial physiology (e.g. acquisition of new spacers into CRISPRs, endogenous gene regulation, and microbial pathogenesis, etc.).My laboratory is broadly interested in CRISPR biology and mechanism. We will use Neisseria species as our model system, and E. coli and human cells as additional platforms. We employ complementary biochemical, microbiological, genetic and genomic approaches. We are also interested in working with the broader scientific community to develop and apply novel CRISPR-based tools to tackle diverse biological questions.
Anti-viral Immune Memory Acquisition in CRISPR-Cas9
CRISPR-Cas systems generate immunological memory of past infections by storing fragments of foreign DNA as new “spacers” in the host CRISPR array. Using a filamentous phage-Neisseria infection model, combined with bacterial genetics, biochemistry, and high-throughput sequencing, we uncovered a surprising role for Cas9 beyond its well-known function as an RNA-guided nuclease mediating CRISPR interference. In Type II-C CRISPR systems, apoCas9 (aka Cas9 lacking its dual RNA partners) potently stimulates spacer acquisition. Physiologically, Cas9 senses low crRNA abundance in cells with short CRISPR arrays—such as those undergoing array neogenesis or natural contractions—and boosts spacer acquisition to rapidly rebuild their immune memory. In essence, Cas9 functions as a crRNA sensor and acquisition regulator, dynamically safeguarding the depth of CRISPR immunity.
Figure legend: Model for type II-C apoCas9 safeguarding bacterial immunity depth. Link: https://www.nature.com/articles/s41586-025-09577-9
Bacterial New Defense Systems and Phage Evasion Mechanisms
To unveil the full landscape of genetic conflict between Neisseria species and their bacteriophages, we use computational and genomics-driven approaches to systematically discover non-CRISPR defense systems in Neisseria, as well as phage-encoded evasion mechanisms. Beyond advancing the molecular understanding of bacteria immunity, this work may also yield new tools to refine or expand CRISPR-based technologies.
Develop Type I CRISPR into New Gene Editing Technologies.
We harness the natural diversity of CRISPR to advance human genome engineering, with a special focus on the multi-subunit Type I CRISPR system. Unlike Cas9 or Cas12, which act like scissors, Type I CRISPR operates as a “DNA shredder”. It uses the RNA-guided Cascade complex to find a DNA target and then recruits Cas3, a helicase-nuclease, to break down long stretches of DNA.
In 2019, we pioneered the use of Cascade-Cas3 to create targeted, 100-kilobase scale deletions in the human genome. In recent work, we have harnessed compact Type I editors through a “supplying-hidden-Cas11” platform, developed phage-encoded anti-CRISPRs into as editing safety switches in human cells, and, in collaboration with Ailong Ke lab, solved six cryo-EM structures revealing how I-C CRISPR is activated and inhibited. Nowadays, Type I CRISPR underpins a versatile toolkit, including precise genome cutters, transcription activators, large-payload integrators, and epigenetic modifiers.
CRISPR-based therapeutics for human diseases
In close collaboration with clinicians and scientists at the Univ. of Michigan and worldwide, we are developing CRISPR-based therapies to address urgent, unmet medical needs. Our efforts span the design of editing strategies, the advancement of delivery methods, and validation in animal models. Current disease targets include ocular and lung disorders, and we welcome new collaborators who share our vision of bringing CRISPR to the clinic.
Report abuse