InaRIS Fellow (2021-2030)

Hiroshi Nishimasu

Professor,Research Center for Advanced Science and Technology, The University of Tokyo*Profile is at the time of the award.

2021InaRISBiology & Life sciences

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Research topics: Exploration of new RNA-dependent enzymes

Keyword

Summary: The RNA-guided DNA-cleaving enzyme Cas9 from the microbial CRISPR-Cas adaptive immune system has been extensively studied and applied to innovative technologies such as genome editing. In addition to Cas9, extremely diverse Cas enzymes exist in nature, but their functions remain largely unknown. In this study, we will explore and elucidate the functions and structures of new Cas enzymes. Furthermore, we will try to develop innovative technologies that revolutionize the life sciences.

Citation

CRISPR-Cas is a "robust" system responsible for acquired immune system in bacteria. When a bacterium is exposed to a viral infection, part of the viral sequence is incorporated into the CRISPR region of the bacterial genome, and when the same virus re-invades, the Cas enzyme uses the "memory" of viral sequence stored on CRISPR to cleave the invader's genome. One of the Cas enzymes, Cas9, is an RNA-dependent DNA cleaving enzyme that uses an arbitrary RNA sequence as a template (guide RNA) to cleave the target DNA sequence at any desired point. Genome editing using CRISPR-Cas9 is a revolutionary technology that enables precise modification of genome sequences, the "blueprint of life", and offers a wide range of applications from basic molecular biology research to drug discovery, gene therapy, and crop breeding. It is also fresh in our minds that it was the subject of last year's Nobel Prize in Chemistry.

Dr. Nishimasu has made remarkable breakthroughs in understanding and applying the structure and function of the CRISPR-Cas system from the viewpoint of structural biology. For example, he was the first in the world to determine the crystal structure of the Streptococcus pyogenes Cas9-guide RNA-target DNA complex, which is widely used for genome editing. Furthermore, through the structure-guided protein engineering, he successfully redesigned the three-dimensional structure of Cas9 based on the structure he discovered and extended the range of application of genome editing technology fourfold. In addition, through collaboration with experts in single-molecule observation, he has succeeded in capturing a movie of the process of DNA cleavage by Cas9.

However, Cas enzymes are diverse, and there are many other types of Cas proteins besides Cas9. The function of many Cas enzymes is still not well understood. Recently, Dr. Nishimasu used cryo-electron microscopy to determine the structure of the guide RNA-target DNA complex of Cas12f, the smallest known Cas enzyme. Through structure-function analyses of Cas12f, he revealed a completely new mode of action of Cas enzyme.

Dr. Nishimasu's research proposal aims to elucidate the operating principles of these Cas enzymes, whose functions are unknown, by utilizing his strengths in structural analysis of protein-RNA complexes and enzymological approaches. Furthermore, by teaming up with experts in marine metagenomics, he aims to search for completely new types of Cas enzymes from microorganisms that grow "flexibly" and "robustly" in extreme conditions such as the deep sea, and to elucidate their structures and functions. Microorganisms that adapt to and grow in extreme environments such as high temperature and high pressure are the frontier for the search for new enzymes: A great example includes Taq polymerase from a thermophilic bacterium has brought about the generalization of polymerase chain reaction (PCR) and innovation in research and diagnosis in medical biology.

Dr. Nishimasu is a rising star in structural biology who has just launched his own laboratory in the summer of 2020. Therefore, with the 10-year support of the InaRIS Fellowship, Dr. Nishimasu can pursue his bold and innovative ideas to advance the world of Cas enzymes . Furthermore, we hope that the fellowship will lead to the discovery of novel protein-RNA complex enzymes beyond Cas enzymes, and contribute to new developments in biology through the elucidation of their structures and operation mechanisms.

Message from fellow

Last year I opened my own laboratory, and this generous grant will allow me to devote my time to research. I am very grateful for support from the Inamori Research Institute for Science (InaRIS) for the next 10 years. The timing is extremely fortunate as I am at a turning point in my research life. I would like to engage in curiosity-driven research about the action mechanisms of proteins and nucleic acids as my research lifework.