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Wolf Prize in Chemistry for 2023 to three researchers who studied RNA

The winners are: Chuan Ha, University of Chicago, USA, Jeffrey Kelly, Scripps Research Institute, USA, Hiroaki Shuga, University of Tokyo, Japan

The 2023 Wolf Prize in Chemistry is jointly awarded to Professors Quan Ha, Jeffrey Kelly and Hiroaki Shoga for pioneering discoveries that illuminate the functions and pathological disorders of RNA and proteins, and the development of strategies to use these biopolymers in new ways to eradicate human disease.

Chuan Ha

Chuan Ha, 2023 Wolf Prize Winners in Chemistry, photo courtesy of the Prize Committee
Chuan Ha, 2023 Wolf Prize Winners in Chemistry, photo courtesy of the Prize Committee

The Wolf Prize is awarded to Professor Chuan Ha for the discovery of reversible RNA methylation and its role in the regulation of gene expression.

Chuan Ha, Chinese-American chemical biologist, professor at the University of Chicago and researcher at the Howard Hughes Medical Institute. Ha graduated from the University of Science and Technology of China in chemistry (1994). He completed a doctorate at the Massachusetts Institute of Technology, and a post-doctorate at Harvard University. He became a faculty member in the Department of Chemistry at the University of Chicago in 2002 and served as the Director of the Institute for Biophysical Dynamics (2017-2012).

RNA molecules inside the cells contain more than one hundred and fifty structural changes that occur at thousands of sites after the transcription process. Some of these changes are dynamic and may have critical control roles, corresponding to changes in DNA and protein molecules. Therefore, understanding the scope and mechanisms of dynamic changes in RNA is of critical importance in biology and medicine, and they represent an emerging research front.

Prof. Chuan is a world-class expert studying post-transcriptional RNA modifications, the role these modifications play in cellular processes, and their broad impact on mammalian development and human disease. His research, which spans a wide range of fields of chemical biology, nucleic acid chemistry, biology, epigenetics, and bioorganic chemistry, focuses on understanding the dynamic changes of RNA and DNA and their roles in the regulation of gene expression.

He is the father of the idea that RNA changes are reversible and can control gene expression. His basic research led to approaches for the development of potential treatments for human diseases, such as cancer, through the control of reversible RNA methylation. He first identified proteins that can delete changes made to RNA molecules, and laid the foundation for a research branch called epitranscriptome. Prof. Ha explained how RNA methylation is recognized by reader proteins – processes known to play critical roles in many types of cancer, including endometrial cancer, acute myelogenous leukemia and glioblastoma.

Reasons of the award committee

Chuan Ha is awarded the Wolf Prize for his pioneering work in deciphering the chemistry and functional consequences of RNA modification. He discovered reversible RNA methylation that led to a breakthrough in how changes in RNA regulate gene expression. Chuan Ha and his team discovered the first RNA demethylase enzyme, which removes the methyl group from methyladenosine-N6, which is the most common derivative in mRNA in eukaryotic animals.

Jeffrey Kelly

The Wolf Prize is awarded to Jeffrey Kelly for developing a clinical strategy to eradicate the formation of protein aggregates that have a pathological effect. Jeffrey Kelly is a professor of chemistry at the Scripps Research Institute. Kelly received his bachelor's degree in chemistry from New York University at Fredonia. He received a doctorate in organic chemistry from the University of North Carolina at Chapel Hill (1986) and did postdoctoral research in bioorganic chemistry at Rockefeller University (1989).

Most protein molecules must fold into defined three-dimensional structures in order for them to function properly. However, some proteins can fold in additional forms, with the biologically active form being stable but with few of the misfolded forms. Those proteins that are folded incorrectly, may coalesce into toxic aggregates and cause diseases. A striking example of this phenomenon are amyloid deposits in the form of fibers, which are associated with neurodegeneration in Alzheimer's disease and many other diseases. All cells in the living body contain an efficient set of chaperones and other factors, which help the correct folding of the proteins. In this way, they prevent the pathogenic forms of folding and especially the creation of the toxic aggregates. But these defense systems tend to weaken in the aging process, and fail to prevent the creation of toxic pathogenic aggregates.

From the reasons of the award committee

Prof. Kelly's research focuses on understanding protein folding, misfolding and aggregate formation. He uses chemical and biological approaches to develop new therapeutic strategies for diseases caused by protein misfolding and aggregation. He contributed significantly to the fight against degenerative diseases of the nervous system by discovering the mechanism of aggregation of the protein molecules in amyloid diseases which attack the heart and nervous system. He demonstrated the mechanism by which the transthyretin protein breaks down and assembles into clusters that kill cells, tissues, and eventually, humans too. He developed a molecular approach to combat the phenomenon by stabilizing this protein.

Kelly successfully developed the first drug, "vyndaqel tafamidis," which was approved for clinical use. This pioneering drug, which is marketed worldwide, significantly slows the progression of the disease familial amyloid polyneuropathy, as well as the progression of the disease sporadic familial cardiomyopathy, TTR, which leads to heart failure.

Jeffrey Kelly is awarded the Wolf Prize for developing a clinically impactful new strategy to ameliorate diseases caused by pathological protein aggregation. His founding contributions revealed basic characteristics of protein homeostasis (proteostasis) at the molecular level, including the interplay between protein folding, misfolding and the formation of protein aggregates.

Dysregulation of proteostasis is associated with a spectrum of human diseases. Kelly's lab used these fundamental insights to develop the drug Tapamidis, which stops or slows disease progression in patients suffering from transthyretin amyloidosis. This approach may be applicable in the treatment of other disorders based on proteostasis.

Hiroaki is wrong

The Wolf Prize is awarded to Hiroaki Shoga for the development of RNA-based catalysts that have revolutionized the discovery of bioactive peptides.

Prof. Shuga studied for a bachelor's degree (1986) and a master's degree in engineering (1989) at Okeima University. He received a doctorate in chemistry from MIT (1994) and performed postdoctoral research at Massachusetts General Hospital. Shuga began his independent career at New York University at Buffalo (2003-1997). In 2003 he moved to the Center for Advanced Science and Technology Research at the University of Tokyo. Since 2010 Shuga has been a full professor in the Department of Chemistry at the University of Tokyo. Currently, he serves as the president of the Japanese Chemical Society.

Prof. Shuga's research interests include bio-organic chemistry, chemical biology and biotechnology related to RNA, translation and peptides. As a young researcher, he broke ground in the use of RNA-based enzymes, or ribozymes, as a tool to incorporate unnatural amino acids into tRNA. This technology, known as "Flexizyme," greatly expanded the potential for reprogramming the genetic code.

Through further research on in vitro translation of proteins, using reconstructed ribosomes, Prof. Shuga was able to combine unnatural amino acids into peptides to create molecules that spontaneously form macrocyclic peptides. Prof. Shuga used oligonucleotide display and guided evolution methods to build the RaPID system. This is a platform for the production and selection of billions of macrocyclic peptides as binders, among which are those with high affinity for target proteins, including many that were previously considered impossible targets for drug therapy.

In 2006, Prof. Shoga founded the company PeptiDream to promote and implement the RaPID system, and use it to find ring peptides that bind proteins, especially for disrupting protein-protein interactions. His discoveries enabled the construction of complex molecules on a large scale, something that was impossible with conventional methods. Shuga's technology produced more unique unnatural molecules than any other approach. These molecules have a unique stereochemistry, a high density of functional groups and a three-dimensional architecture, which are necessary for the investigation and control of biological processes. This technology paved the way for a new generation of drugs. PeptiDream became a company traded on the Tokyo Stock Exchange and is one of the most successful startup companies in Japan.

The Wolf Prize is awarded to Hiroaki Shuga for developing an innovative selection system (in vitro) for the creation of ring peptides as inhibitors of protein-protein interactions. He invented flexizyme, an RNA-based catalyst that surpasses natural mechanisms and significantly expands the range of amino acids that can be incorporated into ribosomal systems. Shuga's strategy allows for the rapid construction and screening of large libraries of cyclic peptides. His unique discovery led to a new approach to medicinal chemistry and created new tools for drug discovery.

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