Chemistry

Jeffery W. Kelly

Chuan He

Hiroaki Suga

“for pioneering discoveries that illuminate the functions and pathological dysfunctions of RNA and proteins and for creating strategies to harness the capabilities of these biopolymers in new ways to ameliorate human diseases”.

Prof. Jeffery W. Kelly is the Lita Annenberg Hazen Professor of Chemistry at The Scripps Research Institute. Kelly received his BS in chemistry from the State University of New York at Fredonia, his Ph.D. in organic chemistry from the University of North Carolina at Chapel Hill (1986), and performed postdoctoral research in bio-organic chemistry at Rockefeller University (1989).

Most protein molecules must fold into defined three-dimensional structures to acquire their functional activity. However, some proteins can adopt several folding states, and their biologically active state may be only marginally stable. Misfolded proteins can form toxic aggregates, such as soluble oligomers and fibrillar amyloid deposits, which may lead to neurodegeneration in Alzheimer’s disease and many other pathologies. All cells contain an extensive protein homeostasis network of protein folding devices, such as molecular chaperones and other factors that prevent or regulate protein aggregation. These defense networks tend to decline during aging, facilitating the manifestation of aggregate deposition diseases.

Prof. Kelly’s research focuses on understanding protein folding, misfolding, and aggregation and using chemical and biological approaches to develop novel therapeutic strategies to combat diseases caused by protein misfolding and aggregation. He contributed significantly to the fight against neurodegenerative diseases by discovering the mechanism of protein aggregation in amyloid diseases that affect the heart and nervous system. He showed the mechanism by which a protein, transthyretin, unravels and agglomerates into clusters that kill cells, tissues, and ultimately patients and developed a molecular approach to stabilize this protein.
Kelly successfully synthesized the first regulatory-agency-approved drug, “tafamidis vyndaqel”. This pioneering drug, marketed worldwide, significantly slows the progression of Familial Amyloid Polyneuropathy, a neurodegenerative disease, and Familial and Sporadic TTR Cardiomyopathy disease, which causes heart failure.

Jeffery W. Kelly is awarded the Wolf prize for developing a new and clinically impactful strategy to ameliorate disease caused by pathological protein aggregation. His seminal contributions revealed fundamental features of protein homeostasis (proteostasis) at the molecular level, including the interplay among protein folding, misfolding, and aggregation. Dysregulation of proteostasis is associated with a spectrum of human diseases. Kelly’s laboratory used these fundamental insights to develop the drug “tafamidis”, which halts or slows disease progression in patients suffering from transthyretin amyloidosis. This approach may be applicable to other proteostasis-based disorders.

Hiroaki Suga

Jeffery W. Kelly

Chuan He

“for pioneering discoveries that illuminate the functions and pathological dysfunctions of RNA and proteins and for creating strategies to harness the capabilities of these biopolymers in new ways to ameliorate human diseases.”

Prof. Suga received his Bachelor of Engineering (1986) and Master of Engineering (1989) from Okayama University, Ph.D. in Chemistry (1994) from MIT, and was a post-doctoral fellow at the Massachusetts General Hospital. Suga began his independent career at New York State University at Buffalo (1997-2003). In 2003 he moved to the Research Center for Advanced Science and Technology at the  University of Tokyo. Since 2010 Suga has been a full Professor in the department of chemistry at the University of Tokyo. Currently, he serves as the President of the Chemical Society of Japan.

Prof. Suga’s research interests include bioorganic chemistry, chemical biology, and biotechnology related to RNA, translation, and peptides. As a young researcher, he made significant advances in using RNA-based enzymes, or ribozymes, to incorporate unnatural amino acids into tRNA. This technology, known as the “Flexizyme,” greatly expanded the potential for reprogramming the genetic code. Through additional research on in vitro translation of proteins using reconstituted ribosomes, Prof. Suga could incorporate various unnatural amino acids into expressed peptides to spontaneously produce molecules that form macrocyclic peptides. Prof. Suga used oligonucleotide display and directed evolution to create the RaPID system, a platform for producing and selecting billions of macrocyclic peptides as high-affinity binders to protein targets, including many that had previously been considered undruggable.

In 2006, Prof. Suga co-founded PeptiDream to advance and apply the RaPID system, which quickly became a widely used technology for finding small molecule protein binders, particularly disrupting protein-protein interactions. His discoveries have enabled the construction of complex molecules on a large scale, not possible using conventional methods alone. Suga’s work has produced more unique non-natural molecules than other approachs, which possess the unique stereochemistry, rich functional group density, and 3D-architecture necessary for interrogating and controlling biological processes. This paved the way for a new generation of drugs. PeptiDream became a publicly traded company on the Tokyo Stock Exchange and is one of Japan’s most successful startup companies.

Hiroaki Suga is awarded the Wolf prize for developing an exceptionally innovative in-vitro selection system for cyclic peptides as inhibitors of protein-protein interactions. He invented an RNA-based catalyst, flexizyme, that transcends natural mechanisms and vastly expands the range of amino acids that can be incorporated with ribosomal machinery. Suga’s strategy enables rapid construction and screening of enormous cyclic peptide libraries. His unique discovery has established a new approach to medicinal chemistry and generated new tools for drug discovery.

Chuan He

Jeffery W. Kelly

Hiroaki Suga

“for pioneering discoveries that illuminate the functions and pathological dysfunctions of RNA and proteins and for creating strategies to harness the capabilities of these biopolymers in new ways to ameliorate human diseases”.

Chuan He is a Chinese-American chemical biologist, the John T. Wilson Distinguished Service Professor at the University of Chicago, and an Investigator at the Howard Hughes Medical Institute. He graduated from the University of Science and Technology of China with a B.S. in Chemistry (1994), Ph.D. at MIT, and postdoctoral research at Harvard University. He joined the Department of Chemistry at the University of Chicago in 2002 and served as the Director of the Institute for Biophysical Dynamics (2012 -2017).

More than 150 structurally distinct post-transcriptional modifications of cellular RNA molecules occur at thousands of sites. Some of these modifications are dynamic and may have critical regulatory roles analogous to protein and DNA modifications. Therefore, understanding the scope and mechanisms of dynamic RNA modifications represents an emerging research frontier in biology and medicine.

Prof. Chuan He is a world-class expert studying RNA’s post-transcriptional modifications, the role these modifications play in cellular processes, and their broad impact on mammalian development and human diseases. His research, spanning a wide range of chemical biology, nucleic acid chemistry, biology, epigenetics, and bioinorganic chemistry, focuses on understanding both RNA and DNA’s modifications and their roles in regulating gene expression.
He was the first to champion the idea that RNA modifications are reversible and can control gene expression. His work is fundamental in developing potential therapies that target RNA methylation effectors against human diseases such as cancer. His research group was the first to identify proteins that can erase, and undo changes made to RNA molecules, which sparked the emergence of the epitranscriptome field. Prof. He explained how RNA methylation functions through characterizing reader proteins—processes that play critical roles in many types of cancer, including endometrial cancer, acute myelogenous leukemia, and glioblastoma.

Chuan He is awarded the Wolf prize for his pioneering work elucidating the chemistry and functional consequences of RNA modification. He discovered reversible RNA methylation, leading to a conceptual breakthrough regarding the functional roles of RNA modifications in the regulation of gene expression. The He laboratory discovered the first RNA demethylase, an enzyme that removes the methyl group from N6-methyladenosine, the most prevalent mRNA modification in eukaryotes.

Benjamin F. Cravatt

Carolyn Bertozzi

Bonnie Bassler

“for their seminal contributions to understanding the chemistry of cellular communication and inventing chemical methodologies to study the role of carbohydrates, lipids, and proteins in such biological processes”.

Cravatt, the Gilula Chair of Chemical Biology and Professor in the Department of Chemistry at The Scripps Research Institute. His research aims to understand proteins’ roles in human physiological and pathological processes and use this knowledge to identify novel therapeutic targets and drugs to treat diseases.

Cravatt was inspired to think about biology by his parents and credits his high school mathematics teachers for nurturing his interest in the quantitative sciences. Cravatt obtained his undergraduate education at Stanford University, receiving a B.Sc in Biology and a B.A. in History. He then received a Ph.D. from The Scripps Research
Institute (TSRI) in 1996 and joined the faculty at TSRI in 1997.

Bridging the fields of chemistry and biology, Cravatt and his research group have developed and applied technologies to discover biochemical pathways in mammalian biology and disease. Cravatt pioneered an approach to identify protein classes based on their activity. His multidisciplinary approach generates all tools and models required to assign molecular, cellular, and physiological functions to enzymes and, as an essential corollary, assess their suitability as therapeutic targets. He achieves a unique balance that cultivates the creation and rapid implementation of cutting-edge technologies to advance basic and translational science.

Cravatt’s work on the endocannabinoid system has radically changed the landscape of proteome analysis by demonstrating how innovative chemical methods can be used to broadly and deeply investigate protein function directly in native biological systems.

The chemical proteomic technology Activity-Based Protein Profiling (ABPP), pioneered by Cravatt employs chemical probes to directly measure enzyme function. For example, a fluorescent label may be used to tag enzymes with certain chemical properties, allowing scientists to survey all active enzymes in a cell at once, and to determine
the targets of drugs in a global manner directly in living systems.

Cravatt has used this and related chemical proteomic technologies to conduct global analyses of protein activities and to elucidate the functions of several enzymes, including those linked to human cancers, neurological disorders, and the endocannabinoid system, which consists of lipid transmitters involved in appetite regulation, pain sensation, mood, memory, and other physiological processes.

Benjamin Cravatt is awarded the Wolf prize for developing activity-based protein profiling, which has emerged as a powerful and widely used chemical proteomic strategy to characterize enzyme function in native biological systems. He used this approach to characterize numerous enzymes which play critical roles in human biology and disease, including the endocannabinoid hydrolases whose lipid products regulate communication between cells.

Carolyn Bertozzi

Benjamin F. Cravatt

Bonnie Bassler

“for their seminal contributions to understanding the chemistry of cellular communication and inventing chemical methodologies to study the role of carbohydrates, lipids, and proteins in such biological processes”.

Bertozzi, an American chemical biologist from Stanford University and the Howard Hughes Medical Institute, is known for developing innovative technologies that have opened new avenues for biological discovery and therapeutic development.

From an early age, Bertozzi found herself naturally enthralled by science. Her father, who taught physics at MIT, encouraged her to explore technological tools from his projects and demonstrations. This resulted in an early enthusiasm for science that later fueled her drive to pursue the education necessary to become a leader in the field of biotechnology and a distinguished professor.

Bertozzi received her undergraduate degree in Chemistry from Harvard University in 1988 and her Ph.D. in Chemistry from UC Berkeley in 1993. After completing postdoctoral work at UCSF in cellular immunology, she joined the UC Berkeley faculty in 1996. In June 2015, she joined the faculty at Stanford University, coincident with the launch of Stanford’s ChEM-H institute.

The cell membrane plays an essential role in protecting the cell from its extracellular environment. As such, extensive work has been devoted to studying its structure and function. Crucial intercellular processes, such as signal transduction and immune protection, are mediated by cell surface glycosylation, which is comprised of large biomolecules, including glycoproteins and glycosphingolipids.

Bertozzi’s research has focused on profiling changes in cell surface glycosylation. She invented the field of biorthogonal chemistry, which allows researchers to chemically modify mol¬ecules within living systems without interfering with native biochemical processes. Using biorthogonal chemistry, she has made fundamental breakthroughs in the understanding of the glycocalyx, the heavily glycosylated cell surface found on nearly every cell which serves as a mediator for cell-cell interactions.

Her pioneering work has opened up basic drug discovery and therapeutic targets associated with cancer, inflammation, bacterial infection, tuberculosis, and most recently COVID-19. These new therapeutic modalities include antibody-enzyme conjugates that can reshape the glycocalyx and lysosome-targeting chimeras (LYTACs)
that can degrade membrane-bound and extracellular targets. These unraveled the role of sugars in biology and in immuno-oncology. Bertozzi extensively commercialized these innovative technologies for both clinical and research applications.

Equally significant are her contributions to mentorship and diversity in the fields of chemistry and chemical biology. Carolyn’s commitment to mentorship is centered on her passion for diversity, equity, and inclusion in STEM.

Bonnie Bassler

Carolyn Bertozzi

Benjamin F. Cravatt

“for their seminal contributions to understanding the chemistry of cellular communication and inventing chemical methodologies to study the role of carbohydrates, lipids, and proteins in such biological processes”.

Bassler, an American Professor, Chair of the Department of Molecular Biology at Princeton, and a Howard Hughes Medical Institute Investigator. She is a member of the National Academy of Sciences and the American Academy of Arts and Sciences.

Just two decades ago, bacteria were besmirched as primitive entities. But research since then has proven otherwise. As an undergraduate in biochemistry, Bassler was disappointed when she was assigned to a project studying bacterial enzymes. She initially thought that bacteria were the simplest organisms but soon found out they are highly sophisticated. After completing her Ph.D. at Johns Hopkins University, she joined the Agouron Institute in La Jolla, focusing her research on what is now called quorum sensing, the process by which bacterial cells communicate chemically.

Quorum sensing involves the production, release, and subsequent detection of chemical signal molecules called autoinducers. This process enables populations of bacteria to regulate gene expression, and therefore behavior, on a community-wide scale. It is wide-spread in the bacterial world, so understanding this process is fundamental to clinical and industrial microbiology and to understanding the development of higher organisms.

Bassler showed that bacteria are multilingual. Her studies are providing insight into intra- and inter-species communication, population-level cooperation, and the design principles underlying signal transduction and information processing at the cellular level. These investigations are also leading to synthetic strategies for controlling quorum sensing.

Therapeutics that interfere with quorum sensing may provide ways of combating drug-resistant infections. This approach manipulates the quorum-sensing conversation to either shut bacteria down when they’re doing things we don’t like or beef up their conversation when they’re doing something we do like. In other words, we make “bad” bacteria incapable of communication while enhancing the conversation between “good” bacteria. Her work has wide-ranging implications for developing novel antimicrobial therapeutics and the next generation of antibiotics.

Leslie Leiserowitz

Meir Lahav

Crystal formation is one of the most fundamental phenomenas in chemistry. The structure of organic crystals is of particular importance because the crystal shape (morphology) reflects the three-dimensional structure (stereochemistry) of the molecules assembled in that crystal. In 1848 Louis Pasteur conducted his famous experiment, physically separating the two crystalline forms of a tartaric acid salt, which mirror one another. Pasteur’s experiment became the basis for modern stereochemistry, and it was followed by the study of the first Nobel Laureate in Chemistry, Jacobus H. van’t Hoff. However, neither Pasteur, van’t Hoff, nor many other famous chemists failed to understand the relationship between crystal morphology and molecular stereochemistry.

It took nearly 140 years until Professors Lahav and Leiserowitz conducted their milestone experiments in the Mid-1980s, demonstrating for the first time that the absolute configuration of molecules can be derived from their crystal morphologies. They not only solved the long-standing puzzle but also pioneered the science of organic crystals’ stereochemistry. They directly related the stereochemistry of the individual molecule to the shape of the macroscopic crystal. They founded the links between molecular structure, crystal morphology, crystal growth’ dynamics, and molecular chirality (the structural property of an object, which makes it different from its mirror image, like the human hands). Their findings laid the foundation for our current knowledge of the selective self-assembly of organic molecules. In this way, their rules powerfully complement our understanding of organic chemistry for covalent assembly and macromolecules’ self-assembly.

Furthermore, Lahav and Leiserowitz applied their theories for the design and engineering of chiral crystals, controlling the relative growth-rate of crystal faces through both acceleration and inhibition with trace amounts of specific chiral additives. They have engineered two- and three-dimensional crystals and explained their crystal growth dynamics. They have demonstrated for the first time that it was possible to design crystals that could lead to products that were not available by conventional methods. They have also explained variety of pathological crystallization, including those of cholesterol in blood vessels, and malaria pigment in Plasmodium infected red blood cells.

Since all biological systems are composed of molecules of a single chirality, the fundamental scientific question of the origin of life on Earth is closely related to the origin of chirality in nature. Lahav and Leiserowitz have addressed possible pathways to this phenomenon by showing that specific chemical reactions can display chiral amplification in forming one component from a racemic mixture (a mixture of both chiral forms in equal proportions). They demonstrated how polymerization within two-dimensional racemic crystallites could generate homochiral oligopeptides. These observations, therefore, valuably link small-molecule organic assembly in crystals to consequent homochiral biopolymers. Thus, their elegant experiments have created theoretical bases for the emergence of life’s complex chemical machinery from simpler prebiotic mixtures.

Meir Lahav

Leslie Leiserowitz

Crystal formation is one of the most fundamental phenomena in chemistry. The structure of organic crystals is of particular importance because the crystal shape (morphology) reflects the three-dimensional structure (stereochemistry) of the molecules assembled in that crystal. In 1848 Louis Pasteur conducted his famous experiment, physically separating the two crystalline forms of a tartaric acid salt, which mirror one another. Pasteur’s experiment became the basis for modern stereochemistry, and it was followed by the study of the first Nobel Laureate in Chemistry, Jacobus H. van’t Hoff. However, neither Pasteur, van’t Hoff, nor many other famous chemists failed to understand the relationship between crystal morphology and molecular stereochemistry.

It took nearly 140 years until Professors Lahav and Leiserowitz conducted their milestone experiments in the Mid-1980s, demonstrating for the first time that the absolute configuration of molecules can be derived from their crystal morphologies. They not only solved the long-standing puzzle but also pioneered the science of organic crystals’ stereochemistry. They directly related the stereochemistry of the individual molecule to the shape of the macroscopic crystal. They founded the links between molecular structure, crystal morphology, crystal growth’ dynamics, and molecular chirality (the structural property of an object, which makes it different from its mirror image, like the human hands). Their findings laid the foundation for our current knowledge of the selective self-assembly of organic molecules. In this way, their rules powerfully complement our understanding of organic chemistry for covalent assembly and macromolecules’ self-assembly.

Furthermore, Lahav and Leiserowitz applied their theories for the design and engineering of chiral crystals, controlling the relative growth-rate of crystal faces through both acceleration and inhibition with trace amounts of specific chiral additives. They have engineered two- and three-dimensional crystals and explained their crystal growth dynamics. They have demonstrated for the first time that it was possible to design crystals that could lead to products that were not available by conventional methods. They have also explained variety of pathological crystallization, including those of cholesterol in blood vessels, and malaria pigment in Plasmodium infected red blood cells.

Since all biological systems are composed of molecules of a single chirality, the fundamental scientific question of the origin of life on Earth is closely related to the origin of chirality in nature. Lahav and Leiserowitz have addressed possible pathways to this phenomenon by showing that specific chemical reactions can display chiral amplification in forming one component from a racemic mixture (a mixture of both chiral forms in equal proportions). They demonstrated how polymerization within two-dimensional racemic crystallites could generate homochiral oligopeptides. These observations, therefore, valuably link small-molecule organic assembly in crystals to consequent homochiral biopolymers. Thus, their elegant experiments have created theoretical bases for the emergence of life’s complex chemical machinery from simpler prebiotic mixtures.

Stephen L. Buchwald

John F. Hartwig 

Stephen L. Buchwald was born (1955) in Bloomington, Indiana. He received his Sc.B. degree from Brown University. and his doctorate from Harvard University. He was a Myron A. Bantrell post-doctoral fellow at Caltech with Professor Robert H. Grubbs where he studied titanocene methylenes as reagents in organic synthesis and the mechanism of Ziegler-Natta polymerization. In 1984, he began as an assistant professor of chemistry Massachusetts Institute of Technology (MIT) He was promoted to the associate professor (1989), to professor (1993), and was named the Camille Dreyfus Professor in 1997. In 2015, he became associate head of the Chemistry Department. During his time at MIT, he has received numerous honors, including the Harold Edgerton Faculty Achievement Award of MIT, an Arthur C. Cope Scholar Award, the 2000 Award in Organometallic Chemistry from the American Chemical Society, a MERIT award from the National Institutes of Health and many more.

The development of palladium-catalyzed carbon-carbon bond formation by Prof. Heck, Prof. Negishi and Prof. Suzuki, resulted in the 2010 Nobel Prize for this innovation. This achievement underscored the immense importance of making new chemical bonds, and at the same time it created an urgent need for going beyond carbon-carbon bonds. This is precisely the achievement of Prof. Buchwald and Prof. Hartwig who have independently harnessed cross coupling for the making of carbon-heteroatom bonds. These bonds and especially the carbon-nitrogen bonds are immensely important, because such bonds constitute a very basis of medicinal chemistry. Thus, the two laureates have pioneered the development of transition metal catalyzed procedures that are broadly applicable and allow carbon-heteroatom bonds of all sorts to be formed with previously unknown efficiency and precision.

In so doing, Profs. Buchwald and Hartwig have profoundly impacted the practice of organic synthesis in general and medicinal chemistry in particular. The transformative nature of their achievement has changed the way whereby ever-more-efficient drugs are discovered and eventually manufactured, for the extensive benefit of society today and in the future. This breakthrough is the fruit of truly basic research and fundamental mechanistic investigations into ligand design and the elementary steps that transition metal complexes are able to entertain. These methodologies proved to be truly potent and represent, as such, a lasting legacy for the art and science of catalysis, and the prime justification for awarding Buchwald and Hartwig with the Wolf Prize for 2019.

John F. Hartwig 

Stephen L. Buchwald

Hartwig is a brilliant scientist who has made contributions to organometallic chemistry that have greatly advanced the field. He has also invented new synthetic methods that are proving to be exceedingly useful for total synthesis of complex molecular targets and new molecules of importance to medicinal chemistry and organic electronic materials.

John Hartwig received his undergraduate degree from Princeton University, obtained his Ph.D. from U.C. Berkeley with Bob Bergman and Richard Andersen, and conducted a postdoctoral fellowship at MIT with Stephen Lippard. In 1992, he began his independent career at Yale University and became the Irenée P. DuPont Professor in 2004. In 2006, he moved to the University of Illinois where he was the Kenneth L. Rinehart Jr. Professor of Chemistry. In 2011, he returned to U.C. Berkley as the Henry Rapoport Professor. He has received numerous awards, including an A.C. Cope Scholar Award, the ACS award in Organometallic Chemistry, the American Chemical Socity H.C. Brown Award for Synthetic Methods, the Nagoya Gold Medal, and the Willard Gibbs Medal. He was elected to the National Academy of Sciences in 2012, the American Academy of Arts and Sciences in 2015, 2018 Centenary Prize from Royal Society of Chemistry and 2018 Tetrahedron Prize for Creativity in Organic Chemistry

The development of palladium-catalyzed carbon-carbon bond formation by Prof. Heck, Prof. Negishi and Prof. Suzuki, resulted in the 2010 Nobel Prize for this innovation. This achievement underscored the immense importance of making new chemical bonds, and at the same time it created an urgent need for going beyond carbon-carbon bonds. This is precisely the achievement of Prof. Buchwald and Prof. Hartwig who have independently harnessed cross coupling for the making of carbon-heteroatom bonds. These bonds and especially the carbon-nitrogen bonds are immensely important, because such bonds constitute a very basis of medicinal chemistry. Thus, the two laureates have pioneered the development of transition metal catalyzed procedures that are broadly applicable and allow carbon-heteroatom bonds of all sorts to be formed with previously unknown efficiency and precision.

In so doing, Profs. Buchwald and Hartwig have profoundly impacted the practice of organic synthesis in general and medicinal chemistry in particular. The transformative nature of their achievement has changed the way whereby ever-more-efficient drugs are discovered and eventually manufactured, for the extensive benefit of society today and in the future. This breakthrough is the fruit of truly basic research and fundamental mechanistic investigations into ligand design and the elementary steps that transition metal complexes are able to entertain. These methodologies proved to be truly potent and represent, as such, a lasting legacy for the art and science of catalysis, and the prime justification for awarding Buchwald and Hartwig with the Wolf Prize for 2019.