LA JOLLA, California—Jeffery Kelly, the H. Lutcher Brown Professor of Chemistry at Scripps Research, has been elected to the European Academy of Engineering in recognition of research that transformed scientists’ understanding of how proteins fold, misfold and assemble into toxic aggregates. His work has connected fundamental chemistry with the development of medicines for diseases in which normally soluble proteins become unstable, misassemble and form amyloid deposits in nerves, the heart and other tissues. The academy’s decision places Kelly among engineers and scientists whose discoveries have produced exceptional advances in technology, medicine and public health. He will join the organization’s Biomedical Engineering class, reflecting the increasingly important role of molecular design in treating disorders once considered difficult, or even impossible, to influence at their biological source.
Proteins are long chains of amino acids that must fold into precise three-dimensional structures before they can perform their functions. This folding process is governed by a complex balance of chemical forces, including hydrogen bonding, hydrophobic interactions, electrostatic attraction and the movement of water around the protein surface. A small change in temperature, pH, genetic sequence or chemical environment can destabilize that balance. When a protein fails to maintain its native structure, it may partially unfold and expose normally hidden regions. These exposed surfaces can interact with equivalent regions on other molecules, allowing the proteins to associate into oligomers, fibers and eventually amyloid deposits. Such assemblies are central features of several neurodegenerative and cardiovascular diseases, but their formation is not a simple chemical accident. It is a dynamic process that can potentially be redirected with carefully designed molecules.
Kelly’s research has focused on understanding that process at a level detailed enough to reveal where therapeutic intervention is possible. His laboratory has combined organic chemistry, biophysics, structural biology and cell-based approaches to examine how proteins move between folded, unfolded and aggregated states. Rather than viewing misfolding as a single catastrophic event, the work has treated it as an energy landscape containing multiple intermediate forms. Some intermediates may be short-lived and harmless, while others can act as especially efficient seeds for further aggregation. Identifying which molecular states initiate disease is essential because a treatment may need to stabilize the healthy protein before it begins to unravel, block the formation of toxic intermediates or prevent already formed assemblies from damaging cells. This framework has helped shift protein-misfolding research from observation toward rational therapeutic design.
One of Kelly’s most influential achievements involved transthyretin, or TTR, a protein produced primarily by the liver and responsible for transporting thyroxine and retinol-binding protein in the bloodstream. TTR normally circulates as a tetramer made of four identical subunits. In hereditary forms of transthyretin amyloidosis, mutations can weaken the interactions holding the tetramer together. The complex may then dissociate into individual subunits, which can partially unfold and assemble into amyloid fibrils. These fibrils accumulate in tissues, damaging peripheral nerves in transthyretin amyloid polyneuropathy and impairing the structure and function of the heart in transthyretin amyloid cardiomyopathy. Even the normal, nonmutated protein can become amyloidogenic with age, making the disease relevant beyond inherited mutations. Kelly’s studies clarified that tetramer destabilization is a critical early event and therefore a promising point for intervention.
That mechanistic insight contributed to the development of tafamidis, the active pharmaceutical ingredient in Vyndamax and Vyndaqel, medicines approved by the U.S. Food and Drug Administration for transthyretin-related disease. Tafamidis functions as a kinetic stabilizer: it binds to thyroxine-binding sites within the TTR tetramer and makes dissociation less likely. The distinction between thermodynamic and kinetic stabilization is important. A drug does not necessarily need to make the folded state the only energetically favorable state; it can instead slow the rate at which the protein reaches a disease-associated state, extending the lifetime of the functional tetramer. By reducing the supply of misfolded TTR subunits, the treatment can limit the production of new amyloid material. The approach demonstrates how defining the molecular sequence of disease can reveal a practical treatment strategy that operates before irreversible tissue damage becomes extensive.
The development of TTR stabilizers also illustrates why protein aggregation cannot be addressed solely by searching for compounds that dissolve visible deposits. Amyloid fibrils may represent the endpoint of a much longer process, and the most harmful species can arise earlier, when small assemblies interact with cell membranes or disrupt intracellular pathways. A drug that targets the earliest destabilizing transition may therefore have greater impact than one aimed at mature deposits. Kelly’s research helped establish this preventive logic by linking the behavior of individual protein molecules to disease progression in patients. It also provided a general model for studying other amyloid disorders, in which the identities of the proteins differ but the underlying challenges—conformational instability, intermolecular association and tissue-specific toxicity—are conceptually related. The work has made protein chemistry a direct engine of therapeutic discovery.
The European Academy of Engineering, founded in Sweden in 1992, brings together experts from a broad range of technical disciplines and advises on issues involving policy, public health and education. Its members are elected by peers across 13 engineering classes, each representing a specialized area. Kelly’s election recognizes a career in which discoveries traditionally associated with chemistry have produced consequences for biomedical engineering, drug development and clinical care. His honors include the Canada Gairdner International Award, election to the U.S. National Academy of Sciences, the Wolf Prize in Chemistry in 2023 and the Breakthrough Prize in Life Sciences in 2022, in addition to numerous other distinctions. Together, these awards reflect the unusual reach of research that began with questions about molecular structure and ultimately helped produce a medicine for a life-threatening protein-aggregation disorder.
Kelly’s election arrives as scientists increasingly seek therapies that modify the physical behavior of disease-linked proteins rather than merely treating symptoms after damage has occurred. Advances in cryo-electron microscopy, nuclear magnetic resonance, mass spectrometry and computational modeling are making it possible to observe unstable conformations and transient protein assemblies with growing precision. These tools may reveal additional opportunities to stabilize vulnerable proteins, remove harmful species or correct the cellular systems responsible for protein quality control. The broader lesson of Kelly’s work is that understanding how a protein fails can be as important as understanding how it functions when healthy. By tracing the molecular steps that connect folding errors to human disease, researchers can convert a seemingly microscopic chemical event into a clear therapeutic target—and, in some cases, into a treatment capable of changing the course of illness.
Subject of Research: Protein folding, protein misfolding and amyloid aggregation, with a focus on transthyretin amyloidosis and therapeutic protein stabilization.
Web References: Jeffery Kelly — Scripps Research
Image Credits: Scripps Research
Keywords
Protein folding; neurodegenerative diseases; cardiomyopathy; transthyretin amyloidosis; amyloid aggregation; protein misfolding; biomedical engineering; tafamidis; Scripps Research; Jeffery Kelly
