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2017 Advancement of Basic and Applied Science Award – Arthur Horwich

Arthur Horwich, M.D.

Sterling Professor of Genetics and Pediatrics at the Yale School of Medicine
Howard Hughes Medical Institute Investigator

Dr. Horwich received his undergraduate (1972) and medical (1975) degrees as a member of the  first class of the Program in Liberal Medical Education at Brown University, in which he graduated  as Valedictorian. Following an internship and residency in pediatrics at Yale, he worked as a  postdoctoral fellow at the Salk Institute for Biological Studies, followed by another postdoctoral  fellowship with Leon Rosenberg at the Yale School of Medicine. In 1984 he joined the faculty of the  Department of Genetics and has been sequestered within that compartment ever since. 

Dr. Horwich’s research has addressed medically important questions which then go on  to elucidate fundamental principles of biology, which in turn then provide insights back  to therapeutic approaches. As a pediatrician, Dr. Horwich explored the mechanisms of  ornithine transcarbamylase (OTC) deficiency in children, wherein abnormal function of a  key enzyme of nitrogen metabolism can have a life-threatening impact. After establishing  a model system in yeast for studying the import of the OTC enzyme into mitochondria  (mitochondrial import is necessary for OTC function), he identified mutants which fail to  establish active OTC in mitochondria. One of these mutants failed to develop OTC activity  because the OTC enzyme, which was transported into the mitochondria in an unfolded state,  subsequently failed to refold to its active form due to loss of a cellular component required  for folding. This was at the time a heretical deduction, since it was widely accepted that the  successful folding of a protein into its final, active three dimensional structure was essentially  spontaneous and dependent only on the primary amino acid sequence of the protein. He  found the mutation to be in a gene subsequently named Hsp60 and demonstrated the vital  role of Hsp60 in the folding of OTC as well as other mitochondrial proteins following  import. Subsequent work established the existence of a large class of proteins termed  “chaperonins” (of which Hsp60 is an example) which serve to prevent the misfolding and  aggregation of proteins in various cellular locales. Dr. Horwich pioneered biochemical studies  of chaperonin activity (using also another chaperonin, the bacterial groEL protein) as well  as structural and biophysical studies to explore via multiple avenues the mechanics of how  chaperonins perform their vital function in cells. 

 In addition to their significance in fundamental biology, chaperonins have been  recognized as being of great medical significance: derangement of protein folding (such  as occurs with the chaperonin mutants) has been implicated in numerous disease states  including, for example, neurodegenerative diseases. Most recently Dr. Horwich’s laboratory  has been studying the role of misfolding of the enzyme superoxide dismutase I (SOD1)  which leads to a specific type of ALS. His research concerns both basic biology of the role  of SOD1 folding in neural function, and identification of possible therapeutic modalities  informed by better understanding of the SOD1 folding pathways. 

Dr. Horwich’s research has been recognized by the biomedical community as evidenced  by numerous honors and awards, including (but not limited to) the Rosenstiel Award for Distinguished Work in Basic Medical Sciences, the Lasker Award for Basic Medical  Research, and an Honorary Doctorate of Medical Science from his original launching  site at Brown University. For his groundbreaking contributions to biology and medicine,  we are proud to honor Dr. Arthur Horwich as the 2017 recipient of the Yale Science &  Engineering Award for Advancement of Basic & Applied Science.