John Paul Merlie (1945–1995)

John Merlie died suddenly and unexpectedly on May 27, 1995, of a heart attack. Hiswork on the regulation of neuromuscular synapse formation has had a major impact on the field, both in its breadth and in its accuracy. In fact, many feel that his most recent contributions and work soon to be published will be perhaps the most influential of his career. After earning a bachelor of science degree in molecular biology from Villanova University, John began graduate studies in molecular biology at the University of Pennsylvania. His thesis research concerned the regulation of phospholipid synthesis in Escherichia coli. After completing his graduate studies in 1973, John went to the lnstitut Pasteur in Paris with the intention of continuing research in microbial physiology. Shortly after his arrival, he became a willing recruit to the nascent molecular neurobiology group within the Departement de Biologie Moleculaire at the lnstitut Pasteur and began his studies of the acetylcholine (ACh) receptor, the protein that would be the center of his scientific career for the next two decades. With Francois Gros and Jean-Pierre Changeux, John investigated the regulation of the muscle ACh receptor. This early work focused on the synthesis and degradation of the receptor in cultured muscle cells and set the stage for later work on the regulation of ACh receptor gene expression. After returning to the United States, he continued studies of ACh receptor degradation and its involvement in the pathogenesis of myasthenia gravis with Jon Lindstrom at the Salk Institute. John’s pioneering work on the metabolism of the ACh receptor led to an impressive and comprehensive set of investigations of the biosynthesis and assembly of this complex, multisubunit protein and the regulation of the expression of its genes, first at the University of Pittsburgh and then, since 1982, at Washington University in St. Louis. His work on the assembly of the receptor subunits led to the concept of “conformational maturation” as a key posttranslational event. Throughout his career, he was a leader in the application of molecular biological techniques to the analysis of the development of the neuromuscular junction. His goal was to describe the complex regulatory mechanisms involved in the formation of this highly specialized synaptic structure. John’s laboratory contributed to the demonstration that receptor transcriptional activity was restricted to synaptic nuclei, thus providing one mechanism responsible for the high density of receptors at the synapse. Among the very first laboratories to apply the transgenic mouse approach to these problems, John and his colleagues published a beautiful and definitive set of experiments on the regulation of receptor gene expression in skeletal muscle by innervation, showing in particular that denervation dramatically increased transcriptional promoter activity. More recently, John’s laboratory was instrumental in identifying and examining the functions of other proteins concentrated at the neuromuscular junction, including a synaptic form of laminin and the 43 kDa receptor-associated protein, rapsyn. In these highly competitive times, John was unusual in his willingness to share reagents and expertise, even with colleagues likely to carry out the same experiments. John’s lab was involved in many fruitful collaborations with other research groups, but he had an especially close friendship and productive collaboration with Josh Sanes that many felt represented an ideal blend of biological and molecular interests. A very supportive mentor in the lab, John set very high standards while fostering the growth and recognition of his young coworkers. He engendered great loyalty from his lab members, whovalued him both for hisscience and for his personal attributes. John’s commitment to science was matched only by his commitment to his family. A hallmark of John’s scientific career was his ability to recognize the importance of a new technique and to set immediately to apply it in the most effective manner. He believed that the best approach was to develop expertise personally, and then teach it to others in his lab. A prime example was his entry at a very early stage into targeted gene knockout technology for the study of synaptic proteins The recent report of aberrant presynaptic function in a mouse lacking S-laminin expression was the first of a series of studies that are not yet completed. We can take some consolation in the fact that results yet to come, even after John’s death, are likely to influence greatly our thinking about the assembly of the neuromuscular junction. John Merlie was a modest person who never promoted his work but simply let his science speak for itself. He had a keen sense of humor, a mischievous smile, and a contagious love of science. John will remain for those who knew him personally an exceptional man of science, fully dedicated to his work, but always mindful that science is done by human beings with strengths and weaknesses who always deserve our help and friendship.