Hugh E. Huxley: the compleat biophysicist

Abstract

The sliding filament model of muscle contraction, put forward by Hugh Huxley and Jean Hanson in 1954, is 60 years old in 2014. Formulation of the model and subsequent proof was driven by the pioneering work of Hugh Huxley (1924-2013). We celebrate Huxley's integrative approach to the study of muscle contraction; how he persevered throughout his career, to the end of his life at 89 years, to understand at the molecular level how muscle contracts and develops force. Here we show how his life and work, with its focus on a single scientific problem, had impact far beyond the field of muscle contraction to the benefit of multiple fields of cellular and structural biology. Huxley introduced the use of x-ray diffraction to study the contraction in living striated muscle, taking advantage of the paracrystalline lattice that would ultimately allow understanding contraction in terms of single molecules. Progress required design of instrumentation with ever-increasing spatial and temporal resolution, providing the impetus for the development of synchrotron facilities used for most protein crystallography and muscle studies today. From the time of his early work, Huxley combined electron microscopy and biochemistry to understand and interpret the changes in x-ray patterns. He developed improved electron-microscopy techniques, thin sections and negative staining, that enabled answering major questions relating to the structure and organization of thick and thin filaments in muscle and the interaction of myosin with actin and its regulation. Huxley established that the ATPase domain of myosin forms the crossbridges of thick filaments that bind actin, and introduced the idea that myosin makes discrete steps on actin. These concepts form the underpinning of cellular motility, in particular the study of how myosin, kinesin, and dynein motors move on their actin and tubulin tracks, making Huxley a founder of the field of cellular motility.