Hugh Esmor Huxley (1924–2013)

View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector J Muscle Res Cell Motil (2013) 34:311–315 DOI 10.1007/s10974-013-9365-6 OBITUARY Hugh Esmor Huxley (1924–2013) Kenneth Holmes Received: 7 October 2013 / Accepted: 9 October 2013 / Published online: 14 November 2013 Ó The Author(s) 2013. This article is published with open access at Springerlink.com Hugh Esmor Huxley was born on 25th February 1924 and group working on the X-ray analysis of crystalline proteins, raised in Birkenhead, Cheshire across the Mersey river where he became John Kendrew’s first research student. from Liverpool. His family originated in North Wales and John entrusted Hugh with calculating the Patterson func- were generally of a schoolmasterly persuasion. Hugh tion of diffraction data from a sheep hemoglobin crystal. attended the Park High School where he became school Hugh felt this tedious job was unbefitting the human con- captain. He spent much of his adolescence making short dition and persuaded John that he might do something else. wave radio receivers. He was also a keen experimentalist: Hugh had come across Dick Bear’s X-ray diffraction pat- his most ambitious experiment was an attempt to make terns from air-dried muscle and, moreover, was amazed to diamonds by dissolving carbon in molten metals in a home- discover no one knew how muscle works. The tradition of made electric furnace. Both he and his 7-year elder sister the Perutz group was to keep things wet, so Hugh set about gained admittance to Cambridge University, he to Christ’s building an X-ray camera and X-ray generator capable of College in 1941. Hugh was fascinated by quantum physics resolving spacing of 300–400 A˚ to take diffraction photo- and the possibilities of nuclear power saving mankind from graphs of wet ‘‘living’’ muscle to see what you could see. an energy crisis. He completed his Part I unusually quickly He saw for the first time the equatorial reflections arising and was offered the chance of starting his Part II in Physics from a hexagonal array of filaments and somewhat pro- in his second year. But Britain was at war; Hugh elected to phetically guessed that these arose from filaments of interrupt his studies and to join the Royal Air Force myosin on the hexagonal lattice points with actin filaments working on the development of radar. He was honoured for in between. The idea of actin and myosin being organized his substantial contributions to this very important field by in distinct filaments was quite new and stems from Hugh. being awarded membership of the Order of the British He also suggested the filaments were linked by ‘‘cross Empire (MBE). bridges’’. He noted the large change in relative intensities He returned to Cambridge in 1947, his enthusiasm for when the muscle goes into rigor. He also noted that the Nuclear Physics irrevocably diminished by the horrors of meridional reflections don’t alter as the muscle is stretched, Hiroshima. Notwithstanding his moral reservations about which argued strongly against the filaments bringing about physics he achieved a first class degree and elected to do contraction by altering their structure in some way—the his doctoral research at the Cavendish Laboratory. Rather then current explanation of contraction. than nuclear physics he sought out Max Perutz’s small Hugh’s Ph.D. viva in June 1952 was with Sir Lawrence Bragg, the Cavendish Professor, and Dorothy Hodgkin from Oxford. Dorothy was intrigued by Hugh’s report of This article is an extended version of the Retrospective of Hugh Huxley published in the Proceedings of the National Academy of the strong changes in the equatorial reflections that occur Sciences USA doi:10.1073/pnas.1318966110. when a muscle goes into rigor. She assumed (incorrectly) that the muscle shortens as it goes into rigor and intuited & K. Holmes ( ) (correctly) that the changes of intensities Hugh reported Max Planck Institut fu¨r medizinische Forschung, Heidelberg, Germany would be produced by letting two sets of interdigitating e-mail: [email protected] filaments slide to produce more overlap. According to 123 312 J Muscle Res Cell Motil (2013) 34:311–315 Hugh she illustrated her idea by interdigitating the fingers basically a pair of cross-bridges. Now myosin biochemistry of her left and right hands to represent two sets of filaments could move forward. and then let them slide together. Hugh pointed out that he In the summer of 1953 Hugh met his namesake (but not had gone to a lot of trouble to make sure that the filaments relative) Andrew Huxley in Woods Hole. Unlike the stayed at constant length when he let them go into rigor and muscle establishment Andrew was sympathetic to Hugh’s with some irritation dismissed Dorothy’s sliding filament ideas of sliding filaments and indeed, using his own hypothesis! sophisticated interference microscope, was reaching simi- In 1952 Hugh went to the Massachusetts Institute of lar conclusions. The next year, together with Jean Hanson Technology (MIT) with a Commonwealth Fellowship as a and Rolf Niedergerke they published the sliding filament post-doc in Frank Schmitt’s department to learn about hypothesis in two papers back-to-back in Nature. This was electron microscopy. Soon his transverse sections of fixed the beginning of modern muscle research. muscle showed the arrangement of filaments he had pos- In the Spring 1954 Hugh returned to Cambridge, Eng- tulated from his X-ray studies together with a hint of cross- land, to a research fellowship at Christ’s College but in bridges connecting the filaments. However, it was the 1956 he moved to a position at University College, Lon- arrival of Jean Hanson at MIT (also intent on learning don, in Bernard Katz’s Department where the Wellcome electron microscopy) that provided the impetus for under- Foundation provided him with a new Siemens Elmiscope standing sliding filaments. Jean was experienced in the then electron microscope. Here he made substantial advances in new technique of phase contrast microscopy. The units of the fixing and sectioning of muscle. He built a microtome cross-striated muscle are sarcomeres, about 2.5 l in length, capable of cutting ultra-thin sections. He produced won- delineated by Z-lines, all in series with each other. In the derful images of longitudinal sections of cross-striated phase contrast pictures of single muscle fibers the sub- muscle barely 15.0 nm thick clearly showing the ‘‘cross- divisions of the sarcomere into H-zone, A-band and I-band bridges’’ connecting the thick (myosin) and thin (actin) can be seen easily. Examining glycerinated rabbit muscle filaments. In collaboration with Bernard Katz he produced fibers after extraction of the myosin with Hasselbach– stained images of the neuromuscular junction. Further, he Schneider solution, which dissolves myosin, it became and Geoffrey Zubay developed ‘‘negative staining’’: if you clear that filaments in the I-bands were just actin, the immerse a biological macromolecule in a solution of a H-zones were just myosin, and the A-bands were overlap heavy metal salt on a microscope grid and let it dry to form zones for actin and myosin filaments. Carrying out these a glass, the electron micrograph shows a cast of the mac- experiments at various degrees of stretch of the muscle romolecule in the heavy metal glass. This method found demonstrated that the muscle consists of two sets of fila- wide application and became very important in unraveling ments that move past each other as muscle contracts. Hugh virus structure. Using negative staining Hugh discovered and Jean wrote up the results for Nature but on the advice that if one applied Andrew Szent Gyo¨rgyi’s HMM prepa- of Frank Schmitt left out the sliding filament hypothesis: he ration to actin filaments the cross-bridges bound specifi- maintained good data should not be spoiled with specula- cally and regularly to the actin filament, one cross-bridge tion. This may have been bad advice since this ground- per actin, with the symmetry of the actin filament. Imme- breaking work was never acknowledged by the Nobel diately this allowed Hugh to see, with some wonderment, committees. Nevertheless, the idea that myosin was con- that the polarity of the actin filaments reverses as you go fined to the A-band was already enough to upset the through the Z-line, which is actually essential if sarcomeres establishment. Albert Szent Gyo¨rgyi, now in Woods Hole, are to shorten in series with each other. This construct was not amused. He knew how muscles contract. Myosin is became known as ‘‘decorated actin’’ and was often used for a negatively charged polymer: when you add calcium ions establishing the polarity of actin filaments in cell biological it undergoes a phase change and shortens. However, if preparations. Ten years later it was the first object with myosin doesn’t extend all the way between the Z-lines this helical symmetry to be reconstructed in three dimensions can’t work! by the method developed by Aaron Klug and David While in Boston Hugh formed a life-long friendship DeRosier. Finally, some 50 years later, high resolution with Andrew Szent Gyo¨rgyi, Albert’s younger cousin. electron microscopy of decorated actin allowed one to see Hugh often went down to the Marine Biological Labora- in detail how myosin binds to actin thus finally enabling an tory in Woods Hole during summer weekends, and stayed understanding of muscle contraction at the atomic level. with Andrew and Eve Szent-Gyo¨rgyi. In the 1950s Andrew In 1962 Hugh moved back to Cambridge, to the newly made an important advance in myosin biochemistry by opened MRC Laboratory of Molecular Biology (LMB) and preparing ‘‘light meromyosin’’ (LMM) and ‘‘heavy mero- to a research Fellowship at Kings College.

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