RETROSPECTIVE Hugh Esmor Huxley (1924–2013) Kenneth C. Holmes1 Max Planck Institute for Medical Research, D-69120 Heidelberg, Germany

HughEsmorHuxleywasbornonFebruary Schneider solution, which dissolves myosin, 25th, 1924 and raised in Birkenhead, Cheshire, it became clear that filaments in the I-bands England. He gained admittance to Christ’s were just actin, the H-zones were just myo- College Cambridge in 1941 and studied sin, and the A-bands were overlap zones for physics. Britain was at war; Hugh elected actin and myosin filaments. Carrying out to interrupt his studies and join the Royal these experiments at various degrees of stretch Air Force, working on the development of of the muscle demonstrated that the muscle radar. He was honored for his substantial consists of two sets of filaments that move contributions by being awarded membership past each other as muscle contracts. Hugh and of the Order of the British Empire (MBE). Jean wrote up the results for Nature (1), but on Hugh returned to Cambridge in 1947, his the advice of Frank Schmitt left out the slid- enthusiasm for nuclear physics irrevocably ing filament hypothesis: Frank maintained diminished by the horrors of Hiroshima. For that good data should not be spoiled with his doctoral research at the Cavendish Lab- speculation. This may have been bad advice, oratory, rather than pursue nuclear physics because this groundbreaking work was never Hugh joined Max Perutz’s group working on acknowledged by the Nobel committees. the X-ray analysis of crystalline proteins, While in Boston, Hugh formed a life-long where he became John Kendrew’s first re- friendship with Andrew Szent-Györgyi, the search student. Hugh had come across Dick younger cousin of Nobel prize winner Albert Bear’sX-raydiffractionpatternsfromair- Szent-Györgyi. Hugh often went down to the dried muscle and, moreover, was amazed to Marine Biological Laboratory in Woods Hole Hugh Huxley on the Boston North Shore. discover no one really knew how muscle during summer weekends and stayed with works. Hugh set about building an X-ray Andrew and Eve Szent-Györgyi. In the sum- actin). He saw with wonder that the polarity camera and X-ray generator capable of re- mer of 1953, Hugh met his namesake (but of the actin filaments reverses as you go through – solving spacing of 300 400 Å to take diffrac- not relative) Andrew Huxley in Woods Hole. the Z-line. “ ” tion photographs of wet living muscle. He Unlike the muscle establishment, Andrew In 1962 Hugh moved back to Cambridge, fi fl ’ saw for the rst time the equatorial re ec- Huxley was sympathetic to Hugh sideasof to the newly opened Medical Research Coun- fi fi tions arising from a hexagonal array of la- sliding laments and indeed, using his own cil Laboratory of Molecular Biology (LMB). ments and somewhat prophetically guessed sophisticated interference microscope, was At the LMB he set up a Siemens Elmiscope-1 fi that these arose from laments of myosin reaching similar conclusions. The next year, and first used it to investigate the spontaneous on the hexagonal lattice points, with actin together with Jean Hanson and Rolf Nieder- assembly of myosin molecules in vitro to form fi laments in between. Hugh also suggested gerke, the researchers published the sliding- bipolar thick filaments. Hugh investigated the the filaments were linked by “cross bridges.” filament hypothesis in two papers back-to- fi Nature structures of the thin actin-containing la- In 1952 Hugh went to the Massachusetts back in (2, 3). This was the beginning ments. He and John Haselgrove were able to Institute of Technology (MIT) as a postdoc- of modern muscle research. find an X-ray diffraction signal from muscle torate scholar in Frank Schmitt’sdepartment In the spring of 1954, Hugh returned to that showed how tropomyosin, one compo- to learn electron microscopy. Soon, Hugh’s Cambridge, England, to a research fellowship nent of the thin filament, moved in response tranverse sections of fixed muscle showed at Christ’s College, but in 1956 he moved to to activation by calcium ions, so as to free up the arrangement of filaments he had postu- a position at University College, London, in the cross-bridge binding site on actin. lated from his X-ray studies, together with Bernard Katz’s Department. Here he made In February 1966 Hugh married Frances a hint of cross-bridges connecting the fila- substantial advances in the fixing and sec- Maxon Fripp from Boston, MA. Frances ments. The arrival of Jean Hanson at MIT tioning of muscle. Hugh produced wonder- brought three teenage children into the mar- provided further impetus. Jean was experi- ful images of longitudinal sections of cross- riage. The family duly moved to Cambridge, enced in phase-contrast microscopy. The striated muscle, barely 15.0-nm-thick and units of cross-striated muscle are sarcomeres, clearly showing the cross-bridges connecting England. In 1970 Frances gave birth to Olwen. about 2.5 μ in length, delineated by Z-lines, the thick (myosin) and thin (actin) filaments. Hugh was still intrigued by the low-angle allinserieswitheachother.Inthephase- With Geoffrey Zubay, Hugh developed “neg- X-ray diffraction pattern of muscle that he contrast pictures of single muscle fibers the ative staining.” Using negative staining, Hugh subdivisions of the sarcomere into the H- discovered that the isolated cross-bridges This article is an abridged version of the Obituary of Hugh Huxley zone, A-bands, and I-bands are clear. Exam- bound specifically and regularly to the actin published in J Muscle Res Cell Motil, 10.1007/s10974-013-9365-6. ining glycerinated rabbit muscle fibers after filament, one cross-bridge per actin, with the K.C.H. wrote the paper. extraction of the myosin with Hasselbach– symmetry of the actin filament (decorated 1E-mail: [email protected].

18344–18345 | PNAS | November 12, 2013 | vol. 110 | no. 46 www.pnas.org/cgi/doi/10.1073/pnas.1318966110 Downloaded by guest on October 5, 2021 had uncovered in his doctoral research. He imminent. Hugh was offered a professorial the cross-bridges attached to actin to be mea- RETROSPECTIVE wished to follow the changes when a resting appointment at the Rosenstiel Basic Medical sured with high precision. Massimo Recon- muscle is stimulated and allowed to contract. Sciences Research Center at Brandeis, which ditiandHughwereabletoworkoutthe Accordingtothe“swinging cross-bridge” hy- he accepted. In 1987 the family moved to distribution of cross-bridges during a contrac- pothesis that he first presented in a Scientific Concord, MA. In 1988 Hugh was appointed tion. This work was reported in Hugh’stwo American article in 1958 (4), the cross- Director of the Rosenstiel Center, a position last papers, which demonstrate his character- bridges bind in an initial conformation and he held for six years. istic rigor and analytical ability (6); they are “row” the actin filaments past the myosin Hugh and Frances built a house in Woods a fitting conclusion to his scientific career filaments by going over into a second more Hole, where Frances spent her summers di- and provide an elegant vindication of the angled conformation, followed by release recting local drama groups and sailing. Hugh swinging cross-bridge. from actin and rebinding in the first confor- came at weekends. After Gordon Confer- Hugh died unexpectedly on July 25th,2013 mation, but for many years the swinging ences on muscle Hugh would invite friends in Woods Hole. Active to the last, he com- cross-bridge hypothesis remained unsubstan- and expostdoctorate scholars to visit Woods bined a wonderful experimental ability with tiated. A change in orientation of the cross- Hole to enjoy a not always uneventful trip to a very analytical mind. He was also a gen- bridge would manifest itself as a change in Martha’s Vineyard on his sloop Saraband. tle humanist and a man of great integrity. the low-angle X-ray scattering pattern, if you In 1997 the Advanced Photon Source at Hugh’s originality and creativity led to his could get enough intensity to measure this in Argonne became available as the world’s being elected to the Royal Society of London a few milliseconds. Conventional X-ray sour- brightest X-ray source. The Biophysics Col- attheyoungageof36.Hewasamemberof BioCAT ces had reached their limit but Synchrotron laborative Access Team ( ) team led the National Academy of Sciences. In 1971 Radiation was in principle a very bright X-ray by Tom Irving set up excellent beam lines Hugh was awarded the Louisa Gross Horwitz ’ source. With Hugh s support, the newly that provided Hugh with the opportunity to Prize. In 1975 he received the Gairdner fi founded European Molecular Biology Labo- investigate a phenomenon rst explored with Award. In 1997 he was awarded the presti- fi ratory in Heidelberg opened an outstation single muscle bers by Vincenzo Lombardi gious Royal Society Copley Medal. The cita- on the DORIS (Doppel-Ring-Speicher) elec- and his collaborators: the 14.5-nm meridio- tion reads: tron storage ring at Deutsches Elektronen- nal reflection is actually split into two closely Synchrotron Hamburg for the exploitation spaced reflections that arise from interference In recognition of his pioneering work on the structureofmuscleandonthemolecular of synchrotron radiation as an X-ray source. between the two halves of the sarcomere. mechanisms of muscle contraction, provid- Here in 1981 Hugh and his team of collabo- Because it is an interference phenomenon, ing solutions to one of the great problems rators were finally able to demonstrate that this process allows the average position of in physiology. swinging cross-bridges actually swung (5). Together with Aaron Klug, Hugh became joint head of the Division of Structural 1 Hanson J, Huxley HE (1953) Nature 172:530–532. 5 Huxley HE, Simmons RM, Faruqi AR, Kress M, Bordas j, and Koch 2 Huxley HE, Hanson J (1954) Nature 173:973–976. MHJ (1981) Proc Natl Acad Sci USA 78:2297–2301. Studies. Later he became deputy Director of 3 Huxley AF, Niedergerke R (1954) Nature 173:971–973. 6 Huxley H, Reconditi M, Stewart A, Irving T (2006) J Molec Biol 383: the LMB, but enforced retirement at 65 was 4 Huxley HE (1958) Scientific American 199:58–67. 743–761, 762–772.

Holmes PNAS | November 12, 2013 | vol. 110 | no. 46 | 18345 Downloaded by guest on October 5, 2021