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An intriguing account of the coincidental publication of two seminal papers by Huxley and Niedergerke, and Huxley and Hanson, in the same issue of Nature (May 22, 1954), which introduced the sliding filament concept in muscle contraction. The document sheds light on the background and context of these groundbreaking discoveries, including the influence of earlier research and the significance of the sliding filament concept in the broader context of biomotility. The document also highlights the role of key figures such as David Hill and Wilhelm Krause in shaping Huxley's research direction.
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Koscak Maruyama Office of the President, Chiba University, Inage-ku, Chiba 263
Received for publication, September 12, 1994
Why were the two classical papers by A.F. Huxley and R. Niedergerke and by H.E. Huxley and J. Hanson on the sliding filament concept in muscle contraction published in the same issue (May 22, 1954) of Nature? This historical survey reveals the background of the two groups' monumental work.
Key words: Andrew Huxley, Hugh Huxley, Jean Hanson, muscle contraction, Rolf Niedergerke, sliding filament concept.
In the 1954 May 22 issue of Nature, two classical papers appeared: "Structural changes in muscle during contrac tion" by A.F. Huxley and R. Niedergerke (1) and "Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation" by H.E. Huxley and J. Hanson (2). It is generally accepted that these two short papers presented the first evidence for the sliding filament concept in muscle contraction (3, 4). By that time it was a prevailing opinion under the influence of English biophysicist William Astbury (1898-
The Huxley-Niedergerke work Andrew Fielding Huxley, born at Hampstead, London, in 1917, was educated as a physiologist at Trinity College, Cambridge, and was an assistant director of research at the
Department of Physiology, Cambridge, from 1951 to 1959. In 1951 he changed his research subject from nerve to muscle after completing the monumental papers with Alan Hodgkin on the excitation mechanism of squid giant axon (Nobel Prize for Physiology or Medicine, 1963) (10, 11). Huxley had become interested in the structure and function of striated muscle through the stimulating lectures of David Hill, a muscle physiologist [son of a great muscle physiolo gist, Archibald V. Hill (1886-1977), Nobel laureate (1922)], while he was asked to take over Hill's lectures in 1948 (10). Huxley started his muscle work by developing a new interference microscope suitable for the observation of striation changes during muscle contraction. Assisted by the firm of R. & J. Beck, he undertook to construct a high-power interference microscope, and his hand-made microscope was successfully in use (12) by the end of 1952 (10). In the autumn of 1952, Rolf Niedergerke, born at Mulheim-Ruhr, Germany, in 1921, joined Huxley's labora tory (13). He had worked on isolated nerve fibers in Alexander von Muralt's Institute in Berne. Robert Stampfli, who taught Niedergerke nerve fiber dissection, recommended him to Huxley as a collaborator for isolation of single muscle fibers (13). Niedergerke had been a demonstrator in physiology at Gottingen (13). Huxley and Niedergerke quickly reached a preliminary conclusion that the A band width in a sarcomere was fairly constant during passive stretch, isometric contraction and also isotonic contraction, to a certain extent. The force was generated while the A band remainded invariant during isometric contraction. These results were obtained by early 1953 (11). However, completion of the work was delayed due to Huxley's duties as the editor of the Journal of Physiology and the secretary of the Council of Trinity College (11). Niedergerke, who had read a number of papers on the myofibrillar structure by 19th century German workers, pointed out to Huxley the idea by Wilhelm Krause (1869) (14) that the A band (width, 1.5ƒÊm) in mammalian muscle consisted of longitudinally parallel rodlets (filaments) and the rodlets did not change in length during contraction, but attracted "fluid" from the adjacent I bands. This is a prototype of the sliding concept, if "fluid" is read as
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"filaments" distinct from the A band rodlets. Huxley carefully examined the microscopists' work and later wrote historical overviews (10, 15). A cine film taken in March 1953 first suggested to Huxley a sliding filament system (10). A single fiber, contracting in response to a slowly increasing current, showed the forma tion of the first contraction band as a narrow dense line at the middle of the A band. Huxley assumed that the A band consisted of one kind of filaments as Krause had already mentioned (14) and further that there were another kind of filaments in the I band. The latter I filaments would be separated in the A band in a sarcomere at rest length. It followed that the first contraction band would be due to the collision between opposing sets of these I filaments at the center of the A band. The second contraction band formed near the Z line on further contraction would be due to the collision of the A filaments with the Z line. Huxley had known of the presence of two kinds of muscle contractile
Fig. 1. Sliding movements of myosin motor and actin rail. a, actin rail is immobilized. Myosin motor moves on actin rail to the direction of barbed (plus) end of the actin filament. b, myosin motor is immobilized. Actin rail moves to the direction of the pointed (minus) end of the actin filament. This is the case with striated muscle contraction. M, myosin; A, actin; Z, Z line; C, connectin/titin. Modified from Hayashi and Maruyama (9). Courtesy of Yukiko Ohtani.
Fig. 2. A.F. Huxley and H.E. Huxley. Near Mt. Fuji, 1979. Courtesy of Mrs. Fumiko Ebashi.
proteins, myosin and actin, discovered and characterized by Albert Szent-Gyorgyi and his school at Szeged (16). Furthermore, Hugh Huxley had reported the presence of two kinds of longitudinal filaments in a sarcomere based on low-angle X-ray diffraction and electron microscopic photo- graphs of rabbit psoas fibers (17, 18). He tentatively regarded the two kinds of filaments to be myosin, located in the A band, and actin, mainly located in the I band. Although the main result of the Huxley-Niedergerke paper was the constancy of the A band width of isolated frog muscle fibers during contraction and relaxation, the insight into deeper understanding of the mechanism of muscle contraction is indeed penetrating (1) : "... makes very attractive the hypothesis that during contraction the actin filaments are drawn into the A-bands, between the rodlets of myosin." "If a relative force between actin and myosin is generated at each of a series of points in the region of overlap in such sarcomere, then tension per filament should be proportional to the number of this zone of overlap" (19). These implications, later proved to be actually the case, are most significant, making the Huxley-Niedergerke paper distinct from a mere observation that the A band width was constant during contraction and relaxation (20).
Hugh Huxley and Jean Hanson Hugh Esmor Huxley, born at Birkenhead, Cheshire, in 1924, was educated as a physicist at Christ's College, Cambridge. H.E. Huxley (HEH) is not related to A.F. Huxley (AFH) (21). HEH became interested in biophysics rather than nuclear physics. After having spent 4 years as a research student at the MRC unit of Molecular Biology at Cavendish Laboratory, working first on crystalline proteins and then on muscle, he went to Francis 0. Schmitt's (1903-) laboratory at the Massachusetts Institute of Technology (MIT), Cambridge, MA, as a Commonwealth Foundation fellow from 1952 to 1954 to continue his work on muscle.
Fig. 3. Jean Hanson. King's College Archives. Courtesy of Dr. Pauline Bennett.
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4 K. Maruyama
sible, but became extensible on addition of MgPP or a high concentration of ATP. The latter was due to dissociation of actin from myosin. Hanson and HEH jointly carried out light microscope study (36). Hanson had become familiar with biochemistry of muscle proteins. When myofibrils were treated with myosin-extracting solution (0.3M KCl, 0.15M phosphate buffer, pH6.5, and 0.4mM ATP or 0.47M KCl, 0.1M phosphate buffer, pH6.4, 10mM PP, and 1mM MgCl2), the A bands largely disappeared. Longitudinal sections of such muscle fibers revealed that the thick filaments at the A band almost disappeared leaving thin filaments probably extending from the original I band region. Thus it was logically concluded that the thick filaments at the A band were composed of myosin. This in turn strongly supported the view that the thin filaments consisted of actin. It is to be pointed out that the 1953 Nature paper (36) was really a major milestone, because it established the fine structure of striated muscle, with actin and myosin in two sets of separate but partially overlapping filaments. In the 1954 Nature paper (2), HEH and Hanson summar ized microscopic observations of isolated rabbit muscle myofibrils reinforced by electron microscopic examinations of the muscle fibers. First, the constancy of the A band length was observed during contraction up to about 65% of the rest length of sarcomeres. The changes in the sarcomere length were taken up by changes in the I band length alone. This was in good agreement with the Huxley-Niedergerke work on intact muscle fibers (1). Using a myofibril one end of which attached to cover slip and the other end of which attached to slide glass, it was possible to manipulate both isometric and isotonic contraction. The constancy of the A band length was also confirmed during isometric contraction. When stretched in the presence of a large amount of ATP (10mM), both I band length and H band width increased. HEH and Hanson also noted that the closing up of the H zone region at constant A band length during contraction, and the corresponding closing up of the H zone gap between the ends of the I bands seen after myosin extraction of contracted myofibrils. In the previous work (36) the extraction of the A band was incomplete. Hasselbach reported that it took some time to remove myosin entirely to give rise to A band-free sarcomeres (37). HEH and Hanson obtained the latter by extraction with 0.1M PP and lmM MgCl2. The A band- free myofibrils did not contract at all in the presence of added ATP. Electron microscopy confirmed the absence of the thick filaments at the original A band region leaving thin filaments extending from both Z lines in a sarcomere. The continuity and elasticity were maintained in the A band- free sarcomeres. Therefore, HEH and Hanson assumed that an elastic filament called the S filament linked opposing pairs of thin filaments from both Z lines in a sarcomere (38). "S" was taken from stretch (34). It is quite clear that this Huxley-Hanson paper presented strong evidence for sliding movement during muscle con traction and relaxation, as described: "... actin filaments slide out of or into the parallel array of myosin filaments in the A bands." A full account was published in 1955 (39).
Why were the two 1954 papers printed jointly? A.F. Huxley stayed at the Marine Biological Laboratory,
Woods Hole, MA, in the summer of 1953 (10). There he met Hans H. Weber, a leading German muscle physiologist (40). Weber told AFH that Wilhelm Hasselbach, his collaborator, had been able to identify myosin as the A band substance (37). Also, AFH met HEH at Woods Hole and they discussed their results. HEH told him his work about the double array of filaments in striated muscle. AFH learned that Jean Hanson and HEH also had observed A band-extracted myofibrils. In turn HEH was told about the constancy of the A band width of frog muscle fibers during contraction. AFH suggested to HEH that they should get in touch with each other on further progress of work of mutual interest (26, 41). AFH (10) acknowledged that HEH's paper (18) in 1953 contained the first proposal of the sliding filament concept. In January or February 1954 (28), HEH was writing a joint paper with Hanson and wrote to AFH that HEH would like to cite AFH's paper if submitted. AFH suggested that they should publish the two papers together in Nature (10, 11, 41). Interestingly, both Schmitt (22) and Randall (26) recalled that each of them transmitted the Huxley-Hanson paper to Nature. The two manuscripts were duly published together in the same issue of Nature (May 22, 1954).
Response to the sliding filament concept The sliding filament concept was not immediately accept- ed by most biologists. Albert Szent-Gyorgyi (1893-1986), father of ATP-actin-myosin research, was strongly against the two kinds of separated filaments system, when HEH personally communicated to him at Woods Hole in early 1953 (28). Szent-Gyorgyi had the view that "actomyosin" filaments run continuously through the sarcomere (28). However, he later admitted that he felt ashamed of himself that he had not thought of a sliding concept. Eventually, he decided to leave muscle research (42). When Jean Hanson spoke at the Symposia of the Society for Experimental Biology held at Leeds in September 1954 (39), William Astbury and other physicists were all negative about the concept of the directional movement of filaments (43). Even in the early 1960s when a symposium of biomacromolecules was held in Pittsburgh, PA, most physical chemists including Paul Flory (1910-1985; Nobel Prize for Chemistry, 1974) strongly objected to the direc tionality of the filament movement. The writer still re members Jean Hanson shouting: "I know I cannot explain the mechanism yet, but the sliding is a fact." The sliding filament concept was gradually accepted by mid 1960s. Visualization of the sliding movement was first achieved in the field of cell biology (44): myosin-coated plastic microspheres moved in one direction on actin filaments oriented in the Nitella gel layer. It was demon strated that the movement of single actin filaments (fluo rescent-dye conjugated) on a slide covered with myosin (45,
Epilogue In 1957 Andrew Huxley published a cross-bridge theory to explain the basis of filament sliding (3) that greatly contributed to the establishment of the sliding filament
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Birth of Sliding Filament Concept 5
theory. He extented his theory together with Robert Simmons in 1971(48). The 1957 theory dealt only with the attachment and detachment of cross-bridges while the 1971 theory with Simmons dealt with what the cross-bridges might be doing while attached. He was the Jodrell Profes sor of Physiology, University College London from 1960 to 1969, then a Royal Society Research Professor (1969- 1983). He served as President of the Royal Society (1980-
The writer is most grateful to Sir Andrew Huxley and Professor Hugh Huxley for their helpful personal communication. He is greatly indebted to ProfesessessssorJohn T. Edsall, the writer's supervisor in the history of science, for his warmest encouragements and reading through the manuscript. Thanks are due to Professors F.O. Schmitt, J. Lowy, A.J. Hodge, R.M. Simmons, S. Ebashi, and M. Endo for their invaluable information. He is especially indebted to Professors Simmons and Hodge and Dr. R.T. Tregear for their scrutinizing the manuscript. Thanks are also due to Professors M.F. Morales, J. Gergely, and H. Noda for their helpful comments.
REFERENCES
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