Neuron theory, the cornerstone of neuroscience, on the centenary of the Nobel Prize award to Santiago Ramón y Cajal
Introduction
The neuron doctrine constitutes the cornerstone on which, throughout the 20th century, all the neuroscientific disciplines were constructed. This year sees the centenary of the award of the Nobel Prize for Physiology and Medicine to Santiago Ramón y Cajal (1852–1934), the great ideologue and driving force behind this theory, for his meritorious work on the structure of the nervous system. One hundred years later, the majority of Cajal's postulates, laid out in his lecture to the Swedish Academy, continue to be of remarkable scientific currency, and have made Cajal the most cited classical scientist in history. It is in recognition and honour of this notable achievement that we examine in this work the circumstances in which the neuron doctrine came into being.
Neuron theory should be considered, from the historical perspective, as the final and definitive link in the development of cell theory, the doctrine that consolidated itself in the second half of the 19th century as a result of extensive progress in the anatomical disciplines, the coming of age of physiological knowledge, the definitive adoption of proper experimental methods, improvements in optical technology and advances in micrographic techniques. The first cell theory began to emerge in the 1830s, thanks to the work of researchers such as Samuel Thomas von Sömmerring (1755–1830), Karl Asmund Rudolphi (1771–1832), Johann Evangelista Purkinje (1787–1869), Ernst Heinrich Weber (1795–1878), Johannes Peter Müller (1801–1858), Friedrich Gustav Jackob Henle (1809–1885) or Gabriel Gustav Valentin (1810–1863), though it was the contributions of Matthias Jacob Schleiden (1804–1881) and of Theodor Schwann (1810–1882) that made possible the definitive formulation of cell theory [2]. Schwann produced one of the first descriptions of cell structure (Zellentheorie) in animal tissue (cytoblasteme, cell membrane, cell nucleus and nucleoli), in which he considered the cell as a structure made up of several superimposed layers. Schwann concludes his work with the proposal of a cell theory (Theorie der Zellen) focusing not such much on anatomical as on physiological aspects: “In general we should attribute autonomous life to cells” [61].
Rudolph Albert von Kölliker (1817–1905), in his Handbuch der Gewebelehre des Menschen, first published in 1852 [45], brought together and gave substance to all the disperse knowledge that could contribute to cell theory. For Kölliker, the cell would be made up of a container vesicle (cell membrane) and a content composed of a liquid surrounding different particles and a special round body (cell nucleus), which contained in turn, another liquid and another smaller corpuscle (nucleus corpuscle or nucleolus). Eleven years later, in the 4th German edition of his Handbuch, von Kölliker stated that cells “should be conceived as the essential formal units of the body”. However, and with no disrespect to all the other authors mentioned, it is fair to acknowledge Rudolf Ludwig Carl Virchow (1821–1902) as the great ideologue of the cellular theory. A disciple of Müller and Professor at Würzburg and Berlin, in 1855 he pronounced his famous sentence: “omnis cellula e cellula” [68], that is, cells can only multiply from themselves. For Virchow, life is essentially cellular activity, so that the life of organisms is the sum of the life of each of its cells.
The enormous technical advances in the field of cytohistology during the second half of the 19th century provided scientists with more and more precise knowledge about the true structure of cells. It suffices to mention, by way of illustration, the comprehensive progress in the construction of microscopes (Leitz), the development of immersion lenses in 1850 (Amici), the introduction of the microscope condenser system in 1873 (Zeiss and Abbe) and the apochromatic lens in 1887 (Abbe), the introduction and refinement of the microtome in 1886 (Minot), techniques of paraffin embedding in 1869 (Klebs) and celloidin embedding in 1879 (Duval), techniques for fixing sections in chromic acid in 1850 (Corti), or in chromic-acetic mixtures in 1854 (Remak), the new colouring methods, such as Gerlach's carmine (1847), Schultze's osmic acid (1865), Perkin and Ehrlich's aniline derivatives (1854–1870), and Böhmer's hematoxylin (1865), von Recklinghausen's metallic impregnations (1863) and the subsequent discovery of silver bichromate by Golgi (1883) or silver nitrate by Cajal (1903), the microphotographic methods developed by Gerlach (1863) and Koch (1877), and so on. Thus, cell theory became definitively consolidated in the 1890s, precisely the same decade that saw the birth of the neuron doctrine, thanks largely to the work of Cajal.
In the words of the great science historian Pedro Laín Entralgo (1908-2001), “the work of Cajal thus constitutes the definitive vindication of cell theory, making Schleiden, Schwann, Virchow and Cajal the four principal figures in the history of the theory” [48]. A similar view was expressed by one of Cajal's disciples, the Uruguayan Clemente Estable (1894–1976), for whom his mentor was “the final illustrious architect of cell theory, the most transcendent of all the biological theories” [29]. In the present work we undertake a historical analysis of the circumstances in which Cajal formulated the neuron doctrine, considering the authors and works that influenced his postulate, the difficulties involved in its dissemination within science, and how it finally became established. Table 1 shows some of the major milestones in the development of neuron theory.
Section snippets
The pre-Cajalian period: first approaches to knowledge of the microscopic anatomy of the nervous system
Although some authors, such as Antoni van Leeuwenhoek (1632–1723), had already, in the early 18th century, carried out some microscopic observations (Fig. 1A), the first descriptions of nerve cells are attributed, almost simultaneously, in the period 1833–1837, to Christian Gottfried Ehrenberg (1795–1876), who analyzed the nervous system of the leech [28], and to Purkinje, Professor at the Universities of Breslau and Prague, who described, in the mammalian cerebellum, some large cells (Fig. 1C)
The formulation of the “neuron doctrine” (1888–1889)
In early January of 1884, Cajal (Fig. 4), having won the corresponding competitive exam, moved to Valencia to take up his post as Professor of Anatomy at the city's University. His time in Valencia (1884–1887) coincided with a period of great development of medical scientific activity there [49]. It is while Cajal was in Valencia that he first came into contact with the intimate texture of the nervous system, “that masterwork of life” [21]. His future success in this field would be due, as he
The culmination of neuron theory: introduction to the concept of synapse
The mid-19th century also saw the emergence of arguments on the way neurons enter into contact with one another or with other structures. Kühne, using histological methods of fixation and staining, described, in the 1870s, the way the nerve endings terminate on a formation of the muscular membrane (subsequently the motor end-plate), labelling the whole structure “the neuromuscular junction”. For Kühne, this neuromuscular junction constituted, from the physiological perspective, a form of
Epilogue: the historical relevance of neuron theory
Cajal's great achievements in defence of neuron theory throughout 45 years of work are compiled in the so-called “scientific testament of Cajal”, in a work first published in 1933 in the journal Archivos de Neurobiología, entitled Neuronismo o reticularismo. Las pruebas objetivas de la unidad anatómica de las células nerviosas [22], and also published, posthumously (1935), in German, with the title Neuronenlehre, in the Handbuch der Neurologie, by Oswald Bumke (1877–1950) and Otfrid Foerster
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