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The Overton in Meyer–Overton: a biographical sketch commemorating the 150th anniversary of Charles Ernest Overton's birth

2015; Elsevier BV; Volume: 114; Issue: 4 Linguagem: Inglês

10.1093/bja/aev069

1471-6771

Misha Perouansky,

Anesthesia and Sedative Agents

Hardly any discourse on anesthetic mechanisms avoids mention of the Meyer–Overton rule. Thanks to the eponymous rule, Charles Ernst Overton (1865–1933) enjoys together with Hans Horst Meyer (1853–1939) the highest name recognition where anesthetic mechanisms are concerned (Fig. 1). It may therefore come as a surprise, especially for clinicians, that the work underlying Overton's contribution to the Meyer–Overton rule was merely a by-product of Overton's principal body of scientific work; his lifelong interest in the movement of substances between the environment and the interior of living cells. Before his anesthesia-related publication1Overton E Studien über die Narkose zugleich ein Beitrag zur allgemeinen Pharmakologie. Verlag von Gustav Fischer, Jena, Germany1901Google Scholar and the subsequent coining of the Meyer–Overton hypothesis, this body of work had led to the 'Overton rule'.2Thunberg T Ernest Overton.Skandinavisches Archiv Für Physiologie. 1934; 70: 1-9Crossref Scopus (2) Google Scholar Overton's work had far-reaching consequences well beyond anaesthesia. It became one of the foundation stones for the conceptualization of the boundary between cell protoplasm and its environment (known today as the cell membrane) and anticipated by several decades the understanding of impulse propagation in excitable membranes. Moreover, his contributions to structure–activity data, to toxicology, and to plant chemistry and genetics are also notable. Charles Ernest Overton was born in Stretton, Cheshire, UK on February 25, 1865 into the family of Samuel Charlesworth Overton and Harriet Jane Fox. aEngland, Cheshire Parish Registers, 1538–2000, index, FamilySearch. His mother was the daughter of the Reverend W. Darwin Fox, an entomologist and friend of Charles Darwin. He attended the Newport grammar school until the family moved to Zurich, Switzerland in 1892, consequent to his mother's chronic illness. There, Charles graduated from the district school (Kantonschule) and enrolled in the University of Zurich in 1884, with botany as his principal subject. During his time at the university, Overton spent a couple of terms at the university of Bonn, Germany in the famous Botanical Institute (Botanisches Institut) headed by Eduard Strasburger (1844–1912). The successful defense of his thesis, 'A contribution to the knowledge about the genus Volvox' (a freshwater green algae, initially described by A. Leeuwenhoek), produced under the mentorship of Professor Arnold Dodel-Port (1843–1908), earned him a doctorate in 1889.2Thunberg T Ernest Overton.Skandinavisches Archiv Für Physiologie. 1934; 70: 1-9Crossref Scopus (2) Google Scholar Shortly after the defense of his thesis, Overton was appointed lecturer bPrivatdozent (abbreviated PD, P.D. or Priv.-Doz.) is an academic title conferred by some European universities, especially in German-speaking countries, to someone who holds certain formal qualifications that denote an ability to teach independently at university level. In its current usage, the title indicates that the holder has permission to teach independently at the conferring university without holding a professorial chair, and the qualification to be appointed as full professor. The title is not necessarily connected to a salaried position, but may entail a nominal obligation to teach at the conferring institution. in biology at the University of Zurich in 1889. Initially, he pursued questions related to the physiology and cytology of freshwater algae and the geographical distribution of water-dwelling plants in the Upper Engadin district of Switzerland. His curiosity, prompted by the colourful autumnal alpine vegetation, led him to discover that the formation of anthrocyanin pigments in plants was correlated with the sugar content of their leaves.3Overton CE Beobachtungen und Versuche über das Auftreten von rothem Zellsaft bei Pflanzen.Jahrb Fuer Wissenschaftliche Botanik. 1899; 33: 171-233Google Scholar While investigating inheritance in plants, Overton showed that the haploid chromosome number is characteristic not only of the sex cells themselves but also of the whole gametophyte.4Overton CE On the reduction of chromosomes in the nuclei of plants.Annals of Botany. 1893; 7: 139-143Crossref Scopus (12) Google Scholar In fact, it was in the pursuit of inheritance-related questions that Overton became aware of the need for substances that could demonstrably and easily penetrate into the protoplasm of living cells. Few such substances were known at that time. One of those he tested early on was ethanol. Much to his surprise, ethanol easily permeated into intact protoplasts. c'Naked' plant cells, from which the cell wall consisting of cellulose had been removed. In his quest for more materials for genetic experiments, Overton entered what would become his field of excellence. Overton began systematically evaluating chemical compounds for their ability to enter cells derived from both plant and animal tissues. What was conceived as a preliminary investigation became the pursuit of his lifetime. The prototype experiment consisted of a cell being placed into a hypertonic solution of a test substance, and the resultant shrinkage of the cell (plasmolysis; Fig. 2) being observed either visually or by weight measurements.5Kanna A Membrane Permeability: 100 Years Since Ernest Overton. Academic Press, San Diego1999Google Scholar Quantification of plasmolysis provided a measure of the capacity of the tested substance to enter the cell interior. In the course of subsequent years and thousands of experiments, Overton, in his own words, examined most if not all commercially available chemical compounds.1Overton E Studien über die Narkose zugleich ein Beitrag zur allgemeinen Pharmakologie. Verlag von Gustav Fischer, Jena, Germany1901Google Scholar, 2Thunberg T Ernest Overton.Skandinavisches Archiv Für Physiologie. 1934; 70: 1-9Crossref Scopus (2) Google Scholar The importance of the permeability question for cellular biology at the turn of the century cannot be overstated. It was obvious that a cell's survival depended on the ability to control and direct the exchange of all sorts of substances between its interior and the surrounding environment, be it fresh or salt water or extracellular fluid. The problem, exemplified by the ability of single-cell organisms simultaneously to resist dissolution in water and to admit nutrients, was as clear as the answer uncertain; the contradictions in the claims of two leading scientific authorities—Max Verworn (cells do not have membranes) and Wilhelm Pfeffer' (cells have 'skins' with 'holes' to pass substances) dMax Verworn (1863–1921) was a German physiologist. He founded the Zeitschrift für allgemeine Physiologie in 1902 and edited the still published Pflügers Archiv für die gesamte Physiologie from 1910 to 1918. Wilhelm F. P. Pfeffer (1845–1920) was a German botanist, since 1887 Chair of Botany at the University in Leipzig, Germany. He developed a membrane osmometer ('Pfeffer's cell'), which made it possible to measure the osmotic pressure of watery solutions. —were unresolved;6Kepner GR From Oil Layer to Bilayer. Liposome Letters. Academic Press, London, New York1983: 15-27Google Scholar even in 1924, believers in the existence of a physical separation still had to admit that convincing evidence for it was lacking,7Höber R Physikalische Chemie der Zelle und der Gewebe. 5th Edn. Verlag Wilhelm Engelmann, Leipzig, Germany1924Google Scholar while non-believers would still declare in the 1930s that Pfeffer's idea had been refuted.8Lepeschkin WW My opinion about protoplasm.Protoplasma. 1930; 9: 269-297Crossref Scopus (3) Google Scholar The (non-)existence of a physical boundary surrounding protoplasm and nucleus was also important with respect to the 'essence of life' problem facing biology. Its answer would determine what could be considered as the smallest unit of life: nucleus-containing protoplasm or the cell as a whole.9Perouansky M Coagulation, flocculation, and denaturation: a century of research into protoplasmic theories of anesthesia.Anesth Analg. 2014; 119: 311-320Crossref PubMed Scopus (3) Google Scholar Before his often-quoted treatise on anaesthetics,1Overton E Studien über die Narkose zugleich ein Beitrag zur allgemeinen Pharmakologie. Verlag von Gustav Fischer, Jena, Germany1901Google Scholar Overton published five papers between 1895 and 1900 reporting the results of his experiments on the permeability (referred to by him, following contemporaneous terminology, as 'osmotic properties') of living plant and animal cells for biological and synthetic substances. In 189910Overton CE Über die allgemeinen osmotischen Eigenschaften der Zelle, ihre vermutlichen Ursachen und ihre Bedeutung für die Physiologie.Vierteljahresschr D Naturforsch Ges in Zürich. 1899; 64: 87-136Google Scholar he expressed his 'suspicion' (note his avoidance of 'hypothesis') that cholesterin or cholesterin-like substances, possibly with lecithin and other oily substances, impregnated the boundary between cell protoplasm and the exterior. This became known as Overton's lipoid theory2Thunberg T Ernest Overton.Skandinavisches Archiv Für Physiologie. 1934; 70: 1-9Crossref Scopus (2) Google Scholar or 'Overton's rule',11Kleinzeller A Charles Ernest Overton's concept of a cell membrane.in: Deamer DW KleinzellerFambrough ADM Membrane Permeability: 100 Years Since Ernest Overton. Academic Press, San Diego1999: 1-22Crossref Scopus (26) Google Scholar which states that the permeability coefficient of a solute is linearly related to its partition coefficient between oil and water. This work has since been celebrated as a foundation stone of membrane science.5Kanna A Membrane Permeability: 100 Years Since Ernest Overton. Academic Press, San Diego1999Google Scholar In 1901 Overton left Zürich with honors for the University of Würzburg, Germany to become an assistant in physiology to Professor Maximilian von Frey (1852–1932). This move coincided with the publication of his classic monograph 'Studien über die Narkose zugleich ein Beitrag zur allgemeinen Pharmakologie' (studies of narcosis and a contribution to general pharmacology).1Overton E Studien über die Narkose zugleich ein Beitrag zur allgemeinen Pharmakologie. Verlag von Gustav Fischer, Jena, Germany1901Google Scholar, 12Overton CE Studies of Narcosis. Chapman and Hall, Wood Library-Museum of Anesthesiology, Schaumburg, IL1991Google Scholar The timing of the publication sheds light on Overton's character as a scientist. In the course of his innumerable experiments on living cells and organisms, it cannot have eluded his keen perception that some of the tested substances reversibly impaired the activity of his experimental subjects. Considering that he had already analysed in detail relevant properties of many substances and had already formulated 'Overton's rule', it was only a small step to translate his findings into the anaesthetic context, and one wonders whether he could not have made this step earlier. In fact, in the introduction to this 195-page monograph, Overton states that the experimental results presented in the monograph had been collected earlier. Characteristically, while recognizing their importance for anaesthesia, he had delayed their publication because he intended to present them in a larger and even more comprehensive context of narcotics, antipyretics, and antiseptics, and only after finishing his work on osmosis.13Overton E Studien über die Narkose Zugleich ein Beitrag zur Allgemeinen Pharmakologie. Verlag von Gustav Fischer, Jena, Germany1901: III-IIVGoogle Scholar Hence, despite the wealth of experimental data in his hands, Overton did not feel that the material was ready, illustrating his tendency to procrastinate and his preference to present conclusions of his experimental work in lectures, frequently without following up with publications. eOnly fragments of Overton's large body of work on ester metabolism were published. This important book may not have been published had Overton not received notice of the impending publication of Hans H. Meyer's work, independently produced in Marburg, Germany. It is notable that Overton expressly acknowledged the antecedence of Meyer's work, and there has never been a dispute about primacy between these gentlemen. While in Würzburg, Overton published a series of papers that dissected the role of cations for muscle and nerve physiology in general, and of sodium ions in particular for the conduction of the action potentials, 60 yr before Eccles, Hodgkin, and Huxley received the Nobel prize for 'discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane'. In his Nobel lecture, Alan L. Huxley referred three times to Overton's 'classical experiments' as foundations of a hypothesis that was successfully tested by the Noble laureates. This work established Overton's lasting reputation in the world of neurophysiology. References to his work in a contemporary standard textbook attest to his influence.14McCormick DA Action potential.in: Squire LRB McConnell SK Roberts JL Spitzer NC Zigmond MJ Fundamental Neuroscience. Academic Press, Waltham, MA2003Google Scholar Remarkably, and a testimony to his genius, we find the most comprehensive publication of this botanist's experimental work as a chapter in a textbook of human physiology.15Overton CE Über den Mechanismus der Resorption und der Sekretion.in: Nagel WA Handbuch der Physiologie des Menschen. Druck und Verlag von Friedrich Vieweg und Sohn, Braunschweig, Germany1905–1910: 743-898Google Scholar In 1907, aged only 42, Overton accepted the invitation to become the first Professor in the newly founded department of Pharmacology at the University of Lund, a position he held until his retirement in 1930. Among the papers on toxicology that he published while based in Lund, we find him for the first time with a co-author, Ivar Bang (1869–1918), a fellow Professor of Physiological Chemistry at the Medical faculty of Lund University. In general, even by the standards of his days, Overton was reluctant to publish with collaborators. Striving to provide an all-inclusive answer, he kept experimenting, delaying publication until finally getting lost in the myriad of results obtained in a countless variety of experimental conditions. He published almost exclusively in German (which remained a foreign tongue to him), with a few papers in Swedish (even more foreign!). With the increasing importance of the trans-Atlantic part of the scientific world, his name gradually lost familiarity among cell biologists. References declined until his work on permeability largely vanished from the scientific horizon. His name is absent from a comprehensive paper on plant cell permeability that originated in the USA and was published in 1930.16Plowe JQ Membranes in the plant cell I. Morphological membranes at protoplasmic surfaces.Protoplasma. 1931; 12: 196-221Crossref Scopus (19) Google Scholar Some of his work was rediscovered only after his death and then became a stepping stone for the development of pharmacotoxicology.17Lipnick RL Charles Ernest Overton: narcosis studies and a contribution to general pharmacology.Trends Pharmacol Sci. 1986; 7: 161-164Abstract Full Text PDF Scopus (41) Google Scholar, 18Lipnick RL A QSAR study of Overton's tadpole data.Prog Clin Biol Res. 1989; 291: 421-424PubMed Google Scholar Another factor contributing to the obscurity that surrounded his work for decades might have been his solitary nature as experimenter; in the 23 yr as professor in Lund, he did not co-author a single paper with someone identifiable as a mentee. This failure to engage young researchers undermined Overton's odds at establishing a scientific legacy in proportion to his personal achievements. Overton's ill health forced him repeatedly to take prolonged leaves of absence. His somewhat secluded, unassuming personality and his imperfect command of Swedish may have contributed to the lack of collaborators, thereby limiting his productivity. His tendency to propose ideas without disclosing the (existing) experimental evidence, paired with the reluctance to defend his theories when they came under attack,19Collander PR Ernest Overton (1865–1933): a pioneer to remember.Leopoldina. 1962–3; 8–9: 242-254Google Scholar all contributed to a lack of recognition proportional to the pioneering nature of his work. In contrast, these professional vagaries in Lund were balanced by a happy family life with the mathematician Hedvig Louise Beata Petrén, PhD, whom he married in 1912. The couple had four children who survived him. None declared. Wood Library Museum, Schaumburg, IL, USA; Department of Anesthesia Lund University, Sweden.