Elsevier

Experimental Neurology

Volume 283, Part B, September 2016, Pages 431-445
Experimental Neurology

Review Article
The history of myelin

https://doi.org/10.1016/j.expneurol.2016.06.005Get rights and content

Abstract

Andreas Vesalius is attributed the discovery of white matter in the 16th century but van Leeuwenhoek is arguably the first to have observed myelinated fibers in 1717. A globular myelin theory followed, claiming all elements of the nervous system except for Fontana's primitive cylinder with outer sheath in 1781. Remak's axon revolution in 1836 relegated myelin to the unknown. Ehrenberg described nerve tubes with double borders in 1833, and Schwann with nuclei in 1839, but the medullary sheath acquired its name of myelin, coined by Virchow, only in 1854. Thanks to Schultze's osmium specific staining in 1865, myelin designates the structure known today. The origin of myelin though was baffling. Only after Ranvier discovered a periodic segmentation, which came to us as nodes of Ranvier, did he venture suggesting in 1872 that the nerve internode was a fatty cell secreting myelin in cytoplasm. Ranvier's hypothesis was met with high skepticism, because nobody could see the cytoplasm, and the term Schwann cell very slowly emerged into the vocabulary with von Lenhossék in 1895. When Cajal finally admitted the concept of Schwann cell internode in 1912, he still firmly believed myelin was secreted by the axon. Del Río-Hortega re-discovered oligodendrocytes in 1919 (after Robertson in 1899) and named them oligodendroglia in 1921, thereby antagonizing Cajal for discovering a second cell type in his invisible third element. Penfield had to come to del Río-Hortega's rescue in 1924 for oligodendrocytes to be accepted. They jointly hypothesized myelin could be made by oligodendrocytes, considered the central equivalent of Schwann cells. Meanwhile myelin birefringence properties observed by Klebs in 1865 then Schmidt in 1924 confirmed its high fatty content, ascertained by biochemistry by Thudichum in 1884. The 20th century saw X-ray diffraction developed by Schmitt, who discovered in 1935 the crystal-like organization of this most peculiar structure, and devised the g-ratio concept in 1937. A revolution happened around the same time: saltatory conduction, the very reason for myelin existence, discovered by Tasaki in 1939 and confirmed by Huxley and Stämpfli in 1949. After the second world war, widely available electron microscopes allowed Geren to finally discover the origin of myelin in 1954, exactly a century after Virchow coined 'myelin' in 1854. Geren had the genial insight that the Schwann cell wraps around the axon and generates a spiral of compacted membrane–myelin. The central origin of myelin took a little longer due to the special configuration of oligodendrocyte distanced from the axon, but in 1962 the Bunges established the definitive proof that oligodendrocyte secretes myelin. The era of myelin biology had begun. In 1973 Norton devised a method to purify myelin which launched the modern molecular era.

Section snippets

1543 Vesalius first mention of white matter

The renaissance physician Andreas Vesalius (1514–1564), considered the father of modern anatomy, was the first to describe white matter and gray matter in the human brain in a monumental treatise known as ‘La Fabrica’ illustrated with many detailed anatomical drawings (Vesalius, 1543). Vesalius, born Andries van Wesel in Brussels, was encouraged early by his family to become physician, his grandfather being the Royal Physician of Emperor Maximilian. Vesalius became Professor at the University

1854 Virchow coins myelin

The word Myelin was coined by German pathologist Rudolf Ludwig Virchow (1821–1902), author of the fame Neuroglia term (Kettenmann and Ransom, 2005). There was much confusion mid-19th century regarding the medullary substance, and Virchow expressed the need for a better terminology in Virchow's Archiv, the journal he founded (Virchow, 1854, page 571): “das Bedürfniss, sie mit einem Worte bezeichnen zu können, vorliegt, so schlage ich vor, um jede Verwechselung mit anderen schon bezeichneten,

1868 Charcot myelin droplets in multiple sclerosis

In 1868, the neurologist Jean-Martin Charcot (1825–1893) used myelin (myéline) in what can be considered its first correct attribution. Charcot was an avid and respectful reader of German literature, until the 1870 French-German war dampened his enthusiasm (Guillain, 1955). Charcot established at the Parisian hospital Salpêtrière the clinical and histological criteria to diagnose multiple sclerosis in two articles. The histology article described demyelination in lesions (Charcot, 1868, Fig.

1872 Ranvier myelin is made by internode adipocyte

Ranvier, a sagacious observer particularly tracking staining artifacts, realized both sheaths of Schwann (1839) and Mauthner (1860) were not simple envelopes but contained a sheet of cytoplasm running from node to node. The question of whether there was cytoplasm in these sheaths was not trivial, because there was no specific stain for cytoplasm at the time. Ranvier hence boldly envisioned the axon enveloped by a muff of cytoplasm with finite boundary at the nodes. All cellular elements being

Myelin functions: myths and reality

By mid-19th century, the concept of axon had replaced myelin as the essential and active component of the nervous fiber. Myelin origin and function puzzled early investigators by appearing relatively late during development and not investing all fibers in adult. The following section, by no means exhaustive or comprehensive, presents the most remarkable theories.

1884 Thudichum biochemistry of myelin

It is beyond the scope of the present review to provide a detailed account of myelin chemical composition discovery. It was known by mid-19th century that in white matter the axons “consist of protein components very similar to muscular fibrin, the marrow sheath especially of fats from various kinds” (von Kölliker, 1863, page 105). Toward the end of the 19th century, Johann Ludwig Thudichum (1829–1901), the founder of neurochemistry, partially characterized many lipids of myelin, including its

1939 Tasaki shows saltatory conduction

The real function of myelin of course is saltatory transmission of nerve impulse, leaping from one node of Ranvier to the next. It was first suggested in 1925 by Canadian born Ralph Stayner Lillie (1875–1952), Professor of General Physiology at the University of Chicago (Lillie, 1925). Lillie experimented on an iron wire, considered a valid ‘passive’ nerve model. In a stroke of genius, he modeled the nodes by enclosing the iron wire in a glass insulant tube with periodic breaks, and noted that

1924 Schmidt birefringence

Myelin optic property of birefringence was discovered only in the second part of the 19th century because of the technical aspect of microscopes. Polarized light is generated by a pair of perpendicular filters, generating positive and negative birefringence. Gabriel Gustav Valentin (1810–1883), German physiologist in Bern University, published the first study with polarized light (Valentin, 1861). When myelinated fibers were analyzed by Theodor Albrecht Klebs (1834–1913), assistant of Virchow

1954 Geren myelin spirals from Schwann cell

The origin of such an exceptionally organized structure remained a mystery. The key person who solved it was Betty Ben Geren (1922–), neuropathologist who graduated MD in 1945 at St. Louis Washington University followed by a pathology internship at Boston's Children's Hospital (Fig. 4). Geren received an American Cancer Society Research postdoctoral Fellowship to study with renowned F.O. Schmitt, and first addressed the question of whether myelin built by ‘crystallizing out’ droplets of

Conclusion

Myelin can be conceived as a gigantic 3-D puzzle in time and space. The best scientists across the world have studied this structure directly or incidentally since the 18th century. Each of them brought a piece to the puzzle. Myelin was first reported as white matter inside the brain during the Renaissance. At the dawn of neuroscience in early 19th century, myelin was considered the most important element of the nervous system. After the axon was discovered, myelin went overlooked for decades

List of abbreviations

    CNS

    central nervous system.

    MIT

    Massachusetts Institute of Technology.

    PNS

    peripheral nervous system.

Declaration of interests

The author declares no conflict of interest and assumes all translations where not specified. Accessing original documents generated discrepancies with their formerly cited references.

Funding

This work was supported by NIH/NLM grant G13LM011465.

Acknowledgements

We thank Jeffrey Dupree (Virginia Commonwealth University) for stimulating discussions on the origin of g-ratio. We are grateful to Boris Zalc (Paris Pitié-Salpêtrière Institute) for interactions on history of myelin. We are indebted to the Classic papers Network Glia website for providing access to quality 19th century plates. We thank Douglas Fields (National Institutes of Health, Bethesda) for providing personal recollection of Dr. Tasaki. We are grateful to Betty Geren (Arkansas family

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