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Department of Anesthesiology



 

 

Historical perspective on oligodendrocytes and myelin

Abstract
Oligodendrocytes represent a major advance in brain evolution because they generate non-linear and rapid conduction of electrical impulses in neurons. This is called saltatory conduction, because the action potential "leaps" along the axon, between gaps in the specialized insulating membrane ensheathing the axons. This membrane is called the sheath of -myelin- and is produced by oligodendrocytes in the brain. The word myelin -myelos for marrow in Greek- was coined in the 19th century in 1858 by the German pathologist Rudolf Virchow because of its resemblance to marrow long before its function or its composition was known. Interruptions between segments of myelin are named "nodes of Ranvier" after the French histologist Louis-Antoine Ranvier who described them for the first time in 1878.

Oligodendrocytes were the last glial cells to be discovered at the beginning of the 20th century, due to their resistance to classical metal impregnations used for staining cells. A new staining method created by the Spaniard Pio del Rio Hortega led him to visualize these cells in 1921. He coined the word "oligodendrocyte" from the Greek -oligo- for few, -dendro- for tree, and -cyte- for cell, to describe a cell with fewer processes than the other cells. Still its function could not be ascertained by classical immunohistochemistry. The definite proof came from the technological breakthrough of electron microscopy which revealed a continuity between Schwann cell and the myelin sheath by Betty Ben Geren in 1954, and between oligodendrocyte and myelin by Richard and Mary Bunge in 1962. In 1951, Jordi Folch-Pi with Marjorie Lees discovered proteolipids in the white matter. Methods for myelin purification were devised later and independently by William Norton and Marian Kies in 1964, and allowed the first hint of its composition in lipids. In 1971, Ed Eylar sequenced fully the first protein called later the myelin basic protein.

A decade later in 1980, cell culture of oligodendrocytes was engineered from neonatal brains by Ken McCarthy and Jean De Vellis using the "shake-off" method that has become the most widely used isolation procedure. The same year, oligodendrocytes were isolated from the adult brain by Sara Szuchet, Paul Polak and Barry Arnason using a different technique of density gradient with sucrose. Seung Kim in 1983 optimized the gradient by replacing sucrose with Percoll in a isolation procedure still used to this day. In 1980, myelination was reproduced in culture by Patrick Wood in an implant of optic nerve containing oligodendrocytes that wrapped myelin around axons after several weeks. In 1982, oligodendrocytes were shown in culture to be more than structural cells by their capacity to generate electrical current from a potassium channel by Helmut Kettenmann. In 1983, Martin Raff identified the bipotential glial progenitor giving rise to oligodendrocyte or astrocyte, depending culture conditions. Mouse mutants such as the shiverer mouse, identified for the basic myelin protein by Leroy Hood in 1983, and the jimpy mouse, identified for proteolipid by Klaus Nave and Pierre Jollès in 1986, have provided a model system to further study the function of myelin proteins. At present, current research is focused on discovering the signaling pathways that control the making of myelin and its architecture, especially at the nodes of Ranvier; understanding the lineage of progenitors in the adult brain; and delineating the intricacies of interactions between oligodendrocytes and other cells, especially neurons.

   
 

portrait Virchow 1849.jpgBiosketch of Rudolf Virchow (1821-1902)
Rudolf Virchow was born on October 13, 1821 in Schivelbein, Germany. He studied medicine at the Military Medical Academy in Berlin from 1839 to 1843. Virchow made an important contribution to the terminology of brain science as he coined the name "glia" -glue in Greek- in 1843 to describe a kind of connective tissue pervading the brain, spinal cord and higher sensory nerves. He worked after 1843 as an assistant at the Charité University and was a student of Johannes Müller. He was urged to quit in 1849 due to his support of the German revolution in 1848. He moved from Berlin to Würzburg where he was appointed Professor of Pathology. In 1856, he accepted the chair of Pathology at the Charité University in Berlin where he founded the Institute of Pathological Chemistry. Rudolf Virchow is viewed as the founder of "Cellular Pathology", a theory which states that diseases are based on changes in cells. In 1858, Virchow coined the word myelin -from myelos for marrow in Greek- after the observation by his fellow Robert Remak that nerve fibers have a white sheath reminiscent of marrow. In 1860, he coined the sentence "omnis cellula e cellula" (each cell develops from a cell) based on the Cellular theory of Theodor Schwann stating in 1839 that a cell is the functional basic unit of the body. This started a new period of scientific thinking in medicine. His investigations allowed him to gain new insights in the properties of diseases such as leukemia. Rudolf Virchow was committed to politics and between 1880 and 1893 he was an active member of the Prussian Parliament. In 1893, he became the Chancellor of the University. He was especially involved in questions concerning social politics and health care that were related for him. In later life, Virchow also addressed questions of anthropology and fought for racial equality. He died on September 5, 1902 in Berlin.
(Sources: Brains of Berlin by Helmut Kettenmann and Wolf Rudolph, 1998; Medical History of Berlin by Heinz Bielka and Helmut Kettenmann, 2005)

   
 

portrait Ranvier 1882.jpgBiosketch of Louis-Antoine Ranvier (1835-1922)
Louis-Antoine Ranvier was born on October 2, 1835 in Lyons, France. His father dedicated himself to the public administration. He studied medicine at Lyons and in 1860 went as intern in the Paris hospitals. He graduated in 1865 with a medical degree and founded with his friend André Victor Cornil a small private laboratory located in the 6th arrondissement. They offered in their laboratory a course in histology to medical students. They wrote together in 1869 an important textbook in histopathology entitled "Manuel d'histologie pathologique". In 1867, Ranvier became the assistant (préparateur) of Claude Bernard (1813-1878) at the Coll├Ęge de France. In 1872 his small private laboratory became officially associated to the chair of Experimental Medicine of Claude Bernard and named "Laboratoire d'Histologie de l'Ecole des Hautes Etudes". In 1875, he was appointed to the chair of General Anatomy at the Collège de France. Ranvier popularized the staining by metal impregnation developed in 1860 by Friedrich von Recklinghausen using silver nitrate. When Ranvier applied silver nitrate on a sciatic nerve of frog, he observed the nerve was stained discontinuously in what he called constrictions. His discovery of the interruptions of myelin later received his name as "nodes of Ranvier". He published this observation in 1878 in a book entitled "Leçons sur l'histologie du système nerveux". In 1897, he founded the journal "Archives d'Anatomie microscopique" with Edouart-Gérard Balbiani. He retired in 1900 to his estate in Thélis and died at Vendranges, France, in 1922.
(Sources: http://www.historiadelamedicina.org/ranvier.htm;
http://en.wikipedia.org/wiki/Louis-Antoine_Ranvier;
http://bris.ac.uk/neuroscience/the_node/caffeine/ranvier
)

   
 

photo Rio Hortega 1924.jpgBiosketch of Pío del Río Hortega (1882-1945)
Pío del Río Hortega was born on May 5, 1882 in Portillo, near Valladolid, Spain. He studied medicine at Valladolid from 1898 to 1905 and obtained a license in medicine in 1905. After practicing medicine for a short period of time, he prepared a doctorate in histology and presented a thesis entitled "Pathological Anatomy of Brain Tumors" at the Central University of Madrid in 1908. He went to work in the laboratory of Dr. Achúcarro in Madrid, where he became acquainted with the topic of normal and pathological neuroglia. There he learned methods of metal impregnation developed by Achúcarro, Nissl, Cajal and Bielschowsky, and got captivated by microscopic images. In 1913, Río Hortega obtained a competitive scholarship to study abroad and went to study histology in Paris, and then to Berlin at the Koch Institute before a forced return to Spain with the advent of the first world war. He went back to Madrid in 1914 in the laboratory of Achúcarro that had been transferred to the Biological Investigations Institute directed by Ramón y Cajal (1852-1934) who had won the Nobel price in 1906. Río Hortega published 18 publications between 1914 and 1918 and invented a new method with ammoniacal silver carbonate adapted from Golgi and Bielschowsky that he published in 1918. In 1919, he identified the "third element" of Cajal (first and second elements were neurons and astrocytes) as microglia cells thanks to his new method of silver carbonate. The discovery of microglia placed Rio Hortega in a delicate position toward Cajal and led to his expulsion in 1920. He pursued his work in a small independent laboratory in the student housing. The silver carbonate staining allowed him to identify in 1921 another cell type exhibiting delicate cytoplasmic extensions that he named oligodendroglia and conducted him in 1922 to the hypothesis that oligodendroglia is the homolog of Schwann cell. In 1924, he had acquired enough fame to attract foreign scientists such as Wilder Penfield, who came to Madrid and confirmed the existence of microglia in gliomas. Consequently, Cajal officially recognized in 1925 that Rio Hortega discovered microglia. In 1925, he went to Argentina, Uruguay and Mexico to give seminars on Normal and Pathological Histology of the Nervous System. In 1928, Rio Hortega published a classical work of histology that was very important to avoid confusing oligodendroglia with astroglia and grounded the classification of oligodendrocytes into four types of according to their morphology in a first attempt at discovering their function. Rio Hortega even had the perspicacity to hypothesize oligodendrocyte were generating myelin, some 30 years before the definite proof was provided by electron microscopy. In 1931, an increased scientific fame led him to Germany upon the invitation of professors Spielmeyer and Borst from Munich university, at a time when Hortega's publications were published only in Spanish. The trip in Germany was a huge success as Rio Hortega gave his lectures in German in front of numerous students in Munich, Berlin, Hamburg, Freiburg and Heidelberg. He could have been nominated for the Nobel price but the political climate was too belligerent. In 1928, he became the head of the investigation section of the Cancer Institute in Madrid and turned to pathology. Between 1928 and 1936, he published important works on neoplasia of meninges and brain, and a new group of tumors was called oligodendroglioma in 1929. He became full director of the Cancer Institute following the advent of the Republic in Spain in 1931. The civil war broke out during summer 1936, and he took the opportunity to leave Spain in November 1936. From 1937 to 1938 he went to work as a pathologist in the neurology clinic at the Pitié Salpêtrière hospital in Paris. Then he went to work at Oxford university where he won the recognition of doctor honoris causa and published his work in The Lancet in 1939. To escape the German bombardments of the second world war he went in exile in Buenos Aires, Argentina, under the solicitation of the Spanish Cultural Institute in 1940. He found peace there, and with the collaboration of a distinguished neuropathologist, Moisés Polak, and the financial support of the Spanish Cultural Institute, he established a Laboratory of Normal and Pathologic Histology. In 1942, he started his own journal "Archivos de Histologia Normal y Patológica" where major publications came out. He developed a distinctive school and was nominated Extraordinary Professor of the medical university of La Plata. During his last two years he worked on oligodendrogliomas and in one of his last publications in 1943 he provided a thorough review of the fruitful silver carbonate method. Commencing the year 1945, he developed a malign neoplasm and died shortly on June 1, 1945 in Buenos Aires.
(Sources: http://www.ibro.org/Pub_Main_Display.asp?Main_ID=12; http://www.whonamedit.com/doctor.cfm/3099.html ; Ortiz Picon, 1983 Archivos de Neurobiologia 46:209-226; Myelin Biology and Disorders by Robert Lazzarini, 2004)

   
 
Oligodendrocyte type 1.jpg
Oligodendrocyte type 2.jpg
 
Oligodendrocyte type 1
Oligodendrocyte type 2
   
 
Oligodendrocyte type 3.jpg
Oligodendrocyte type 4.jpg
 
Oligodendrocyte type 3
Oligodendrocyte type 4
   
  Carbonate silver impregnation of brain tissue by Pio del Rio Hortega illustrating the four types of oligodendrocytes. Type 1 oligodendrocyte is sheathing many axons of small diameter in diverse orientations. Type 2 oligodendrocytes are wrapping many aligned axons of small diameter. Type 3 oligodendrocytes have protruding cell body sheathing fewer axons of large diameter. Type 4 oligodendrocytes show a cell body closely apposed to a single very large axon akin to Schwann cells.