As a Ph D candidate in Zoology at the Unversity of Wisconsin in 1960, Mary Bartlett Bunge chose to study myelin breakdown and reformation in an adult cat spinal cord. Through McMaster University Library a three day loan was arranged for me to read the original thesis and study the full colour electron microscope photographs of the remyelination process. Bunge’s post doctoral paper was published in 1961. Bunge Mary B, Bunge RP and Ris H, 1961, Ultrastructural Study of Remyelination in an Experimental Lesion in Adult Cat Spinal Cord. J Biophys Biochem Cyto 10:67-94. 7:685. Journal of Cell Biology since 1962.
After diagnosis in 1967, in spite of the predictions, I recovered and returned to work as a junior lab technician at the Ontario Veterinary College in Guelph Ontario. There I found reference to Bunge’s paper and was able to obtain a copy. Veterinary researchers assured me that adult cats and humans are in the same biological class – large mammals, and that humans should be able to experience healing just as the adult cats in this study. I knew they must be right; I had just done it.
In Bunge’s study, the first sign of myelin repair was observed after 19 days; by 64 days all nerve damage was thinly repaired. The author observed that reformed myelin resembles that which is formed in normal development.
“The neurological condition of the experimental animal (adult cat) begins to improve at a time when remyelination begins and has returned to normal by the time most axons are at least partly remyelinated.”
It had taken me from March 17, St Patrick’s Day to the first of June. Purrty close!
Since 1967 I have found many papers to coroborate Bunge’s work and some follow in reverse order. It’s interestinh to follow the thinking process. MY comments are in square brackets.
Chamberlain KA, Nanescu SE, Psachoulia K, Huang JK (2016) Oligodendrocyte regeneration: Its significance in myelin replacement and neuroprotection in multiple sclerosis. Neuropharmacology. 2016 Nov;110(Pt B):633-643.
… oligodendrocytes readily regenerate and replace myelin membranes around axons in the adult mammalian central nervous system (CNS) … these studies may offer novel pharmacological targets for regenerative medicine in inflammatory demyelinating disorders in the CNS such as multiple sclerosis …
Raine CS (2016) Multiple sclerosis: The resolving lesion revealed. J Neuroimmunol. May 27,Epub ahead of print] … Unusual features of early resolving lesions … fibrous astrogliotic parenchyma replete with lipid-laden (foamy) microglia/macrophages widely scattered throughout and lined up at the edge (gitter cells?) … these observations may provide for the first time evidence for a role in MS for mitigating factors … known to be associated with wound-healing and repair …
AK Foote, WF Blakemore (2005) Inflammation stimulates remyelination in areas of chronic demyelination. Brain Volume 128, Issue 3 Pp. 528 – 539 – A major challenge in Multiple Sclerosis research is to understand the cause or causes of remyelination failure and to devise ways of ameliorating its consequences … rat is a myelin mutant that shows progressive myelin loss and by 1 year of age, its CNS tissue has many features of chronic areas of demyelination in Multiple Sclerosis [NOTE EM – the EAE virus used to prepare animals for research is NOT the MS virus.]
BDJ Miller, K Asakura and M Rodriguez (1995) Experimental Strategies to Promote Central Nervous System Remyelination in Multiple Sclerosis: Insights Gained From the Theiler’s Virus Model System. Mini-Review. J Neurosci Res 41:291-296. Remyelination is a normal physiological response to myelin damage … central issue in CNS repair in MS is not whether remyelination occurs, but rather can we determine therapies to stimulate myelin repair.
Raine CS (1991) Multiple Sclerosis: a pivotal role for the T cell in lesion development. Neuropath & App Neurobiol 17: 265-274 – counteraction of the inflammatory response in the CNS appears to lead to cessation of the immune mediated disease and encouragement of remyelination – entire lesions remyelinate.
Ghatak NR, Leshner RT, Price AC and Felton WL (1989) Remyelination in the human nervous system. J Neuropath Exp Neurol 48(5):507-518. Thinly myelinated axons play role in continuous conduction … flu like … substantial remyelination possible in MS. Remyelination is often considered as a possible explanation for remission in MS. To our knowledge, [in depth literature review needed] clinically significant functional recovery as a result of remyelination has not been documented in humans …
Smith KJ WF Blakemore and WI McDonald (1979) Central remyelination restores conduction. Nature 280:395-396 … we have found that secure conduction is restored with remyelination. (cats) Remyelination had begun by 14 days.
Lampert PW (1978) Autoimmune and Virus-Induced Demyelinating Diseases. Am J Path 91:176-197 – CNS single oligodendrocyte is connected to many myelin segments by long cytoplasmic projections – regeneration in remission limited to margin of demyelinated plaques – abortive remy …
Ghatak NR, A Hirano, H Lijtmaer and HA Zimmerman (1974) Asymptomatic Demyelinated Plaques in the Spinal Cord. Arch Neurol 30:484-486. Poor correlation between lesions and clinical symptoms in MS … extent of lesions in MS frequently far greater than would be anticipated from the clinical assessment.
Gledhill RF (1973) Pattern of Remyelination in the CNS. Nature 244:443-444. – myelin destruction is followed by remyelination in 3rd week in cats – known prerequisites for generation of signals is present in remyelinated fibres – segments shorter than undemyelinated – SCHWANN cells migrating in spinal cord and forming myelin around central axons …
Gledhill R, Harrison BM, MacDonald WI, (1973) Demyelination and Remyelination After Acute Spinal Cord Compression. Exp Neurol 38:472-487, Remyelination in cats commenced 7-21 days after demyelination and majority of demyelinated fibres showed evidence of remyelination by 1 month.
Gledhill R, Harrison BM, MacDonald WI, (1973) Demyelination and Remyelination After Acute Spinal Cord Compression. Exp Neurol 38:472-487, Remyelination in cats commenced 7-21 days after demyelination and majority of demyelinated fibres showed evidence of remyelination by 1 month …
Harrison BM, McDonald WI and Ochoa J, (1972) Remyelination in Central Diphtheria Toxin Lesion. J Neurol Sci 17:293-302 . … even the limited amount of remyelination observed may be sufficient to restore transmission – although conduction would still be slow in the thinly myelinated fibres, the return of the ability to conduct at all is clearly a necessary first step in the recovery of function in damaged pathways. p301.
Rasminsky M and Sears TA, (1972) Internodal Conduction in Undissected Demyelinated Nerve Fibres. J Physiol 227:323-350 – intracellular sodium accumulation is also offered as the explanation for (affected activity) seen in demyelinated fibres – position of nodes inferred from assumption that nodes are the only sites of inward membrane current – 3% myelin sufficient for normal function [EM Steroids affect the balance of sodium and potassium ions (mineralocorticoids) vital for signal transmission.]
Millar JHD, (1971) Multiple Sclerosis: A Disease Acquired in Childhood. Charles C. Thomas. Springfield, Illinois, U.S.A. If normal turnover of myelin during development, then mechanisms must exist both to demyelinate and remyelinate axons. p45.
Raine CS and Bornstein MB, (1970) EAE: A Light and Electron Microscopy Study of Remyelination and Sclerosis in Vitro. J Neuropath Exp Neurol 29:552 … total demyelination in living mice embryo tissue cultures … Tissue fragments began to remyelinate after 8 -10 days and process was well advanced by 18 days. By three weeks, almost total remyelination.
Silberberg DH, (1970) Recent Concepts of Etiology. Mod. Treat. 7:882-886.- seasonal patterns of acute exacerbations – abortive attempts at remyelination occur, gliosis (excess astroglia in damaged areas of CNS) resulting from astroglial proliferation following demyelination may retard remyelination – corticosteroids found to offer only questionable benefits. [EM – how could an excess of repair material possibly interfere in healing?]
Hirano A, Levine S and Zimmerman HM, (1968) Remyelination in the Central Nervous System after Cyanide Intoxication. J Neuropath Exp Neurol 27:234-245. By one week after demyelination [in adult rats] we observedremyelination … recently several fine structural studies have established this phenomenon beyond reasonable doubt. p235
Bunge Mary B, Bunge RP and Edith R Peterson, (1967) The Onset of synapse formation in spinal cord cultures as studied by electron microscope. Br Res 6: 728-749. Demonstrates close correlation between the initiation of synaptic formation and the onset of functional synaptic network. [NOTE EM … formation of synapses related to function, ie movement speeds healing and reconnection …]
Feigin I and N Popoff, (1966) Regeneration of Myelin in Multiple Sclerosis. Neurol 6:364-372. Nerve fibers myelinated by peripheral myelin (Schwann cells) were found within plaques in five cases of Multiple Sclerosis. These fibers were present singly, in small clusters, and, occasionally, in large groups. p364. … did not exceed 10% of the number thought to be demyelinated … found only within plaques, not in normal tissues … The five cases in which regenerative myelin was recognized, differ from eighteen other cases of Multiple Sclerosis available for study in that four were women, while men predominated in the rest.
[EM though fewer number of women subjects, 80% of women subjects and 6% – of men showed remyelination] …remissions observed in many cases where no remyelination observed … The regeneration of myelin may play a role in the clinical remissions of Multiple Sclerosis, but other factors appear to be more important. If ways were found to enhance the regeneration observed in this study, a clinically useful purpose might be served. [EM The prevailing paradigm that recovery is impossible is so strong that no one recognizes the importance of movement!!] the importance of movement!!ple Sclerosis. Neurol 6:364-372. Nerve fibers myelinated by peripheral myelin (Schwann cells) were found within plaques in five cases of Multiple Sclerosis. These fibers were present singly, in small clusters, and, occasionally, in large groups. p364. … did not exceed 10% of the number thought to be demyelinated … found only within plaques, not in normal tissues … The five cases in which regenerative myelin was recognized, differ from eighteen other cases of Multiple Sclerosis available for study in that four were women, while men predominated in the rest.
[EM though fewer number of women subjects, 80% of women subjects and 6% – of men showed remyelination] …remissions observed in many cases where no remyelination observed … The regeneration of myelin may play a role in the clinical remissions of Multiple Sclerosis, but other factors appear to be more important. If ways were found to enhance the regeneration observed in this study, a clinically useful purpose might be served. [EM The prevailing paradigm that recovery is impossible is so strong that no one recognizes the importance of movement!!] the importance of movement!!