Brain, Vol. 127, No. 9, 2144-2147,
September 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh271
Book review |
MYELIN BIOLOGY AND ITS DISORDERS: TWO-VOLUME SET
Edited by Robert A. Lazzarini 2004. San Diego: Elsevier Academic Press Price £340.00. ISBN 0-12-439510-4
University of Bristol Institute of Clinical Neurosciences, Department of Neurology, Frenchay Hospital, Bristol, UK
‘The third element’
It is the title of this fine book that stirs the blood. It is neither a dusty dry tome on myelin, nor a clinicians' handbook on myelin diseases: it bestrides science and medicine and proclaims that these must not be divorced, but remain joined together in sickness and in health.
There is surely no other area in medical neuroscience—arguably in all of clinical science—where science and medicine have been so closely intertwined. Why is this? How does the biology of the neural cell filter through to, and so dictate myelin order and disorder? It is not such a tortuous path to the answer.
Originally, the brain was held to contain two cell types—neurons, whose function Cajal first proposed, and neuroglia, originally described by Virchow in the mid 19th century. He attributed to the latter, two activities: the mechanical support of nerve cells and the repair of tissues. Three further activities were proposed before the turn of that century: the nutritional support of neurons (by Golgi), the engulfment of cellular debris (Bevan Lewis) and the isolation of nervous conduction (probably first suggested by Santiago Ramon y Cajal's younger brother Pedro). Whilst broadly all true, the further recognition of cell types within the neuroglia allowed a division of these labours in the first few decades of the 20th century. Cajal (the elder) described in 1913 the ‘third element’ of the nervous system, a cell population separate from neurons and neuroglia (otherwise termed astroglia). It fell predominantly to Pio del Rio Hortega to distinguish not one but two cell types within the third element. Microglia make up one-fifth of the CNS glial population and are of haemopoetic (mesodermal) origin—as indeed originally suggested by del Rio Hortega. Oligodendrocytes, which elaborate and maintain myelin membranes around axons in order to ‘isolate’ conduction, were likewise discovered and named by del Rio Hortega.
Have the last six or seven decades added anything fundamentally different or new? Well, yes, actually. Of astroglia we now know, extraordinarily, that they are electrically active: they thereby respond to and influence neighbouring astrocytes, propagate waves of electrical activity and, moreover, communicate with neurons. No less remarkably, the last 10 years have taught us too that there is a fourth estate of neural cells: progenitors and stem cells play literally vital roles in disease and repair, possibly residing within astroglial subpopulations, or ependyma, or elsewhere. And of course, unimaginable detail concerning the biology and pathology of the classically recognized glia has been painstakingly discovered. The precise inflammatory behaviour and immunological competencies—and inadequacies—of microglia are increasingly understood. The development and differentiation of glial cells has been subject to greater inspection and study than perhaps any other cell lineage. We now know an enormous amount about both the mechanisms and molecules involved in effecting the principal (but not the only) function of oligodendrocytes, i.e. the making of myelin.
So, completing the circle, the term myelin was indeed introduced originally by Virchow: it puts the white in white matter, and lies at the heart of white matter disease.
If science and medicine combine so inextricably in myelin disease, surely there is also no area of medicine whose development owes so much to clinically trained, active and pioneering scientists? Indeed a single, extraordinary generation, working mostly in that best of times and worst of times, the first half of the last century, offers witness both sobering and inspiring to the unique power of what we now almost glibly call the clinician-scientist.
We might look briefly at three of the most strikingly pre-eminent: Pio del Rio Hortega (1882–1945), Wilder Penfield (1891–1976) and the perhaps rather quieter Dorothy Stuart Russell (1895–1983).
Their remarkable stories are intertwined; all led truly extraordinary and dramatic lives. Rio Hortega studied medicine at Valladolid (1898–1905), and obtained his doctorate in Madrid in 1908. He soon became a member of Cajal's staff. By this time, Cajal had already achieved a pre-eminence nowadays hard to imagine—the father of modern neurobiology, he was himself (of course) a clinician. He had returned to Spain following some years' service as an army doctor in Cuba to purchase with his military pay a microscope. He had then worked in splendid isolation to develop the neuron theory of the brain, had recognized the ‘third element’ in the brain, and had in 1906 won the Nobel prize (which he shared with Camillo Golgi). Hardly then a man to upset, but this is precisely what the upstart Rio Hortega managed. Determined to establish the nature of Cajal's ‘third element’, Rio Hortega described in 1917 a novel ammoniacal silver carbonate staining method, and in 1919–1921 announced that the element consisted of two types of cell, which he named microglia and oligodendroglia. He correctly guessed, and in the case of microglia ultimately proved, the principal functions of both ‘his’ glia. In doing so, he contradicted a number of Cajal's fundamental observations and proposals; a profoundly fruitful master–disciple relationship came abruptly to an end, with Cajal writing to dismiss Rio Hortega from his own, eponymous, institute with the chilling words ‘your ex-friend and ex-protector addresses you for the last time’: Rio Hortega continued his work thereafter in laboratories he established (happily in the end with Cajal's help) in the Madrid Students' Residence.
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The American-born Canadian Wilder Penfield visited these laboratories for 4 months in 1924 to learn Rio Hortega's staining techniques. Penfield, then 33 years old, had studied medicine at Princeton and then in January 1915 arrived as a Rhodes scholar in Oxford. In the course of one momentous year, three life-shaping experiences fell upon the young Penfield. First, he came under the spell of Sir William Osler (also a Canadian), who gave Penfield much personal encouragement and practical assistance, and whom (like most) Penfield adored, regarding him as ‘the least sentimental and most helpful man I've ever seen—and the most lovable’. Also whilst at Oxford, Penfield was first drawn to the brain by his contact with Sherrington, who Penfield much later acknowledged had influenced his scientific thinking ‘more profoundly than anyone else’. Penfield's grandson Jefferson Lewis comments tellingly that ‘Sherrington, like Osler, was a connection to an earlier era of scientists who wrote poems, collected old manuscripts, travelled widely—and regarded all these things as part of a balanced life’.
Finally during 1915, the year of zeppelins, Gallipoli and Ypres, Penfield crossed to France to assist in a Red Cross Hospital: there his experiences gave birth to his abiding interest in surgery. Sailing back, his ship the Sussex was torpedoed by a U-boat, and Penfield, fracturing a leg, was reported drowned. He was in fact convalescing at the Oslers' in Norham Gardens only a fortnight after a glowing obituary was published in the Pioneer Press (Minnesota). Five years later, Penfield returned to Oxford to undertake joint research with Sherrington, then moved to London where he became a pupil and friend of Gordon Holmes. In 1924, he returned again to Europe, this time to Madrid and Rio Hortega, where the techniques he acquired enabled his fundamental contributions to the biology of oligodendrocytes and later, in collaborative studies with Rio Hortega, to the role of microglia and astrocytes in injury. Penfield went on to found the Montreal Neurological Institute in 1928 (aged 37 years) and to pioneer surgery for focal epilepsy. He operated on the 1st Baron Tweedsmuir, Governor-General of Canada (aka John Buchan) in a makeshift operating theatre in Governnment House. He met Nehru, the Queen and Chian Kai Shek (but refused to meet General de Gaulle) and speculated importantly on the neuroscience of the mind. He was universally held in reverence. (‘And still they gaz'd and still the wonder grew/that one small head could carry all he knew.’)
Meanwhile, Rio Hortega's classical work on the origins of microglia had appeared in 1921. He turned to pathology in the early 1930s, with lasting work on meningeal and glial tumours, and was appointed director of the new Madrid Cancer Institute: this was, however, one of the first buildings in Madrid to be razed to the ground by the Luftwaffe. Rio Hortega fled Spain, arriving via Paris in Oxford. There he worked in the wartime head injury unit established by Hugh Cairns with Cairns' long time close friend and collaborator, the formidable neuropathologist Dorothy Russell. Russell had, remarkably, spent a year (1929) in Montreal with Penfield learning the very techniques he had learned from Rio Hortega (and some of Penfield's own new modifications). Russell, an Australian bought up in Fowlmere, Cambridge, and educated at the Perse School, studied medicine at The London Hospital (entering in only the second year that the school admitted women as students), qualifying in 1922 and going on to win the London University Gold Medal for her MD Thesis. With Penfield, Russell made further fundamental contributions to our understanding of microglia, published in 1929. Six years later, Dorothy Russell was the first to grow glial tumour cells in culture. Working in the histopathology laboratories of St Bartholomew's and The London with J. O. W. Bland (who sadly died before many of their findings were published), they used Ronald Canti's time-lapse cine microscopy techniques to record pulsatile contractions of human, tumour-derived oligodendrocytes, and the behaviour of other living glioma cells. Russell showed the cine film to an audience of neuropathologists in New York on December 27, 1935: Penfield was in the audience, and found it ‘a very thrilling experience’.
Russell concentrated thereafter on neuropathology rather than neurobiology. Forced by the impending evacuation to move out of London, she joined Cairns in Oxford the day before war was declared in September 1939, helping to develop his new military hospital (sited in St Hugh's, half-way between Cairns' house and the Radcliffe). Rio Hortega—‘Don Pio’, as he was known—had been with Cairns in Oxford since 1938. Rio Hortega and Russell were to work closely together for 2 years as what would now be called academic neuropathologists. Hortega left in 1940 and spent his latter days in Buenos Aires with Polak. Russell returned to London in late 1944; she went on to be Director of the Institute of Pathology and the first woman to be appointed to a chair in pathology in Western Europe.
What extraordinary clinical scientists they were, and how their careers coincided! All were moulded by the odd combination of the great European wars and Oxford. All shaped the future of both glial biology and their clinical fields. All wore their greatness with a remarkable lightness touched by humility and generosity. Russell supervised the young Dr W. Stewart Alexander in a research project in the early 1930s. She oversaw his studies of an unusual post-mortem, which he later published (in Brain) as the first case of what became known as Alexander's disease. Penfield, looking back, considered his work on ‘neuroglia was nothing but steadfast study and description of simple, obvious things all of which should have been seen by someone else somehow’. Of course, all left textbooks universally recognized as definitive, and whose influence—and common usage—lasted decades. Will Myelin Biology and its Disorders have the same impact as Cytology and Cellular Pathology of the Nervous System, The Microscopic Anatomy of Tumors of the Central and Peripheral Nervous System or Pathology of Tumours of the Nervous System? Or is this even a fair question? Are not things far more complicated now, 50 years on—too complicated for the same breadth and depth to be achieved in a single text?
In short, Dr Lazzarini has certainly set himself a serious challenge. He has, however, set about the task admirably in this book. Understandably and probably wisely (in view of the magnitude of this task) but disappointingly (in view of his own serious and important contributions to the field), Lazzarini has channelled his energies into editing rather than writing (not even an Editor's Preface or introduction). Breaking the (two-volume, 6 kg) text into five sections (Glial and Myelin Biology, Glial Development, Myelin Genes and their Products, Human Diseases and Animal Models), he has assembled a small team of outstanding section editors and a formidable array of no fewer than 76 writers of an even trans-Atlantic spread.
The two volumes are indeed outstanding. Over 1100 pages there are, chapter after consistent chapter (48 in all), supremely authoritative, comprehensive reviews from universally recognized masters of their trade. And they tell the story promised in the title, outlining in the first volume the normal order of the building blocks of myelin—its components, structure and function—and the glia responsible for its synthesis, maintenance and repair. The second has disorder as the theme—genetic and acquired diseases, with a hefty emphasis on multiple sclerosis, and finally a whole, six chapter section on animal models of myelinopathies. The illustrations deserve particular mention—chapters on the node of Ranvier and the introduction to leukodystrophies are a joy to behold (though this cuts both ways; some dire reproduction in the chapter Neural Cell Specification spectacularly ruins more than one figure).
Is it a worthy descendant of the three great textual forbears? Undoubtedly its span is the greater—all human life (as far as myelin is concerned) is intended to be here, not just tumours or glial biology. But here is its problem. For despite its size, and length, and weight and six football teams of writers, Myelin Biology and its Disorders is not comprehensive, and this, in such a tome, disappoints.
The question of whether textbooks remain a viable life form is far from new. Decades ago, the late Professor Tony Mitchell wondered whether their fate, like that of dinosaurs, would be extinction as a consequence of their own unbearable weight. Dangerous not only to lift, but also to open, was the charge—the work being necessarily out of date (in the case of medical therapeutic books, perhaps culpably so) before groaning their way out of the printers' delivery vans. The pace of science and medicine has not slackened, and the IT revolution has sharpened the debate: ever-increasing on-line access further threatens paper journals and textbooks alike. Throughout Myelin Biology and its Disorders, which carries a 2004 imprint, references to research published later than 2002 are vanishingly rare. If I wanted to read a review of periaxin, or the node of Ranvier, would I not do better to turn to PubMed than this hefty tome?
Well no, actually: I might think so but I would be wrong. Try a dozen or so chapter subjects or titles and only one in 10 yields a 2003 or more recent authoritative review; then likely as not a full text version is not available. So this begins to hint at the why-ness of it. The Internet is not (yet) as useful as it threatens, and scientific journals must follow fashion: they do not carry reviews of everything every year. In any case, ‘new’ is not necessarily what is proper and necessary in a textbook. For sure, there is no prospect of finding in this 2004 textbook mention of current controversies—Prineas's tentative and careful suggestion, for example, that inflammation could just represent something other than a primary driver in demyelination, in at least some cases of multiple sclerosis (Annals of Neurology, 2004, 55: 458–68), or the recent challenging Cochrane review suggesting that glatiramer acetate does ‘not show any beneficial effect on the main outcome measures in MS, i.e. disease progression, and it does not substantially affect the risk of clinical relapses’ (Cochrane Database Systematic Review, 2004, CD004678). However, these do not yet belong in a textbook. They need digestion, study, reflection and confirmation—or otherwise. A textbook must be solid.
As the editors of the Oxford Textbook of Medicine put it 10 years ago, ‘no student or practitioner can own [or access] a library of monographs and journals that covers the whole of internal medicine, so medical textbooks still have an important part to play in providing a sound basic account of the many disorders that comprise medical practice. Textbook accounts of common and rare disorders provide students and doctors with a ‘way in’ to the published work on the bulk of diseases they are likely to encounter’. So has it consistently and persuasively been argued for clinical texts, likewise for science, and all the more so for clinical science.
So there's the nub of it. What's included in this book is outstanding, but to be useful and reliable as a ‘way in’, such a text as this must be inclusive and wholly comprehensive—and Myelin... is not.
Arguably, the history of myelin and glia is a minority interest, only meriting the 15 preliminary pages allowed here, but the complete omission or serious short-changing of other subjects are harder to understand. In general, and notwithstanding a really outstanding chapter on Schwann cells, peripheral myelin and its diseases take a fairly distant second place to the CNS. Why 115 pages of multiple sclerosis and only 16 of Guillain–Barré syndrome; surely a disorder of myelin not only important clinically but instructive immunologically? No chapter or even a subsection on CIDP, or multi-focal motor neuropathy. A chapter on EAE but nothing on EAN. (And perhaps insufficient analysis—the conspicuous failure of 60 years' worth of EAE yet to yield MS-halting therapies, for example, might deserve more detailed comment.) Why are there not one but two chapters on Alexander disease (no mention of Dorothy Russell!), two on Krabbe's and two on Pelizaeus–Merzbacher—important diseases all, of course, and these are truly excellent accounts of both disease and of models—but no account of metachromatic leukodystrophy, Refsum's disease (which gets barely a buried sentence or two), Niemann–Pick disease or Canavan disease. What of the ‘new’ leukodystrophies, such as vanishing white matter disease (also known as childhood ataxia with CNS hypomyelination, an autosomal recessive oligodendrogliopathy caused, surprisingly, by various mutations in ubiquitously expressed housekeeping genes)? Concerning acquired disorders, where are the chapters or sections on nutritional and/or metabolic disease—vitamin B12 deficiency, central pontine myelinolysis, Marchiafava–Bignami disease, tobacco/alcohol, carbon monoxide and other exogenous toxins, paraproteins, drugs, HIV-related demyelination, leprosy, SSPE, mitochondrial diseases and radiation? Or what of oligodendrocyte and/or white matter involvement in some of the classical neurodegenerative disorders such as multiple system atrophy, Parkinson's and Alzheimer's diseases? All hover like so many Banquos; a large, pervasive absence.
Who carries the can? Impossible of course to blame the writers—but very hard also to imagine that Dr Lazzarini, given a free hand, would have chosen to omit significant topics such as these. Far easier to see the fell hand of that usual suspect, the publisher's counting house, where these chapters would all, one suspects, have been seen as straws looking for a camel's back. (‘What, Dr Lazzarini... a third volume ... and in colour?’)
Let there be no doubt: this, to repeat myself, is a splendid book, an important addition to any serious clinical neu roscience bookshelf, and of lasting value: it is an outstanding achievement on the part of the Editor and the publisher. But two cheers could have been three, given another volume. Then this might truly have earned its place in the long and extraordinary story of the clinical science of myelin and glia. Dr Lazzarini should impress yet further upon Elsevier the importance of the third element.
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