A tale of two books: milestones on the path to understanding multiple sclerosis

The publication of a new work is always exciting—whether this is a novel offering pathos, humor or other insights into the human condition, or a work of non-fiction whose object is to inform, stimulate or clarify. The recent publication of two landmark books on multiple sclerosis (MS), both very different in scope and objectives, but with many elements in common, provides an opportunity for personal comment and an historical perspective on the modern elucidation of this complex disease. How do we conceptualize illness? This question has been at the centre of medical investigation over the millennia, and the issue continues today, at both individual disease and broad ethnoanthropological levels. Cultural differences in the approach to illness and wellness are most striking in considering differences in attitudes between ‘developed and undeveloped’ populations, and especially in the comparison of Eastern and Western traditional medical practices. These have seen subtle shifts in the relationship between what is considered normal and abnormal. Now, the process of ageing, accepted as an integral part of the human condition throughout the ages, has assumed in Western culture the status of a disease to be treated, modified and avoided. The more one investigates the practice of medicine, the more one is struck by how pervasive are these social and cultural influences on the fabric of clinical science. Medicine has always hovered at the interface of science and the art of healing, and this duality has often created tensions for its practitioners. Most modern clinicians would like to believe that their practice is soundly based in science, and that the exercise of their healing arts is done in the setting of evidence-based knowledge and wisdom derived from experience. Similarly, basic and clinical scientists feel that they approach a given problem with open minds, and base their hypotheses and experimental plans purely on objectivity. These aspirations are most easily met in simple disease models, where there is a direct relation between cause and outcome. How different is the situation in complex conditions, where the described symptoms and signs may or may not be part of one disease, the aetiology that could possibly link these is unclear and the management is invariably uncertain? In this situation, differing scientific backgrounds and training may bias investigation and conceptualization, and social, cultural, political and economic factors start to influence medical behaviour. Many aspects of MS have been exquisitely detailed for >150 years, but the accounts have not always avoided these confounds, and the disease (or diseases) is still shrouded in mystery. Lest any of its practitioners or investigators believe this not to be the case, it would be well to review the evolution of neuroscience thought in the context of societal and cultural development and, more specifically, how concepts of MS have been subject to these influences. Critical study of this history helps to place our modern view of MS in perspective, and to judge how successful two new books that tell the contemporary story are in showing where we have come from, where we are now and how we should go forward in a way that helps to eliminate some roadblocks of the past. The history of neuroscience reveals a marvelous amalgam of human discovery with all its genius and folly, insight and stubbornness, perceptiveness and blindness. With the distance of time, it is easy to see how this discipline was firmly embedded conceptually into the philosophy, culture, technology and art of each era in which progress was made. The development of studies and practice in MS has followed an analogous pathway, but this history is compressed, and the ideas are still in flux. Indeed, theories once discarded are now being rediscovered, and we are as yet not altogether clear where we stand on the evolutionary pathway towards a complete understanding and solution to the problem. That, ultimately, is why we write and read, and, each in its own way, these two books fulfill this mandate wonderfully. MCALPINE'S MULTIPLE SCLEROSIS, 4TH EDITION, By Alastair Compston, Ian R. McDonald, John Noseworthy, Hans Lassmann, David H. Miller, Kenneth J. Smith, Hartmut Wekerle and Christian Confavreux 2005 Price: $(US)199.00 £145.00 ISBN: 044307271X ISBN-13: 9780443072710 MULTIPLE SCLEROSIS AS A NEURONAL DISEASE, By Stephen Waxman 2005. Academic Press (Elsevier) Price: £107.50 $170.00 ISBN: 0-12-738761-7 The Greeks were the first seriously to study anatomy and physiology, including the brain, but their approaches to science and philosophy were indivisible. It is easy to forget that Aristotle, the philosopher, was also steeped in scientific practice, and his theories on the order of the universe were firmly rooted in personal scientific investigation. This Greek legacy persisted into the Roman era and was exemplified by Galen, the first towering figure in neuroscience. His studies were exhaustive and careful, although mostly based on animal dissection. It is not known whether he ever dissected the human body. The effects of this restriction to animal studies were profound: the benefit was that he confirmed the use of hands-on observation, remaining scornful of those who theorized without doing the practical work themselves—a problem that has continued over the centuries; conversely, he made some fundamentally incorrect assumptions about the human brain, which were not corrected for centuries. Galen perpetuated the myth that the rete mirabile, a vascular network described by Herophilus and seen in sheep, pigs and other animals, is present in humans, and he formulated the concept of ‘animal spirit’, the activating agent of all nervous activity. This had a dominant negative effect on investigation across the ensuing centuries. It is also one of the first examples of the perils that arise from extrapolating the animal situation to the human, a subject that has generated some considerable discussion in the modern debate on the aetiology of MS. The concept of the animal spirit was also tied in with the fixation of investigators on the cerebral ventricles as the locus of thought processes, a concept much favoured by the Church, and one that also survived for several centuries. Medieval drawings of the brain are stylistic and explanatory rather than accurate. They show huge ventricles surrounded by barely perceptible brain tissue. However, besides the direct fear felt by anatomists of challenging this Church-imposed concept, one also notes that anatomical drawings echo some early religious paintings of the time. Artists too were painting stylistically, and direct observation gave way to representation of previously held concepts. In how many instances in modern times have we seen this happen? It was in the Renaissance, with its flowering of thought in art, science, architecture and geography, and with the first hesitant steps to break free from the confines of the Church, that neuroscience started on the modern path. Interestingly, it was artists who led the way. The revolution in painting by Leonardo da Vinci, whose realistic art mirrored an amazing capacity for understanding science, and Michaelangelo, who demanded realistic models for his portraits, forced anatomists to depict the brain accurately, which in turn shaped a re-evaluation of the way that it functions. The extraordinary partnership between Andreas Vesalius and the painter Titian led to production of one of the most influential medical texts of all time, De Humani Corporis Fabrica Libri Septum (1543), which laid the foundations of modern neuroscience. His accurate observations rejected the concept of the rete mirabile and the functional importance of the ventricles. Gone was the time when university Readers, beautifully depicted in many early woodcuts, merely read to their students from the great texts, perpetuating ancient myths. Vesalius set the stage for Thomas Willis, who depicted the circle of blood vessels, which bears his name, and emphasized the functional role of the cerebral convolutions. Concepts in neuroscience progressed over the next few centuries according to the social fabric of the times, the advent of new technologies and gradual freedom from ecclesiastical doctrines of medicine and science, especially during the Age of Enlightenment. But other institutions—governments, funding agencies, universities, learned societies and journals—have since imposed their own orthodoxies. During the Industrial Revolution, the introduction of parallel advances in technology and experimentation, and the increasing importance of public health, suggested a role for infectious and environmental agents in the generation of many diseases, and Robert Koch drew up his postulates. These trends have continued during the 20th and 21st centuries with the emergence of new disciplines such as immunology, neurochemistry, molecular biology and genetics and the introduction of animal experimentation to establish models of disease on which to base hypotheses. Clinically, the introduction of scientifically motivated therapeutic strategies has led to ever-increasing improvement in the practice of well-controlled clinical trials, and evidence-based prescribing and management. Given these observations on social and cultural factors governing the conduct and interpretation of scientific investigation, which we see so clearly with the benefit of hindsight, it is reasonable to ask whether the study and concept of MS as a disease has been similarly constrained over the years, and continues to be influenced by these forces. Viewed from an historical perspective, it is obvious that, even though compressed into a relatively shortened period, theories of aetiology, nomenclature and definition of MS have varied with the general theories and fashions of the times. Even the purists among MS researchers acknowledge that remarkable changes in medical fashion over the last 2 centuries have not spared their discipline. In a way this is to be expected. Scientists, although forever curious, generally tend to investigate along directions that have been imprinted on them—consciously or subconsciously—by mentors, colleagues and (more subtly) societal influences. It is the rare individual who breaks free from ingrained thought and investigates a problem accordingly. Such individuals may miss the mark completely, or make major breakthroughs in conceptualizing a disease and explaining its mechanisms. It is sobering to consider that some of the key issues first raised by those who pioneered the study of MS remain unsolved. The basic concept of the disease make-up, including the scope of the condition and its classification, the aetiology, relative importance of separate pathological constituents and its treatment, are all still controversial. Current debates mirror those of our neurological ancestors. What is MS? To most people, it is an autoimmune inflammatory demyelinating disease, occurring in people with a genetic predisposition, and triggered by some additional factor, environmental or perhaps even a second genetic step. How did this idea develop? Again, we note that the elements of this concept were imprinted many years ago. 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