Recollections and reflections: A neurologist's tale
It is just 50 years since I finished my first period of research in the Department of Physiology at the University of Otago and on the occasion of the Centenary Celebrations of the department it is instructive to reflect on what it was like then, half way through its history, and how it influenced the development of a young man whose sights were already set on a clinical career. What I learnt then and was reinforced five years later when I returned to the department is as important now as it was then. My first year was as a BMedSc student. I was supremely fortunate. Though the department had been depleted by Eccles’s departure for Canberra taking much electrophysiological equipment with him, it was still well furnished with Toennies amplifiers and other eqipment of the kind Archie had used at the Rockefeller Insitute and had set up when he came to Dunedin in 1949. The staff was small, with only Wilf Rall, Ken Bradley and Russell Harwood to share the teaching load. Archie’s own research interest at that time was in what we would now call plasticity in the nervous system. He was working on the changes in the properties of neurones induced by chromatolysis and disuse. Having no other research assistant he recruited me to help in his surgical preparations for the chronic experiments. During these sessions he would talk not only about the work in hand but about broader issues of science and education. I began to absorb his approach to both and the principles which guided him: an over-riding interest in mechanism informed by a knowledge of structure; meticulous attention to detail and the importance of considering new observations in a broad context, both scientific and historical. At the same time of course he introduced me to the techniques of spinal reflex physiology which were specific to my own project. In that year too I came to understand the importance for a young man’s d broader intellectual development of the special relationship which can develop between teacher and pupil. Crucial in this was the warmth with which he and Anne welcomed me to their home where I was treated as if an equal. Archie also saw to it that I started to gain teaching experience from an early stage.
After this year – arguably the most important in my medical education – I returned to the medical course and then had a year as a house surgeon. It was characteristic of Archie that he retained an interest in his students’ development. He encouraged me throughout this period and in the last of these years having made the point that the best possible preparation for a career in academic medicine would be to return to a period of research in physiology, he arranged for me to have a fellowship to support a PhD. And so I returned to the Department in 1959. It had grown. Jimmie Robinson (who had spent a sabbatical year there in 1954 ( my B Med Sc year) had returned as a Professor. (Archie had told me that during the negotiations he had made it clear to the University that if Jimmie didn’t come he went!) Geoff Satchell encouraged by Archie had moved to physiology from Zoology. Thus there were new and important influences in the department, in renal and electrolyte physiology an in comparative physiology. There were more postgraduate students too, attracted by Archie’s breadth of vision, and his reputation for suggesting interesting thesis topics and for providing the warmest of support.. The atmosphere of enthusiasm in the department infused by intellectual rigour encouraged one to hone ones ideas through bracing discussion with fellow students. Particularly valuable were the discussions with Julian Jack (who later became Professor of Neurophysiology at Oxford and as an FRS and deputy chairman of the Governors of the Wellcome Trust was one of the most influential figures in Neuroscience in Britain in the late 20th century) and Austin Sumner who like me became an academic neurologist.
When I look back and ask myself what I learnt over and above the methods of neurophysiology which influenced me as a physician and an academic I would say that it was Archie’s style: his of breadth of approach, his commitment to the highest standards and his example of generosity of spirit in relationships between colleagues and students. It was a happy department. There was a family feeling engendered by Archie and Anne, Jimmie and Marion Robinson and Geoff and Truda Satchell. Social interaction was frequent and warm. The staff were enthusiastic about the work of the students and gave generous credit to their achievements. They made sure that each of us had the opportunity to present our work in circumstances most advantageous to us. We were to publish alone when the work was all ours – or almost so – irrespective of the fact that the inspiration and ideas had originated with our supervisors who had also introduced us to the techniques we needed.
These cardinal virtues are well illustrated by the topic Archie suggested I work on: the electrical consequences of demyelination for conduction in nerve.
The background was this.
The 1950s had seen the final proof of the electrical nature of nervous action, an idea first mooted by Stephen Hales and Alexander MonroII in the mid 18th century. But as Sir Andrew Huxley recently pointed out to me it was still not fully accepted even in the late 1930’s by the Doyen of nerve Electrophysiologists Joseph Erlanger who did not accept Alan Hodgkin’s evidence that the nerve impulse propagated by local circuits, as their correspondence shows. In 1948 Huxley and Stampfli had demonstrated that in myelinated nerve conduction is saltatory. i.e. that excitation jumps between the successive little gaps (nodes) in the insulating myelin sheath of the nerve fibre. Within four years Hodgkin and Huxley had provided compelling evidence for the ionic hypothesis of the nature of the nerve impulse, work for which they received the Nobel Prize a decade later. Archie saw that the results of the study he proposed would be of interest not only to physiologists but to neurologists who at that time understood little about how symptoms are generated in the prototypical demyelinating disease multiple sclerosis.
It is worth telling the story of how the project developed because it so well illustrates Archie’s style and strengths as a supervisor. Julian Jack has remarked that Archie was “very gentle and relatively permissive as a supervisor…without making one feel he did not care.” He encouraged independent thought and experiment. In my case this began with Archie’s departure on a 15 month sabbatical just before I started. He left me a letter with three references to possible methods of demyelination that I might consider. I admit that the first year and a half was somewhat traumatic, but by the time he returned I had mastered the necessary histological techniques (with the guidance of Geoff Satchel) and had settled on what I thought was a suitable method for producing a lesion. I was in fact still wavering – even considering a quite different kind of pathophysiological project. But a few wise words of encouragement led me back to the original aims, and within a few months we had a reproducible method of experimental demyelination which turned out to be eminently suitable for electrical study. Now Archie’s flair for devising the definitive experiment came to the fore. The method of demyelination that I was using (parenteral injection of diphtheria toxin obtained by post from the Wellcome laboratories outside London) produced a highly circumscribed lesion in the region of the dorsal root ganglion leaving normal nerve on either side. Archie saw that such a lesion was ideal for two kinds of approach.
The first was direct recording from the abnormal area following stimulation at a distance. It was at once clear that exactly at the place where demyelination began electrical conduction was blocked, providing direct experimental confirmation of the physiological prediction. The observation was of no less interest to neurologists. As far back as 1906 Gordon Holmes had concluded from pathological studies of spinal compression that demyelination must lead to conduction block and Denny-Brown had reached the same conclusion from experiments performed during the second world war. But this was the first time it had been proved by direct recording. Here then was a sufficient explanation (though not necessarily the only one) for the loss of function – paralysis, blindness, sensory loss – characteristic of multiple sclerosis.
The second experiment was recording from single active nerve fibres in the dorsal roots after peripheral stimulation. This was possible because conduction was not completely blocked in all fibres. Archie had been using this method during his sabbatical when he was studying the properties of skin receptors. His approach was typical. He showed me how to do it and left me to get on, expressing the greatest interest when the next, and unexpected, new finding emerged. This was that conduction was slowed, often profoundly, a result which was later to have considerable practical significance.
All these observations were made in the peripheral nervous system. But multiple Sclerosis is a disease of the brain and spinal cord. While it seemed likely that similar results would be found after central demyelination, this had to shown. It was some time before it was. Over the next five years I completed my clinical training in general internal medicine and then neurology. In 1967 having obtained a consultant appointment at the National Hospital Queen Square I was able to set up my own laboratory and begin a highly fruitful collaboration with Tom Sears who had just retuned from three years with Sir John Eccles in Canberra. Using a modified diphtheria toxin method suggested by Tom and physiological techniques partly based on Archie’s and partly on a different approach of Tom’s own, we soon showed that central demyelination too produced conduction block and slowing. Other changes relevant to the mechanism of symptom production were also elucidated. The next important step was the move from experimental animals to the human.
In the mid 1960s neurologists interested in peripheral neuropathy (for example that due to diabetes or immunological disturbances) had exploited the finding,,which had been widely confirmed, that demyelination was associated with slowing of conduction whereas degeneration was not. They increasingly used nerve conduction studies in patients s a diagnostic tool In 1972 as we were completing our electrical studies on central demyelination, the question naturally arose whether some analogous approach might be diagnostically useful in relation to diseases of the brain. The opportunity to find out came through another collaboration at Queen Square, this time with Martin Halliday. Martin was using the visual evoked potential to map the projection of the retina on the visual area of the brain. The technique was straight forward. The subject sat and watched a chequerboard of black and white squares reversing at two per second while the consequent electrical activity in the brain was recorded from small electrodes applied to the scalp over the visual cortex. At that time I was seeing numerous patients with disease of the optic nerve in a clinic I had at the Moorfields Eye Hospital. Many had acute (though recoverable) loss of vision due to optic neuritis, often the first manifestation of multiple sclerosis. So we decided to combine forces. The results were immediate and dramatic. There was in 90% of cases a substantial delay in the response from the affected eye. Moreover the delay persisted even when the vision had returned to normal. It was quickly apparent that this method could be used to detect asymptomatic damage in the optic nerves and that accordingly it should be useful as a diagnostic aid in multiple sclerosis. And so it proved. The method was quickly adopted around the world resulting in a flood of papers confirming ours (which later turned out to be the 22nd most cited paper in the British medical Journal between 1945-1989. Here was a supremely practical outcome from a study originally conceived by Archie as primarily physiological. The visual evoked potential represented the first major non-invasive advance in the diagnosis of multiple sclerosis.
At this stage it was not clear how the study of the pathophysiology of multiple sclerosis could be taken forward. A major unsolved problem was the mechanism of remission (so characteristic of the disease, and illustrated by the recovery from optic neuritis just mentioned). What was needed was a way making a closer correlation between the clinical state of the patient and the detailed pathological and electrical changes in the lesions, an example of Archie’s principle of studying mechanism informed by a knowledge of structure. But this was impossible.
Everything changed after December 1981 when the first report of the use of Magnetic Resonance Imaging (MRI) in Multiple Sclerosis was published by Ian Young, Graham Bydder (an Otago graduate) and others in the Lancet. The lesions were easily visible and MRI became a powerful diagnostic tool. More important for our questions about mechanism was the demonstration by David Miller (another Otago graduate) and others over the next five years or so that it was possible to use MRI to tell us something about the pathology of lesions. Of particular importance was the discovery that using a special technique (“gadolinium enhancement”) it could detect the presence of inflammation which was known by this time to be the mechanism of demyelination in multiple sclerosis.
As you will have realised the optic nerve has many advantages for the study of pathophysiology. And so it proved again. What we now needed was a way of producing high resolution images of the optic nerve. This was achieved by our physicists led by Glyn Johnson who was working closely with David Miller.
By 1990 we were able to put everything together. Bryan Youl (a Melbourne graduate) working with David Miller and Martin Halliday’s team studied another cohort of patients with optic neuritis from Moorfields. He confirmed that visual loss was due to conduction block, and showed that recovery was due to its reversal. Of special interest was the conclusion the whatever contribution the physical effects of demyelination made to coduction block in this context, inflammation played an important part and that it was its resolution of which allowed the inherent recovery mechanisms in the nerve fibre to be expressed and vision to return. The nature of these mechanisms is the subject of another whole field of endeavour pioneered by Tom Sears at Queen Square.
Not surprisingly as each question about the pathophysiology of multiple sclerosis has been answered, others have arisen . I want to consider just one more. What is the nature of the blocking agent in the inflammatory process? Ken Smith (now professor of Physiology at Guy’s, King’s and St Thomas’s Medical School has been addressing this question in collaboration with Raj Kapoor. Ken started in the Archie tradition as transplanted to Queen Square in the 1970s and went on to work in Tom Sears’s laboratory with Hugh Bostock. Raj was a student of Julian Jack’s at Oxford and is now a neurologist. They have shown that one of the substances produced by inflammatory cells – nitric oxide – blocks conduction in concentrations known to occur in multiple sclerosis lesions. Of particular interest in relation to the irrecoverable disability that develops in the later stages of multiple sclerosis they have found that when nerve fibres are continuously active in the presence of nitric oxide they undergo degeneration which of course results in permanent loss of function. This experiment opens up the possibility of a new therapeutic strategy to slow progression of the disease by controlling the effects of nitric oxide, a topic which is currently under intense investigation because of its relevance to stroke and trauma.
And so I come to the end of my tale. I began by describing simple experiments devised Archie with a view to answering a physiological question with the hope that it they might also help us to understand the mechanism of symptoms in a common disabling disease. As each decade has passed the analysis has been pressed to deeper levels and the complexity of the mechanisms has become more apparent. Along the way there have been practical advances – in diagnosis and most recently in the approach to treatment and its monitoring, a field which David Miller has made his own. It is interesting that so much of the work has been done by, as it were, the extended physiological family founded in the 1950s in Dunedin in the 1950s. The story provides I believe a triumphant affirmation of the principles and approach of a great physiologist, a great teacher and a much loved man: Archie McIntyre.