In medical school, I remember being impressed as a second-year student by Raymond Adams's superb clinical neuropathological teachings. A year later, I had a poor course in neurology, and to compensate for this, I felt I had to take extra elective courses in neurology in the fourth year.
But in most other respects my background as a Midwesterner, Unitarian, middle- to upper-middle class, with German-English-Swiss genes, falls well within the boundaries found for the average researcher.' Beyond this, I write with some personal bias and out of some eccentricities which should be declared at once. I find medicine and science are meaningless unless they are interwoven with the rest of nature, the arts, and humanities. To me, they are all connected and the links between them have always been fascinating. Tourism pales, as does airline travel. I enjoy the novelty of living for months in a foreign land and in absorbing its culture first-hand.
I yield any time, anywhere, to a visual imperative. I have been a Sunday painter of sorts and paint in watercolors exclusively. Using this medium, colors can be splashed on at first with broad brush strokes instead of being applied precisely; a watercolor is finished quickly and need not be worked over repeatedly; completely unexpected effects occur. I prefer intense, realistic colors, and usually choose landscape scenes with plenty of clouds and a long view sweeping out to a low horizon. This hobby perfectly complements my other self-the reasonably compulsive physician that a neurologist usually is. When preparing slides to be shown at various scientific meetings, I enjoy coloring the slides or designing them myself. And, from the standpoint of color, the diseases I've been interested in have always been visually rewarding ones to study.
I also enjoy music. In music, too, I have inherited the interests of my father, who played the piano and composed songs in order to support himself through college. The kind of music that really rivets my attention is good Dixieland jazz. What delights me besides the obvious enthusiasm of the performers, are the alternations between free flights of improvisation and exuberant, throbbing reunions of the ensemble as a whole.
My active participation in music now is chiefly through barbershop harmony. But the melody has always had less appeal for me than other notes improvised spontaneously and tucked into the one place in the chord that makes for close resonating harmony. As for symphonic or other classical music, after only a few minutes of listening, my sequences of association are speeded up, and my mind rapidly goes off in many different directions. New combinations of ideas pop quickly into my head, skipping about like summer lightning. The result is that the whole exposure to music turns out to be more stimulating intellectually than musically. Because many new (and some useful) ideas about experiments or methods flash into my thinking anywhere and anytime, I keep a shirt pocketful of file cards to quickly jot down these ideas before they vanish.
By now you are familiar with at least some of the preamble.
Part I
The Meandering Chase
Experimental ideas are very often born by chance as a result of fortuitous observations. Nothing is more common, and it is really the simplest way to begin a piece of scientific work. We walk, so to speak, in the realm of science, and we pursue what happens to present itself accidentally to our eyes.
Claude Bernard
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Of Nerves and Neurologists; Boston, 1950
The destinies of man are guided by the most extraordinary accidents.
Hans Zinsser
I am in neurology because it is inherently rational. When the neurologist elicits a clinical history from his patient, then performs his specialized examination, he should be able to reason his way to the correct diagnosis, sometimes literally with pinpoint accuracy. One likes to think that the mental sequences involved in neurological diagnosis are intellectually rigorous, scientific, logical, and predictable. This is the core of my belief.
But let me now share some experiences on the periphery of my beliefs which have shaken the center from time to time. These experiences, both in the clinic and laboratory, are, in essence, happy accidents. They involve events which are irrational, nonscientific, and unpredictable. In the language of today, they are "happenings" of a special sort. That "happenings" do occur has been known for centuries. The experiences of Claude Bernard, the pioneering physiologist, occurred during what he called walks in the realm of science; my own have occurred more circuitously, during what I would characterize as meanderings.
Let us begin this narrative with an incident in 1950.' By then I had already completed college, four years of medical school, and a one-year internship. I was twenty-five years old and starting my first year as a resident physician at the old Boston City Hospital. At that time, my ultimate goal was to be a specialist in internal medicine and enter private practice. First, however, I wanted a year's experience in neurology, because I still didn't know enough about the diagnosis and treatment of diseases of the nervous system. I was drawn to the neurology service at City Hospital both by its fine academic reputation and its wealth of clinical material. Moreover, the chief of service there was an excellent teacher, Harvard Professor Derek Denny-Brown. Born in New Zealand, he had had his training in neurophysiology at Oxford and Yale, and in clinical neurology at the famous National Hospital, Queen Square, London.
Professor Denny-Brown was very familiar with the neurological literature, foreign and domestic. He could therefore inject unusual and stimulating observations into a discussion. His comments were provocative, sometimes to the point of heated controversy. But for present purposes, it doesn't matter whether the data he used and the interesting hypotheses he developed were correct or incorrect. What was important was that a given issue was dramatized and people were set into motion.
So it was, one Saturday morning in the drab conference room at Boston City Hospital when another neurology resident presented the first patient. She was a woman in her forties who over several decades had slowly developed the symptoms of a degenerative disease of the nervous system. The essential findings were those caused by a failure of her peripheral nerves to conduct impulses. As a result, the muscles of her hands and feet were wasted and weak, her reflexes were lost, and her sensation was impaired.
The professor-a tall, distinguished-looking man, formal in manner-stepped forward to check the findings. He felt for the ulnar nerves at the elbow and the peroneal nerves at the knee. This was interesting. I had not seen this done before.
The nerves were not enlarged. Perhaps a bit firm, but not enlarged. Dr. Joseph Foley, the attending neurologist in charge of the ward at the time, gave a good discussion of the several. diagnostic possibilities and then turned to Dr. Denny-Brown for his final comments. Dr. Denny-Brown thought the patient might have hypertrophic neuritis.
"Hypertrophic neuritis?" questioned Joe with a startled look. "How can the patient possibly have this when her nerves are not enlarged?"
"In some the nerves are not enlarged," said Denny, quite casually.
A certain amount of heat began to displace light. It seemed increasingly evident-almost by definition-that a patient with hypertrophic neuritis deserved to have enlarged nerves, if anything (figure 1).
Joe Foley became eloquent in his perplexity, but Denny sputtered on with some firmness. The issue was left hanging, unresolved. The staff hurried on to the next patient. We were left with the impression that Denny's view of the first case was unique.
It was only some years later that I found an isolated report of a patient whose nerves were not enlarged. The article was buried in the French medical literature of 1912. However, to the point of this anecdote, this 1912 case doesn't really matter. What did matter was that opinions were stated forcefully, and that a controversy was aired. Students and residents inhaled a heady atmosphere: there were still facts left unsettled in neurology; there were big gaps in our information; the facts, and their interpretation mattered.
It is always very difficult to remember to feel for peripheral nerves. Neurologists often forget to do so, because most patients with ne
urological diseases will have nerves neither too large nor too small. Hence it is assumed that there is really no point in routinely feeling for nerves. The trouble is that sooner or later the rare patient does come along with the rare disease that causes peripheral nerves to become enlarged. How, then, does one remember to palpate his nerves? What is the special mental set which prompts one to remember to elicit the unusual but crucial sign when it is there? As for me, my mind retrieves best after I have participated, even as an onlooker, in a dramatic issue. Teachers who made an academic issue come alive have stimulated my enduring interests. Thus, to me it is clear that I remember to palpate peripheral nerves because of Professor Derek Denny-Brown. What happened at that Saturday morning conference profoundly influenced me to this day and had an incalculable effect on the rest of this story.
Figure 1
A normal nerve fiber, and the way it is affected in hypertrophic neuritis. A normal nerve fiber is shown at the top. Its cell body at the left has a nucleus (N) and an axon (AX) which conducts its nerve impulses from left to right. The myelin sheath (M) is the fatty layer surrounding the axon. It is synthesized by the sheath cell (S.C.) which envelops it.
In hypertrophic neuritis, the myelin sheath breaks down (dotted lines), and some axons also degenerate. Sheath cells multiply (note the three oval nuclei instead of one), and they produce an abnormally thick layer of connective tissue (C.T.). This forms a large fibrous cylinder around the nerve fiber, causes the nerve trunk as a whole to enlarge, and makes the peripheral nerve palpably enlarged beneath the skin.
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Enlarged Nerves; Oakland, 1951
Concerning all acts of initiative (and creation), there is one elementary truth... the moment one definitely commits oneself, then Providence moves too. All sorts of things occur to help one that would never otherwise have occurred. A whole stream of events issues from the decision, raising in one's favour all manner of unforeseen incidents and meetings and material assistance which no man could have dreamt would have come his way. I have learned a deep respect for one of Goethe's couplets:
"Whatever you can do, or dream you can, begin it. Boldness has genius, power, and magic in it."
W. H. Murray
A year after the Saturday conference I was a naval medical officer stationed at the Oak Knoll Naval Hospital. My wife, Judy, and I lived in a small bungalow nestled in the hills above Oakland overlooking San Francisco Bay. To a native Midwesterner who had spent his summers in the flat farmland of Ohio, the Bay Area was an eye-opener. Its ambient sunshine, mild winters, abundant garden crops, mountains, and salmon fishing made a deep impression, one that would soon convert me into a Westerner.
One day at the hospital I admitted a twenty-two-year-old seaman by the name of Knox who had noticed a progressive weakness of his hands and feet for the past seven years. The findings on my standard neurological examination were those of a chronic peripheral nerve disorder. So, then what? The next moment was critical. Subliminally, I must have recalled the events at that earlier conference back in Boston. Somehow, I did remember to feel for the size of his peripheral nerves.
The nerves were enlarged. I had encountered my first patient with hypertrophic neuritis (see figure 1). But what was this illness? And, more important for the patient, what could be done about it?
The answer was: nothing, until one found out the cause. I still knew almost nothing about hypertrophic neuritis and accordingly set out to inform myself. Textbooks weren't very enlightening, and when I started to search the medical literature, it was clear that much remained to be learned. The disease was something of a puzzle. How much of it I was really going to understand would depend largely on my own efforts. This in itself was provocative. I began to haunt the library and soon became totally involved in the subject. As the project grew, it focused my interests on neurology instead of internal medicine, and within the year I had made the big decision to become a neurologist.
Toward the end of my two years in the Navy, I was accepted for the two final years of training as a resident in neurology at the Neurological Institute of New York, a part of the Columbia-Presbyterian Medical Center. Another important decision then faced me. The job as a resident would not start until six months after I left the Navy. What was the best way to spend these six months? During my earlier training, Dr. Raymond Adams had made a strong impression on me as an outstanding teacher, both of neuropathology and clinical neurology. Given his example, I decided that it would be best to use the intervening months to learn some neuropathology. So it was in this offhand way that I fell into a neuropathology fellowship that, happily, Professors Houston Merritt and Abner Wolf improvised for me at Columbia-Presbyterian in New York. Before I left Oakland, I called up former seaman Knox, who had since been discharged from the Navy, and told him I would keep trying to find out the cause of his disorder. I still am.
Those fortuitous months in neuropathology became a springboard for much of what followed. During this period, I could continue the studies on hypertrophic neuritis.' Later, this interest would branch out and lead to a treatment for still another disorder of peripheral nerves. And, during these months, the rest of my research career would take form.
What factors shape a career? Are they readily definable? Are they the product of a free choice, decision, or logic alone? Not in my case. For thus far, the pivotal influences have been more subtle or unplanned things: the resonance of an uncle's voice, impromptu drama in a Saturday conference, the happenstance of military assignment and of job scheduling. And from now on, the turning points in the story will hinge on other fragile events: the words of a friend, a mother's resolve against a fatal disease, and the vigor of a dog running wild and free on a chase in the field.
3
Metachromasia; New York City, 1953
I find that a great part of the information I have was acquired by looking up something and finding something else on the way.
Franklin P. Adams
New York City was a far cry from the splendor of the Sierra mountains, but we escaped by living in semirural New Jersey. Still, the big city must have impressed me. It was from the Palisades overlooking the Hudson River that I would paint its details into my first watercolor landscape: the soaring bridge in the foreground, then the Neurological Institute of New York, and finally the long, hazy view south down Manhattan Island to the skyscrapers in the distance.
As I rode in to the medical center on the bus each day, I was still reading articles about hypertrophic neuritis. Even to the unaided eye, the peripheral nerves in typical hypertrophic neuritis are large, firm, and elevate the skin as might an underlying pencil. Under the microscope, the nerve is a sea of connective tissue surrounding the few islands of remaining nerve fibers (see figure 1). It is this loose connective tissue which causes the nerve to enlarge. Some investigators had even described areas of metachromasia in the loose connective tissue.
Metachromasia? What did that mean? I had to look up the term in a medical dictionary. I found that metachromasia refers to a color change from blue to red, something similar to the way blue litmus paper changes when it is placed in an acid solution. The differences are that metachromasia is a staining reaction, and the blue indicator dye used to detect it is in solution, not on paper. What causes the dye to turn red is intimate contact with a large acid molecule. The prefix meta (change) is used because the blue dye turns a color other than that of the original dye, and chromasia refers to color.
I became excited about the neurological implications of metachromasia. For when metachromasia was seen tinder the microscope, it meant that an acid molecule was there carrying a net negative charge. It seemed an important concept that molecules that were charged negatively could exist within the nervous system. We know that the nerve impulse itself and excitability in general are intimately associated with fast changes in the position of positively charged ions (sodium, calcium, etc.). Opposites attract. Therefore, it was plausible to think that negatively charged molecules in the nervous system mig
ht sometimes, like a powerful magnet, attract these crucial positively charged ions.
With the concept of opposite charges strongly in mind, I decided to look further into what was known about metachromasia. I had a vague feeling of being drawn to the word as though it were the pole star. Fortunately, a key feature of the neuropathology fellowship at Columbia was that I was largely left on my own to repair my ignorance. This gave me considerable time to browse in the library. There, one day, meandering, and looking up the term in the Cumulated Index Medicus, I chanced across the pivotal cross-reference. The prime article was written by two eminent English physicians, W. Russell Brain, a neurologist, and J. G. Greenfield, a neuropathologist. It had been published three years earlier and was entitled "Late infantile metachromatic leukoencephalopathy."' I was frustrated because, as is so often the case, the whole volume containing this one article was out of the library. It would have been quite easy to have let the matter drop right there. But I was mildly curious to know what this new disease was, and persistent enough to put the volume on reserve.
Weeks later, when I first saw the article itself, its contents had an almost physical impact. I still remember vividly the entire flash of discovery at the library table. During the moment itself, I was all a participant, suffused not only with a compellingly fresh intellectual idea but with the feeling that all my perceptions were on edge. As it was then, so I can easily visualize it now, but with one curious difference. Now, I am the onlooker; my vantage point is always about fifteen feet up and about five feet over to the left. There is the large library, the big library table, and at its center is the lone figure of a young doctor in white, sitting and peering into a large book.
The sequences of illumination at the library table that day went somewhat as follows. First, I found myself reading with increasing fascination about this other intriguing disorder, also characterized by metachromasia. Indeed, I was impressed by the special feature of the new disease: massive amounts of metachromatic material were scattered throughout the nervous system. Next, I was struck by the black and white photograph. It showed that other deposits (said to be metachromatic) also lay in and near the kidney tubules. Suddenly, my mind raced and turned inward, a burst of blurred images flashing in quick succession: kidney deposits entering the urine; a centrifuge; a metachromatic stain; a microscope. The complete working hypothesis leaped forth in sharply visual form: the material present in the kidney has entered the urine; being heavier, it will be centrifuged down into the urine sediment; there, the deposits turn a metachromatic color when stained with toluidine blue; this disease of the central nervous system can be diagnosed during life by looking at the urine sediment under the microscope.
Chase, Chance, and Creativity Page 2
