Chase, Chance, and Creativity

by James H Austin

  It took months to work out all the "bugs" in the method. By this time, our chemical techniques were accurate enough to analyze even minute amounts of globoid-body material by chromatography. Analyses showed that the bodies contained more cerebrosides and fewer sulfatides than normal brain tissue.

  How was this to be interpreted? Were cerebrosides increased locally because the enzyme that breaks them down was deficient? Or, were sulfatides decreased locally because the enzyme which builds them up was deficient?

  These questions set us off on a new series of experiments.' Our first hypothesis was that the deficient enzyme was cerebroside galactosidase-the specific enzyme which splits galactose from cerebroside (see figure 6). Unfortunately, at the time, there was no adequate way to measure just this one enzyme. Assays of other related galactosidases were normal. Tests of our second hypothesis showed that the enzyme activity which forms sulfatides was low, but not really low enough in all tissues to satisfactorily explain the disease. Clearly, GLD research had to wait for a new method to resolve the nature of the primary enzyme deficiency.

  It finally arrived. Kunihiko Suzuki at Pennsylvania used an accurate new method for measuring the specific galactosidase that splits off galactose from cerebroside. This was the pertinent enzyme. Indeed, he and his group showed beyond question that in GLD this was the enzyme that was chiefly deficient.' Collaborating with him and with Roscoe Brady' at the National Institutes of Health, we could jointly confirm his finding in our own case material. The deficiency of this galactosidase readily explained why cerebroside was locally increased in the globoid bodies.

  A form of GLD also occurs in dogs-in certain inbred strains of West Highland terriers. I knew I had seen this dog somewhere before: it is the white dog on the label of the bottle of "Black and White" scotch! Soon we followed up the studies in human GLD with a collaborative study of the same enzyme in terriers who inherited GLD. We found that GLD dogs had the same galactosidase deficiency as did humans.' As we shall see, this would not be the only time dogs would play a vital role in our research.

  Two things counted in the GLD studies (see figure 8). One was the unexpected finding in control experiments that a globoidlike response occurred in rats injected with cerebroside. The other was Saul Korey's prodding to develop a new method. Once we had this basic method, we could then modify it. Later, it would be these modified techniques that would enable us to go on to isolate a whole series of different abnormal structures from human brains in several other diseases (see figure 13). But these studies would not unfold for years, and in the interim, some hard international realities, confronting everyone, would have tangible unforseen effects on my personal and professional life.

  8

  Enzymes and India, 1961, 1962-1963

  There can be no more important education today than education for personal effectiveness and a sense of connection with big events. However impressive a man's acquisition of worldly knowledge, however proficient his ability to marry theory to technique, if he cannot use his thinking ability and his skills to work for a safer and better world, his education is incomplete and he is in trouble.

  Norman Cousins

  My own research has been indelibly influenced by my personal beliefs and style of living. Nonscientific interests have repeatedly come back to enrich and invigorate my scientific career.

  Take my interests in the outdoors as one example, and those in a rational world order as another. Judy and I enjoyed hiking around Mount Monadnock in New Hampshire before we were married. Later on, we were drawn to the American West by its splendid opportunities for camping, hiking, and fishing. At a faculty party in Oregon, we happened to meet George Dana and his wife, Betsey, and soon found out that they too had lived earlier near Mount Monadnock. It then turned out that the Danas were local pillars of an organization called the United World Federalists. Through the Danas we then became friends with Phil and Rhita Feingold. Phil, a personable insurance executive, had been working actively in the World Federalist movement since college. Through Phil we then met Norman Cousins, President of the World Association, and were immensely impressed, both by the man and by his writing. We learned from all these new friends about the goal of the World Federalists: gradually to strengthen the United Nations into a really effective body for world government. Judy, and then I, became very much interested in this movement.

  Those who remember the start of the cold war, the nuclear overtones of the 1950s, the fears of an atomic holocaust, and the ominous talk of bomb shelters throughout the United States, will understand why we preferred the ultimate alternative of a federal system of law and order transposed onto the international level.

  By then, I had a firsthand familiarity with the consequences of war, because I had dressed wounded flesh both in World War II and during the Korean episode. I came to an intense personal realization that my puny efforts to save a few neurological patients would be futile if we were all wiped out by atomic warfare. Moreover, there seemed to be little point in expressing myself creatively as a father of three and as an investigator if everything were soon to be expunged. Thus, like many other citizens, I grew increasingly alert to political issues. Passive acceptance of the situation was not for me. If I were to have any relevance to society, and it to me, I must become involved in political activity-and not work solely in the hospital or in the laboratory.

  What was the best course of action under these circumstances? What concrete action should I take-something more than a token demonstration-that might have some remote chance of altering political events in the future?

  India. We were drawn toward India for several reasons. It was a country that did not yet have a centralized World Federalist movement, and we thought we could help organize this effort there. Under Prime Minister Nehru, India was then one of the leaders of the nonaligned nations. Citizens of these neutral nations were increasingly called upon to be "honest brokers" between the Communist and non-Communist world (a role exemplified by UN Secretaries General Dag Hammarskjold and U Thant). India was also a pivotal country: the largest democratic country, racked by unrest, it could readily fall into a dictatorship. We were under no illusions about how much we could really accomplish in a subcontinent this vast. But however small the result, we knew that making the constructive effort was the only way to live and to respond to the situation in the world at that time.

  In medicine, it turned out that New Delhi offered an interesting opportunity. The new medical school at the All-India Institute lacked both a neurology department and a head of neurology. If I could make even a small personal contribution in a school this young, it might lead to a relatively more lasting impression on the subsequent development of neurology.

  My first big conflict was whether to spend one-half of my year's sabbatical from Oregon at the Karolinska Institute in Stockholm. Some months before I had completed plans to learn electron microscopy in Sweden, but I soon decided that the experience in India was more in tune with the realities of the times. So, India, it would be.

  In 1961, I made a trip to India to see which of several positions would be most fruitful. At that time, the international situation was not merely grim, it was downright ominous. Neighbors in Portland were building bomb shelters in their basements. During my trip, the USSR resumed atomic testing in the atmosphere, and the Berlin Wall was erected. Democracy seemed imperiled. It was difficult to keep a sense of perspective in the downhill spiraling thrust of world events. What influence could one man have?

  I stopped over in Athens and attended the "Sound and Light" performance, a superb outdoor dramatization of the ancient history of Greece. I was oddly reassured by what I saw. For that night, the performance vividly reminded me that once before, in 499 the whole future of Western civilization also had hung in the balance. The issue was decided then by the narrow margin of the efforts of a bare handful of men who managed to eke out a victory over the Persians.

  From a scientific standpoint, the key portion of my first two-week visit to Ind
ia was the trip to the Christian Medical College in Vellore. There, in the south of India, I first met Professor Bimal Bachhawat and visited his laboratory. I had followed his research reports in the journals for some years, and knew we had interests in common. Since receiving his Ph.D. in biochemistry at Illinois, he had been studying many different enzymes. He and I were in our mid-thirties and soon became close friends. I mentioned our histochemical studies on sulfatases and our ideas about a sulfatase deficiency as the enzymic cause of metachromatic leukodystrophy. We decided to pool our resources.

  Our meeting in India produced a true cross-fertilization of ideas. Thereafter, our Oregon laboratory would become more oriented toward the assay of enzymes in the test tube and Bimal's would become more oriented toward sulfatides.

  When I returned to Oregon from this brief visit to India, I set about creating a shipping box. We needed a special container to carry our frozen MLD specimens and pertinent control tissues of other diseases all the way to India. The logistics of this effort were complicated, but with the help of much insulation and repeated packings of dry ice en route, the shipment finally reached Bimal by air express still safely frozen.

  Fortunately, Bimal and I had chosen to start our analyses on that special variety of MLD found in the McLean family (pp. 26-27). (It seemed appropriate to call this form multiple sulfatase deficiency, or MSD).' We didn't know it then, but in most tissues these patients were deficient in all three sulfatases (sulfatase A, sulfatase B, and sulfatase C).' We couldn't miss finding a sulfatase deficiency, regardless of which sulfatase method we used. Studying any of the three enzymes would still have shown the deficiency. The chemical method used would give a low result if either sulfatase A, or sulfatase B, or both were deficient. And, when we tested histochemically with our modified method for sulfatase C, the deficiency was so marked that my first thought was we must have made some mistake. In contrast, we were delighted to find normal values for all the other nonsulfatase enzymes in the MLD tissue. We controlled and repeated all the observations several times to be certain they were valid. They held up. Clearly, the sulfatase deficiency was specific for MLD.

  But which sulfatase deficiency caused the usual form of MLD-the form in which there was a sulfatide excess only? By this time I was in the midst of my sabbatical year, 1962-63, in New Delhi, but fortunately, I had kept our laboratory running in Oregon. In Portland, we still had living MLD patients and could analyze their urine for sulfatase activity. This was possible because some of the enzyme normally made in the kidney escapes into the urine. After studying several MLD patients and many controls, it was clear that all our living patients with the usual form of MLD were deficient in sulfatase A only. Sulfatase B (and C) were normal (figure 7).

  Had we not chosen to go to India for largely nonscientific reasons, I would not have met Bimal Bachhawat and started our fruitful scientific venture. The sabbatical was personally rewarding for other reasons. Judy and I worked with a number of enthusiastic Indian men and women of Federalist persuasion. We were able to help start in motion the union of these World Federalist groups that was finally centered in New Delhi. Something else got started: four young Indian doctors who studied neurology with me elected to go on and specialize in neurology. Men and women whose training one influences are among the deepest satisfactions that come in academic medicine.

  The sabbatical year in India was packed full of colorful cultural surprises. There was, for example, a matter of adjusting to cultural differences in communication and to the sanitary realities of food and drink. We got our first taste of this when a fellow American told us about an enlightening experience she had with her cook. To avoid food infections, she had gone to great pains carefully to instruct her cook to first soak all vegetables from the market in a solution of potassium permanganate. This burgundy colored, penetrating liquid has the useful property of killing microscopic cysts that are an ever-present cause of amebic dysentery. For weeks all went well in the kitchen with the carrots, lettuce, spinach, and other vegetables. But one day, while checking periodically (as one does), she discovered to her amazement that the beets had gone unsoaked. "Why?" she asked. The cook's explanation was simple. "I didn't think I had to soak beets, because they were already red to begin with!"

  And then there was the festival of Holi. On this day of celebration, everyone dresses in old apparel appropriate for the rigors of the occasion, and then ventures out of the house laden with powdered pigments of many bright colors-reds, blues, greens, oranges, and yellows. The object is, quite literally, to transform one's friends and neighbors-turning them into a kaleidoscope of colors and dousing them with water too-until everyone, in a frenzy of sputtering, gasping and giggling, turns into a walking Jackson Pollock painting. On Holi day, no one is spared the creative mayhem of his fellows, and if anything, the medical school faculty catches more than its share from the emancipated medical students, residents, and interns. The festival takes its legendary roots in the playful behavior of the milkmaid, Radha, toward her lover, Krishna, but nowadays it assumes the proportions of a gigantic Halloween prank in which people of all ages and stations, friend and stranger alike, share in the mass excitement of giving and receiving. No Westerner will ever forget the unique experience of this riot of color, of being painted on, and painting in return.

  Figure 7

  Evolution of the sulfatase research

  Looking back, it is clear that this sabbatical year in India involved some political meddling. This kind of extracurricular activity is not automatically bad, but it is next to impossible to justify to some of your scientific colleagues. I can still see the arched eyebrows with which Professors Adams, Swank, and Korey greeted the announcement that I was going to India for a year. Still, as James Newman has put it: "The responsible scientist must be a meddler. The tendency to regard the scientist as defiled if he mixes in social and political activities arises from the widespread failure to understand that science lies at the center of the network of human affairs."'

  In this chapter we have observed how intimately one's personal and professional life can be interwoven in the course of an ongoing scientific quest. But there are other elements of the search taking shape long before the investigator comes to maturity. It is from the chase that, years later, the quest evolves. Even now, it is still possible to perceive the earlier behavior patterns, but you have to know where and how to look. Let us, then, climb up the stairs into the attic, open a dusty trunk, and peer into a musty old family album. As our eyes accommodate to the dim light, we begin to perceive in outline an earlier version of the search and see why it sometimes takes on the flavor, persistence, and curious impracticality of the chase.

  9

  Flashback; The Chase, 1942

  In the album are old clippings from the local newspaper, faded and yellow with age. The print remains clear, however, and the reporter's words, given verbatim below, are still revealing. The photograph (taken in the police station) documents this reporter's unlikely tale. On the lap of a tired youth sits a rabbit, very large and very alert.

  WEARIED RABBIT ADMITS DEFEAT AFTER TWO HOUR CHASE

  (From The News, Robert Edgar, editor)

  It was a toss-up, which was more winded, the boy or the rabbit, last Saturday afternoon when Jim Austin stood sweating and dirty in the Police Station, clutching in his arms the weary but squirming body of a wild rabbit.

  Jim, age seventeen, was brought into the station after police answered the calls which began to pour into the station from frantic housewives along Bedford Road who reported that a "mad man" and a "lunatic" was seen dashing through the grounds, diving under fences, leaping hedges, and in general cavorting in a "highly suspicious" fashion all around the neighborhood.

  The capture came at the conclusion of what Jim later told police had been a two hour chase, all around that section down as far as Three Mile Drive during which he had kept on the trail of the rabbit by its footprints in the snow. "I thought I had lost him one time, " Jim confessed, "but I got
my second wind."

  After the first hour, Jim was on his trail, which by this time was becoming more and more difficult to follow, for Peter was using the same route over and over again. Once Peter ran down the middle of Bedford Road for almost a block and Jim was dismayed,- there were no tracks left. He started to walk up the road when he saw Peter, who had paused for a breathing spell, resting near the sign on the corner. The chase was on again.

  The rabbit ran into a hole one time, and Jim about gave the chase up, but luck was with him. Another rabbit was already in the hole, an inhospitable rabbit who chased the visitor out. When Jim finally picked up the wild bunny, he instantly recognized him as a former victim whom he had previously caught and let go.

  Jim's wind and his ambition may have been proven beyond contradiction last Saturday. But it was a wearied and disarrayed boy who took his way home. His face was muddy with combined dust and sweat. The scarf, tied around his throat, was wet to the saturation point, and his trousers and sweater were completely covered with brambles and burrs.

  Assured that, since he was planning to turn the animal loose, there was no criminal or civil charge, Jim was pretty relieved. After all, it would be pretty hard to face the kids as an ex-con.

  10

  Tom and Lafora Bodies, 1965

  Because new elements, variable and unforeseen can introduce themselves into the conditions of a phenomenon, it follows that logic alone will never suffice in the experimental sciences.

  Claude Bernard

  Among chosen combinations the most fertile will often be those formed of elements drawn from domains which are far apart.