Walle J. H. Nauta 1916–1994

NATIONAL ACADEMY OF SCIENCES WALLE J. H. NAUTA 1916–1994 A Biographical Memoir by EDWARD G. JONES Any opinions expressed in this memoir are those of the author and do not necessarily reflect the views of the National Academy of Sciences. Biographical Memoirs, VOLUME 88 PUBLISHED 2006 NATIONAL ACADEMY OF SCIENCES WASHINGTON, D.C. WALLE J. H. NAUTA June 8, 1916–March 24, 1994 BY EDWARD G. JONES ALLE NAUTA WAS ONE of the leading neuroanatomists of W his generation and a key figure in neuroscience his- tory as a consequence of his development of a revolution- ary technique for tracing connections in the nervous system. It was a technique that dominated the field of neuroanatomy at a time when it was forming one of the semi- nal influences in the rise of neuroscience as an integrated discipline. Nauta came from that once large but now almost van- ished group of Dutchmen that for centuries had made its home in the East Indies. He was born on June 8, 1916, in Medan, Sumatra, a thriving commercial center on the Mal- acca Strait. His father, from Leiden, had gone there as a missionary of the Dutch Reformed Church but had soon turned to issues of public health, education, and better governance for the Indonesian people and it was into this milieu that Nauta was born. As was typical, he was sent to Holland for his later elementary schooling. The whole family returned to Holland in the late 1930s, thus escaping internment during the Japanese occupation of the East Indies during World War II. Reportedly, Nauta was never a par- 3 4 BIOGRAPHICAL MEMOIRS ticularly engaged student until he entered medical school at Leiden University, where he found his métier. By 1937 he had completed the preclinical part of his medical training at Leiden and before proceeding to the clinical years he served for two years as a student assistant in the Anatomy Department. It was there that his interest in neuroanatomy began. He was commencing his clinical rotations in 1940 when the German army occupied the Neth- erlands. On completing his clinical studies in 1942, he was about to return to an instructorship in anatomy when Leiden University was closed by the occupying authorities on ac- count of its being a hotbed of subversion. He therefore received his qualifying medical degree from the State Uni- versity of Utrecht and began to work in the Pharmacology Department there. It was at this time that he married Ellie Plaat, another Dutch Indonesian who had been stranded in the Netherlands without resources by the outbreak of war. In order to support herself she had become a nurse. After graduation and until 1946 Walle Nauta was both a practic- ing physician and a researcher at the University of Utrecht. The war years were periods of great hardship and want for all Dutch citizens. As a physician, Nauta was fortunate in having a permit that enabled him to pass beyond check- points and thus treat farmers in the countryside in return for food. But it was still a period of great privation. At one point in the lab, where he had begun studying the effects of hypothalamic lesions on sleep in rats, supplies ran out and the rats had to be fed with milk from Mrs. Nauta, who was at that time nursing their first child. His doctoral thesis was completed and the degree awarded in 1945. The Nautas, like all the Dutch people, suffered not only hunger but also indignity and sometimes worse at the hands of the occupying forces. Despite these experiences, Walle Nauta never stereotyped individual Germans, and it was typical WALLE J. H. NAUTA 5 of him that he and his family at the end of the war protected the local German administrator—who had turned a blind eye to the Nautas’ harboring of a Jewish girl for most of the war—until his bona fides could be established and safe passage back to Germany secured. For protecting that Jewish girl the names of Ellie and Walle Nauta are inscribed on the Wall of the Just in Jerusalem. In a reversal of for- tunes the Nautas were to send care packages to the German administrator after his return to his homeland. At the end of the war Nauta, now again at Leiden and in the Anatomy Department, contemplated a career in oph- thalmology but felt that the circumstances prevailing at that time precluded this, and so he sought a permanent position in anatomy. He claimed that as a student assistant at Leiden he had been attracted to the hypothalamus by the work of Walter R. Hess on the sleep-waking cycle, by Philip Bard’s studies of “sham rage,” and by the mounting evi- dence for its endocrine and neurosecretory relationships. And he recognized that many of the issues raised by these reports demanded anatomical answers that could not be pursued with contemporary neuroanatomical techniques. His fluency in several languages gave him the opportunity to look for a position beyond the Netherlands, and in 1947 he was appointed to a lectureship at the University of Zürich, Switzerland. While many might imagine that it was the pres- ence in Zürich of Walter Hess—perhaps the most promi- nent investigator of the hypothalamus at that time—that had attracted Nauta, Hess in fact had rejected Nauta’s work as lacking behavioral relevance, and Nauta became a lec- turer in the Department of Anatomy under the direction of Professor Gian Töndury. In his four years at Zürich Nauta established himself as a very popular teacher, something that was to characterize him for the remainder of his career and something that 6 BIOGRAPHICAL MEMOIRS was particularly important in Zürich, since his income de- pended upon student attendance at his lectures and labs. But it was also here that his obsession with developing an improved neuroanatomical tracing technique came to the fore. The direct investigation of neural connections in the hypothalamus, in which most fiber tracts are not myelinated, had always been hampered by the lack of a practical experimental method for revealing unmyelinated fibers belong- ing to particular functional systems. At the hands of earlier neuroanatomists such as Cajal, the study of normal fibers impregnated by the Golgi technique had yielded some ba- sic information on local connectivity; but the sheer tangle of fibers in their fine meshworks in the hypothalamus made imperative a more selective technique for labeling fibers that began or ended among identified neuronal groups, some of them—such as the hippocampus—far removed from the hypothalamus. For nearly three-quarters of a century the identification of fiber tracts experimentally had meant placing a surgical lesion in one part of the brain of an animal and then following the anterograde (Wallerian) degeneration of axons away from the cell bodies affected by the lesion, or identifying the cells projecting their axons to the region lesioned by their retrograde reaction to destruc- tion of their axon terminations. Unfortunately, in the 1940s the single available anterograde stain—that of Marchi—revealed only the degenerating myelin sheaths of myelinated fibers, which were generally lacking in the hypothalamus, and the cells of origin of many fiber systems afferent to or within the hypothalamus itself were protected from retrograde degeneration, probably because of their widespread axon collaterals. What was needed was a stain that would selectively pick out degenerating axoplasm, hopefully against a background in which staining of normal fibers unaffected by the experimental lesion was suppressed. In this way any WALLE J. H. NAUTA 7 fibers, myelinated or unmyelinated, could be traced from the point of lesion to their regions of termination. It was to this that Walle Nauta assiduously applied himself during his years in Zürich. Fortunately, he enjoyed both enormous popularity as a teacher and the unstinting support of Pro- fessor Töndury, because, from the point of view of publica- tions, it was far from a productive enterprise. The Nauta method, as we all came to call it, had its origins in the reduced silver methods of Bielschowsky and Cajal, in which metallic silver is deposited in axons in thin histological sections by reduction of a weak solution of silver nitrate. Regrettably, this lacks specificity, and all pro- cesses of all nerve cells, axons and dendrites, are impregnated. A modification—that of Paul Glees—described in 1946, could reveal the endings of those fiber systems in which the terminal boutons on degenerating axons enlarged and assumed a ring-like configuration as the result of what was later revealed as a neurofilamentous hyperplasia. How- ever this technique did not suppress staining of that obscuring mass of normal fibers, and was plagued with false positives. Nauta had had some success in identifying degenerating terminal ramifications with other forms of silver stain (1947), such as that of Bodian (1936) but he saw in the Bielschowsky method, in which silver is precipitated from an unstable ammoniacal salt, a better chance of revealing degenerating fibers in their entirety (1993). The Nauta stain in its first prototype (1951) did reveal quite clearly the frag- menting axons undergoing anterograde degeneration, but it suffered from a failure to suppress the co-staining of the intact and still obscuring normal fibers. The suppression of the normal fibers was to come in a later iteration (1952; 1954,2; 1955), in which by mordanting the sections in potassium permanganate and potassium bisulfite, the later deposition of silver in normal fibers could be suppressed. 8 BIOGRAPHICAL MEMOIRS In retrospect it became clear that this was obtained at the cost of also suppressing staining of many of the finer degenerating fibers.

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