CHEMOAFFINITY IN THE ORDERLY GROWTH OF NERVE FIBER PATTERNS AND CONNECTIONS.

In early observations on the outgrowth and termination of nerve fibers, it appeared that different fiber types must be guided to their respective end organs and other connection sites by selective chemical or electrical forces. Explanatory terms like chemotaxis, chemotropism, galvanotaxis, and neurotropism were commonly employed by Cajal7 and others early in the century. These selectivity concepts later came under attack, especially during the 1930's and 40's when the application of more analytic experimental approaches to the mechanics of nerve growth seemed to rule out the presence of either chemical or electrical selectivity in favor of a predominantly mechanical interpretation.347 The numerous examples of apparent selectivity described earlier, as well as the developmental patterning of the central nerve tracts and fiber systems in general, we came to believe, were more properly and correctly explained on a mechanical basis, particularly in terms of the orienting effects of mechanical stresses on tissue ultrastructures and the resultant formation of submicroscopic systems of mechanical guide lines in the colloidal matrix of the growing medium. At the height of this antiselectivity movement I was led, from evidence indirect and partly behavioral, to postulate again in 1939 a form of chemical selectivity in nerve growth even more extreme in some respects than in the earlier proposals. The hypothesis, 18-24 in brief, suggested that the patterning of synaptic connections in the nerve centers, including those refined details of network organization heretofore ascribed mainly to functional molding in various forms, must be handled instead by the growth mechanism directly, independently of function, and with very strict selectivity governing synaptic formation from the beginning. The establishment and maintenance of synaptic associations were conceived to be regulated by highly specific cytochemical affinities that arise systematically among the different types of neurons involved via self-differentiation, induction through terminal contacts, and embryonic gradient effects. Coming at a time when "instinctive" was still a disreputable term in most scientific quarters, and when concepts of nerve growth were strongly dominated by the mechanical theory, this seemed a long shot at first and hardly less wild than some of the opposing interpretations of the day like the "resonance principle"2' 33 that it was proposed to replace. When tested experimentally, however, study after study through the 1940's18-24, 29 yielded results that fit nicely. In brief, whenever central fiber systems were disconnected and transplanted or just scrambled by rough surgical section, regrowth always led to orderly functional recovery and under conditions that precluded re-educative adjustments. The functional outcome was always as if the scrambled fibers somehow unsorted themselves in regeneration and managed to "home in" on their original and proper central nerve terminals. It seemed a necessary conclusion from these results that the cells and fibers of the brain and cord must carry some kind of individual identification tags, presumably