In the early 1940s, a future Nobel laureate, Roger Sperry, then at the University of Chicago, revived the research into chemical guidance of growing and regenerating axons. Sperry would later be called “the rebellious graduate student” because he began these studies while still working on his doctorate and challenged the views of his teachers, among them some of the strongest proponents of the physical guidance idea.7 He devoted more than a decade to nerve regeneration studies in fish, frogs, and salamanders and showed that growing nerve fibers did not follow a fixed mechanical path but appeared to carry chemical labels that enabled them to sort each other out.
In one of his most famous regeneration studies, Sperry showed that even when regenerating fibers are artificially deflected from their course, they adopt tortuous routes and find ways to grow back to their normal targets. In one experiment, he cut the optic nerve of a frog, which, unlike that of mammals, can regenerate and restore normal vision. He then rotated the eye 180 degrees, waited for the nerve to regenerate, and submitted the frog’s vision to a simple test. When presented with a bug, the frog flicks its long tongue to snap its favorite delicacy; if it can see well, it won’t miss. Sperry found that the regenerated optic fibers from the frog’s rotated eye followed a roundabout route to their original targets in the brain. For example, the axons from what had originally been the bottom side of the retina restored connections with the part of the brain normally responsible for receiving signals from the bottom of the retina. As a result, the frog now saw the world upside down and backwards; the floor appeared to be above its head and the ceiling below, and on the vision test the frog acted accordingly: It erroneously flicked its tongue downward to catch the bug above its head and upward to catch the bug below. The preprogrammed wiring had been restored with ruinous consequences for the frog’s ability to feed itself. These results suggested that the axons did not follow a predetermined mechanical path but searched out the appropriate target, apparently guided by chemical cues.