Ross Harrison's "The outgrowth of the nerve fiber as a mode of protoplasmic movement".

Ross Harrison’s ‘‘The outgrowth of the nerve fiber as a mode of protoplasmic movement’’ is likely the most important paper ever published in the Journal of Experimental Zoology (Harrison, ’10). It is also among the most important papers published in the field of neuroscience during the first half of the 20 century. In a single stroke Harrison invented the method of tissue culture, and then used it to prove the neuron doctrine. It is easy to dismiss the misguided ideas that dominated neuroscience at the turn of the 20 century. The field was at war with itself over the most basic of questions: whether the nervous system was composed of neurons. Although the prevailing theories of the time were eventually shown to be spectacularly wrong, they were nevertheless highly attractive to neuroscientists because of their apparent explanatory power. The idea was that the nervous system was not made up of distinct cells, but was a syncytium through which electrical current flowed. Although the syncytial or reticular theory was starting to lose credibility when Harrison published his paper in 1910, it was still widely accepted, and in modified form was to live on as late as the 1940s. It was plainly obvious to many physiologists that there could not be any gaps in the wiring of the nervous system any more than there could be gaps in the wiring of a house. The physics of electric current flow called for continuity. Opposing this view was the great neuroanatomist Santiago Ramon y Cajal, who argued that the nervous system was composed of discrete neurons, and that axons grew toward their targets behind motile structures called growth cones. This controversy raged on in the most public of possible venues: When Golgi and Cajal jointly received the Nobel Prize in Physiology in 1906, the two leading anatomists of the day took diametrically opposed views on the neuron doctrine, in lectures given from the same platform in Stockholm (Ramon y Cajal, ’06; Golgi, ’06). The syncytial theory was first proposed by Victor Hensen in 1864 and was later elaborated upon by the embryologist Hans Held. Hensen thought that he had seen fine cytoplasmic threads connecting cells after they had divided. What if, he mused, all neurons retained threadlike ‘‘plasmodesms’’ with each other? The nervous system would begin development as a thoroughly interconnected meshwork. Functional wiring would involve deciding which threads mature into axons. Hensen imagined that this would be through functional validation, where the threads that linked electrically active neurons would selectively dilate into axons. In this way initially weak cytoplasmic threads would develop into larger axons with stronger current flow. In a single stroke Hensen and Held had solved the problem of how neural connectivity is established during development, how the strength of neural signaling is determined, and how electrical current could flow freely through the nervous system. It was a brilliant theory, but as Cajal would point out in his Nobel lecture, Nature had other ideas. In addition to Hensen and Held’s plasmodesmic theory there were other incorrect but popular views about nervous system organization. For example, Theodor Schwann had proposed that axons were secreted from chains of ensheathing glial cellsFthe Schwann cells of the periphery and the oligodendrocytes of the CNS. This strange hypothesis attracted many supporters, and still had proponents as late as the 1920s. The neuron doctrine however, also had impressive support. In addition to Cajal it was defended by the physiologist Charles Sherrington, who argued that neurons made functional contacts at sites that he termed synapses. Neurons that were born in isolation and contacted each other during development would use synapses to communicate with each other. The problem of how electrical signals could be conveyed across a synaptic cleft