American Scientist

Nerve Endings: The Discovery of the Synapse. Richard Rapport. 240 pp. W. W. Norton, 2005. $23.95.

The War of the Soups and the Sparks: The Discovery of Neurotransmitters and the Dispute over How Nerves Communicate. Eliot Valenstein. xviii + 237 pp. Columbia University Press, 2005. $31.

Scientific style and personality loom large in Nerve Endings and The War of the Soups and the Sparks, two new books documenting discoveries about the neuron's anatomical structure and its modes of transmitting nerve impulses. These volumes tell a story that begins in the late 19th century and is still being written today. Both accounts meld individual biographies of scientists with descriptions of experimental procedures and raise questions about the ways in which styles of research, creativity and intuition have contributed to the practice of experimental neuroscience.

In Nerve Endings, Richard Rapport, a neurosurgeon by training, focuses on the life and work of the Spanish artist and scientist Santiago Ramón y Cajal and to a lesser extent on Cajal's Italian rival, Camillo Golgi. Cajal's late 19th-century conception of a discrete nervous cell, separated from other cells by a gap (later called a synapse), came to replace the older reticular theory, which postulated that nervous tissue comprised a seamless, continuous web—an unbroken network, or reticulum—through which nerve impulses could travel in any direction. Golgi's adamant advocacy of the reticular theory was the source of his conflict with Cajal.

Golgi, after attending medical school, began his scientific career in experimental pathology by joining the even younger histologist Giulio Bizzozero, who was doing original research at the University of Pavia. In 1872, at age 28, Golgi left the university and, to support himself, took a job as chief physician at a mental hospital near Pavia. In his spare time, working in the kitchen of his hospital apartment, he strove to find a stain for neural tissue that could more clearly isolate neural structures. The following year he achieved what he termed the black reaction by using a silver nitrate stain that affected only a small percentage of neurons, allowing him to trace nerve structures more precisely than had been done before. He was then able to detect branching of axons (now understood to be the single fibers that conduct impulses away from the cell body) and to confirm the existence of protoplasmic extensions, or dendrites (now known to be the fibers on a cell body that receive signals sent from the axons of other cells). However, he was convinced that dendrites did not actually participate in neural transmission but instead merely played a supportive role in the network. His silver nitrate stain was nonetheless a formidable advance and was in widespread use by the 1880s. For his accomplishments, Golgi accepted a chair in histology at the University of Pavia.

Cajal, who was nine years younger than Golgi, took to drawing, watercolors and photography as a young boy. Eventually he turned toward anatomical studies, employing his artistic skills for medical illustration. After his medical training at the University of Zaragoza, he taught histology, and in 1887 he began experimenting with the Golgi stain in his own kitchen laboratory. Cajal pioneered an improved method that he referred to as the double impregnation procedure. It involved soaking embryonic nerve tissue and cerebellar tissue first in fixative and then in silver nitrate, and then repeating this process. This method provided a deeper stain of nerve tissue, allowing Cajal to visually track the paths of axons and map the structure of neuronal cell bodies in greater detail. He found that axons ended in gray matter, meaning that the bulges (boutons) on the ends of axons conformed to patterns of dendrites on nearby cells. Most strikingly, he noted that the ends of axons were not seamlessly connected to other neurons but were separated from them by a gap. He also proposed a theory of dynamic polarization, in which nerve impulses were transmitted in one direction only, from the neuron's dendrites to the axon.

Cajal made many artistic renderings of his observations, some of which are helpfully reprinted in this volume. As Rapport reminds us, however, the gaps between neurons were not actually visible to Cajal, and it was only 50 years later with the aid of an electron microscope that they could be directly seen. How then did Cajal intuit such gaps? Rapport suggests that Cajal, because he was relatively isolated from the scientific mainstream and was not wedded to the reticular theory, did not have preconceived notions of what he might find. He used his imaginative capacity to see what others could not.

Nonetheless, the validity of Cajal's findings was not so easily apparent to others. He resorted to creating his own journal to publish his results, but his writings in Spanish attracted little attention. He therefore translated his work into French (which was considered a more acceptable language for reporting scientific findings) and submitted it to prominent German journals. As Rapport tells it, acceptance of the neuron theory began when the renowned histologist Albert von Kölliker was converted from the reticularist position at an 1889 Anatomical Society meeting in Berlin. Yet Golgi still adamantly opposed the neuron theory, a rejection that Rapport suggests may have been due to Golgi's rigid personal style. Indeed, even in 1906, by which time the theory had become widely accepted, Golgi attacked it in the speech he gave when he and Cajal were awarded the Nobel Prize.

Influenced by the work of Pierre Flourens, Golgi was a staunch holist with regard to brain function, a position that may have contributed to his opposition to the existence of discrete cell entities and one-way transmission in the brain. Yet, aside from mentioning the work of Karl Dieters and Joseph von Gerlach, Rapport does not give much attention to the assumptions and findings of the reticularists. He points out the prevalence of their views in various scientific circles of the time but does not elaborate on the stakes of their debates with the neuronists. One also wonders how those debates might have intersected with the drive in Germany and France, beginning in the 1870s, to localize brain function to certain areas of the cortex. Rapport's narrative focuses instead on the personal dynamics between Cajal and Golgi, leaving broader aspects of the debate out of view. Cajal emerges as the clear hero as Rapport tells it: Not only was he right, but he was also more keenly observant, more creative and more psychologically balanced than Golgi.

Three decades after Cajal intuited gaps between neurons, the German pharmacologist Otto Loewi had another creative neuroscientific insight, one that came to him in a dream. As Eliot Valenstein recounts in The War of the Soups and the Sparks, this dream (which recurred two nights in succession in 1921) gave Loewi the inspiration for an experiment that he conducted using two frog hearts to demonstrate that the vagus nerve produced its effect on the heart by secreting chemical substances. Merely performing this crucial test was not sufficient proof of chemical transmission, however, and it took Loewi a decade to carry out a decisive series of experiments to satisfy his critics.

Valenstein, an emeritus professor of neuroscience and psychology at the University of Michigan, uses the example of the dream to characterize Loewi's scientific style as speculative and bold, in direct contrast to that of the British pharmacologist Henry Dale. Years earlier Dale had begun research on the effects of ergot extracts on biological functions and had found amine substances that could mimic the actions of sympathetic or parasympathetic nerves. Yet in 1914, when Dale performed his experiments, amine substances such as noradrenaline and acetylcholine were not understood to be present in the body. As Valenstein points out, Dale never made the theoretical leap to imagine that such a chemical could be emitted by the nerves themselves. Despite the stylistic differences between these two scientists, it was their combined experimental work that led to the finding of neurohumoral secretion of the nerves, a discovery that earned them the Nobel Prize in 1936.

The idea that chemicals were the conduit between neurons was not a popular one, however—especially among neurophysiologists, who thought this mode of transmission would be too slow. In a short but important chapter, Valenstein uncovers the professional differences between neurophysiologists and pharmacologists, noting how these differences played a role in the war between "the soups and the sparks"—between those who argued for chemical transmission and those who supported electrical transmission. Neurophysiologists saw themselves as practicing an elevated discipline, and they looked down on pharmacological work as labor carried out with "spit, sweat, snot, and urine."

The tension between these very different disciplines, which receives only limited attention in this book, formed an important reason for the slow acceptance of a neurohumoral theory of transmission. Valenstein does discuss the views of the prominent neurophysiologist John Eccles, but the sparks side of the "soups and sparks" debate takes a backseat to the careers and life stories of Loewi, Dale and Walter Cannon, the pioneers of the neurohumoral theory.

Even after neurohumoral transmission had been established for nerve stimulation of various organs such as the heart, there was still a good deal of hesitation to ascribe similar mechanisms of transmission to the brain. By the 1950s, a number of different monoamines, such as adrenaline and serotonin, had been found in the brain, and the electron microscope revealed vesicles in the axon that looked like possible containers for neurotransmitters. Despite such findings, however, few drew the conclusion that brain synapses were crossed by chemicals. It would take another decade to track neurotransmitter action across brain synapses and for neurohumoral secretion in the brain to become accepted. It remains puzzling why such findings were so slow in coming, a point Valenstein underscores but does not fully explain.

These two books solidly document the personal and professional lives of scientific "winners." Yet it is important to heed the final cautionary notes of the respective authors: Even as chemical transmission has now been established as the rule in neuronal communication, there are a small number of instances (in the retina, for example) in which neurons communicate directly through electrical transmission, without a gap but with protoplasm stretched between neuronal membranes, the so-called gap junction. Stories, then, of overcoming outdated assumptions, when viewed over the course of time and further research, can sometimes demonstrate that the losers were partially right, their views becoming a special case rather than the general one.

One drawback of histories such as these, which sharply focus on the heroic successes in neuroscience, is that they obscure the rationale and stakes for the different scientific viewpoints held at the time. That said, however, these books are, in the end, aimed less at charting the contours of broad scientific debate than at documenting creative leaps in the process of scientific discovery.