Everything Is Just Dandy!

The Father of Modern Neuroscience Discovered the Basic Unit of the Nervous System

Scientific American Content
Benjamin Ehrlich
2022 04 09
https://www.scientificamerican.com/article/the-father-of-modern-neuroscience-discovered-the-basic-unit-of-the-nervous-system/

Hour after hour, year after year, Santiago Ramón y Cajal sat alone in his home laboratory, head bowed and back hunched, his black eyes staring down the barrel of a microscope, the sole object tethering him to the outside world. His wide forehead and aquiline nose gave him the look of a distinguished, almost regal, gentleman, although the crown of his head was as bald as a monk’s. He had only a crowd of glass bottles for an audience, some short and stout, some tall and thin, stopped with cork and filled with white powders and colored liquids; the other chairs, piled high with journals and textbooks, left no room for anyone else to sit. Stained with dye, ink and blood, the tablecloth was strewn with drawings of forms at once otherworldly and natural. Colorful transparent slides, mounted with slivers of nervous tissue from sacrificed animals still gummy to the touch from chemical treatments, lay scattered on the worktable.

With his left thumb and forefinger, Cajal adjusted the corners of the slide as if it were a miniature picture frame under the lens of his microscope. With his right hand, he turned the brass knob on the side of the instrument, muttering to himself as he drew the image into focus: brownish-black bodies resembling inkblots and radiating threadlike appendages set against a transparent yellow background. The wondrous landscape of the brain was finally revealed to him, more real than he could have ever imagined.

A young cajal appears in an 1871 photographic portrait.
A young Cajal appears in an 1871 photographic portrait. Credit: Cajal Institute, Cajal Legacy, Spanish National Research Council (CSIC), Madrid, Spain

In the late 19th century most scientists believed the brain was composed of a continuous tangle of fibers as serpentine as a labyrinth. Cajal produced the first clear evidence that the brain is composed of individual cells, later termed neurons, that are fundamentally the same as those that make up the rest of the living world. He believed that neurons served as storage units for mental impressions such as thoughts and sensations, which combined to form our experience of being alive: “To know the brain is equivalent to ascertaining the material course of thought and will,” he wrote. The highest ideal for a biologist, he declared, is to clarify the enigma of the self. In the structure of neurons, Cajal thought he had found the home of consciousness itself.

Cajal is considered the founder of modern neuroscience. Historians have ranked him alongside Darwin and Pasteur as one of the greatest biologists of the 19th century and among Copernicus, Galileo and Newton as one of the greatest scientists of all time. His masterpiece, Texture of the Nervous System of Man and the Vertebrates, is a foundational text for neuroscience, comparable to On the Origin of Species for evolutionary biology. Cajal was awarded the Nobel Prize in 1906 for his work on the structure of neurons, whose birth, growth, decline and death he studied with devotion and even a kind of compassion, almost as though they were human beings. “The mysterious butterflies of the soul,” Cajal called them, “whose beating of wings may one day reveal to us the secrets of the mind.” He produced thousands of drawings of neurons, as beautiful as they are complex, which are still printed in neuroanatomy textbooks and exhibited in art museums. More than 100 years after he received his Nobel Prize, we are indebted to Cajal for our knowledge of what the nervous system looks like. Some scientists even have Cajal’s drawings of neurons tattooed on their bodies. “Only true artists are attracted to science,” he said.

Nerve endings that Cajal drew from a section of mouse thalamus.
Nerve endings that Cajal drew from a section of mouse thalamus, a key neural signal relay point. Credit: Cajal Institute, Cajal Legacy, Spanish National Research Council (CSIC), Madrid, Spain
Astrocytes, support cells for neurons, surround a blood vessel.
Astrocytes, support cells for neurons, surround a blood vessel. Credit: Cajal Institute, Cajal Legacy, Spanish National Research Council (CSIC), Madrid, Spain

A New Truth

In Cajal’s day, the most advanced method for visualizing cells was histology, an intricate and temperamental process of staining dissected tissue with chemicals whose molecules clung to the subtle architecture of the cells, rendering them miraculously visible through a light microscope. With the primitive stains available, researchers across Europe tried and failed to clarify the question of what lies inside the brain, believed to be the organ of the mind. Then, in 1873, in the kitchen of his apartment in Abbiategrasso, outside Milan, Italian researcher Camillo Golgi, through some combination of luck and skill, hit on a new technique that revolutionized neuroanatomy. “I have obtained magnificent results and hope to do even better in the future,” Golgi wrote in a letter to a friend, touting his method as so powerful that it could reveal the structure of nervous tissue “even to the blind.” He called it the black reaction. One of Golgi’s students recognized “the marvelous beauty of the black reaction … [which] allows even the layman to appreciate the images in which the cell silhouette stands out as if it had been drawn by Leonardo.” Cajal, who first saw the technique in the home of a colleague who had recently returned from studying in Paris, was absolutely smitten. “On the perfectly translucent yellow background,” Cajal recalled, “sparse black filaments appeared that were smooth and thin or thorny and thick, as well as black triangular stellate or fusiform bodies! One would have thought that they were designs in Chinese ink on transparent Japanese paper … Here everything was simple, clear, and unconfused … The amazed eye could not be removed from this contemplation. The dream technique is a reality!”

Although the black reaction dramatically reduced the number of nerve elements visible on a microscope slide, those elements were still so densely packed that their fibers appeared inextricable from one another. Traditionally, researchers studied nervous tissue from adult humans who had died naturally after a normal life span. The problem was that in the adult nervous system, the fibers were already fully grown and therefore extremely structurally complex. Looking for a solution to this problem, Cajal turned to embryology—also known as ontogeny—which he had first read about in a college textbook. “If we view the natural sequence in reverse,” Cajal explained, “we should hardly be surprised to find that many structural complexities of the nervous system gradually disappear.” In the nervous systems of younger specimens, cell bodies would in theory be simpler, fibers shorter and less numerous, and the relationships among them easier to discern. The nervous system was also well suited to the embryological method because as axons grow, they develop myelin sheaths—insulating layers of fat and protein—which repel the silver microcrystals, preventing the enclosed fibers from being stained. Younger axons without thick sheaths more fully absorb the stain. In addition, mature axons, which sometimes grow to be a few feet long, are more likely to get chopped off during sectioning. “Since the full-grown forest turns out to be impenetrable and indefinable,” he wrote, “why not revert to the study of the young wood in the nursery stage, as we might say?”

At the age of 36, Cajal found himself incubating eggs, just as he had loved doing when he was a child. This time, instead of waiting to witness “the metamorphosis of the newly born,” Cajal cut into the eggshell after a few days and removed the embryo. Embryonic tissue was too delicate to withstand pressure from the clasp of a microtome. So, holding the block of tissue between the thumb and forefinger of his left hand, he cut sections with a razor blade, applying his training as a barber during the hated apprenticeships of his youth, in a fashion that he could never have foreseen. A private student of Cajal’s in Barcelona who worked in the laboratory with him attested that his hand-cut sections—often between 15 and 20 microns thick—were as perfect as those cut with any machine.

In April 1888 Cajal prepared samples from the cerebellum of a three-day-old pigeon embryo. Through the microscope, he fixed his gaze on a clear, fine axon as it arced downward from its base—a soft, conical bulge on the cell body—and followed the black line, transfixed, as if he were still a boy following the course of a river. The axon curved, running alongside the layer of cells below it until it started to branch. In Cajal’s eyes, the Purkinje cell stained with the black reaction resembled the “most elegant and leafy tree.” He traced a branch from the cell’s central “pearlike” body all the way to its end, where it approached other cells, known as stellate cells, each forming a kind of “basket” shape. Though intimately related, the “pear” of one cell and the “basket” of another never touched. Cajal sensed a “new truth” arising in his mind: nerve cells ended freely. They were distinct individuals.

Layers of cells from the retina.
Layers of cells from the retina. Cajal made studies of sections of retina from different animals, noting their structural similarities. Credit: Cajal Institute, Cajal Legacy, Spanish National Research Council (CSIC), Madrid, Spain

The Tangled Jungle

Since researchers first began to study the nervous system in ancient times, they have tended to compare its structure to contemporary technologies. The ancient Egyptians saw in the exterior casing of the brain, with its fissures and convolutions, the corrugated slag left over from smelting ore. The ancient Greeks thought the brain functioned like a catapult. René Descartes believed that animal spirits flowed from the brain through hollow nerves and inflated the muscles, just as hydraulic fluid traveled through machines in the royal gardens at Saint-Germain. In the 19th century, a new era of transportation, anatomist Otto Deiters, among many others, conceived of the nervous system as a railroad, with junctions at which traffic could be routed.

In the mid-19th century the railway metaphor for the nervous system gave way to another transformative technological advance: the telegraph. The German biophysical school, headed by Hermann von Helmholtz and Emil du Bois-Reymond, led the charge. “The wonder of our time, electrical telegraphy, was long ago modeled in the animal,” du Bois-Reymond said in an 1851 speech. He argued that the similarity between the nervous system and the electrical telegraph ran far deeper. “It is more than similarity,” he wrote. “It is a kinship between the two, an agreement not merely of the effects, but also perhaps of the causes.” In turn, engineers who designed telegraph networks, such as Samuel Morse and Werner von Siemens, looked to the biological nervous system as a model of centralization and organization. With people traveling across countries for the first time and communicating with one another across the world, interconnectedness became a social ideal. When Germany finally unified in 1871, its telegraph network, centered in Berlin and reaching all its territories, became both a symbol and an instrument of imperial power. Around that time, perhaps influenced by the predominant metaphor, German anatomist Joseph von Gerlach looked at nervous tissue through his microscope and saw the tangle of fibers—a reticulum.

Cajal, who grew up in the preindustrial countryside, saw in the nervous system the natural images of his childhood. “Is there in our parks any tree more elegant and leafy than the Purkinje corpuscle of the cerebellum or the psychic cell, in other words, the famous cerebral pyramid?” he asked. He observed branchlets of axons “in the manner of moss or brambles on a wall,” oftentimes supported by “a short, delicate stem like a flower”; a year later he settled on the term “mossy fibers.” These fibers, he found, end in “rosettes” that approach the dendrites of other cells but, again, do not touch them. There are “nest endings” and “climbing fibers,” which cling “like ivy or vines to the trunk of a tree.”

Above all, the cells seemed to connect like “a forest of outstretched trees.” Gray matter was an “orchard”; pyramidal cells were packed into an “inextricable grove.” Cajal hit on the embryological method for studying the nervous system, he said, while reflecting on the difference in complexity between the “full-grown forest” and the “young wood.” The cerebral cortex, impenetrable and wild, was a “terrifying jungle,” as intimidating as the one in Cuba, where he had fought in the Ten Years’ War. By force of will, Cajal believed, human beings can transform “the tangled jungle of nerve cells” into “an orderly and delightful garden.” Cajal always feared that the backwardness of his environment had stunted his intellectual growth. “I regret that I did not first see the light in a great city,” he wrote in his autobiography. But the undeveloped landscape of his childhood became the rich ground that nourished an understanding that was distinct from that of his contemporaries.

Although he evoked the telegraph from time to time, in an address written by him and read in his absence at the 1894 International Medical Congress in Rome, Cajal fundamentally rejected the metaphor. His opposition was rooted in both his anatomical findings and his observations of his own mind. “A continuous preestablished net—like the lattice of telegraphic wires in which no new stations or new lines can be created—somehow rigid, immutable, incapable of being modified,” he said, “goes against the concept that we all hold of the organ of thought: that within certain limits, it is malleable and capable of being perfected by means of well-directed mental gymnastics.” He knew, in other words, that he could change his own mind. That was why he could not tolerate the reticulum, whose structure was fixed. The nervous system must have the capacity to change, and that capacity, he argued, is crucial to an organism’s survival. Cajal relied on a variety of terms to express this concept: “dynamism,” “force of internal differentiation,” “adaptation [of neurons] to the conditions of the environment”—and, most consequentially, “plasticity.”

Cajal was not the first to use the term “plasticity,” although his Rome address, delivered before a broad international audience, was probably responsible for its popularization. The concept remains one of Cajal’s most enduring contributions to science, inspired by his unique and unconventional worldview.