SOURCE: "Summation and Appraisal—By Way of Epilogue," in Explorer of The Human Brain: The Life of Santiago Ramón y Cajal (1852-1934), Henry Schuman, 1949, pp. 263-75.

[In the following excerpt, Cannon surveys Ramón y Cajal's scientific and literary work, and describes his character and influence.]

What then remains? Courage, and patience, and simplicity, and kindness, and, last of all, ideas remain; these are the things to lay hold of and live with.

—A. C. BENSON

NEURONISM AND ITS IMPLICATIONS

That a man situated as Cajal was in a country where science was neglected and even despised should be the one to furnish modern neurology with so many new facts and such well-substantiated theories is the last thing one might expect. Study of the minute anatomy of the nervous system would seem to call for the finest of equipment and a delicacy of technique that is difficult to achieve even under the direction of a skillful teacher. Yet when Cajal began his work he had only the most meager equipment and nothing but foreign textbooks to guide him. The patience needed for the meticulous detail of preparing sections for microscopic study is enormous. Only those who have attempted many times to follow such directions as textbooks offer, and have failed again and again because they neglected some seemingly trifling matter, can fully realize how trying such work can be. In the early years, too, Cajal had to work without the stimulus and reward that come from original research and discovery. For he was occupied at first only in repeating the observations others had made. He worked for five years in obscurity without contact with the leaders in histology outside Spain and without the incentive of emulation. Yet his findings were to revolutionize neurology.

The core of Cajal's discoveries was his neuron doctrine. He pointed out to a skeptical world the fact that the basic unit of the nervous system is not the nerve fiber, as had been thought up to that time, but the nerve cell. Drs. Augusto and Jaime Pi-Suñer give a striking interpretation of the significance of this concept, which in the 'eighties was pure heresy:

The thesis that "everything communicates with everything" could bear some appearance of truth and clearness, but would have made absolutely impossible the actual psychological notions about the nervous system with the concepts of facilitation, summation, and inhibition, which at that time were unknown terms. It particularly disagrees with the pregnant theory of the final common path. The valuable help lent by the learned Spaniard in destroying the reticular theory and laying the foundations for the theory of the final common path may well be considered his best contribution to the knowledge of physiology of the central nervous system. [Journal of Nervous and Mental Disease 84:525, 1936.]

In the years to follow, the neuron doctrine became an established part of nervous anatomy. It was soon substantiated by new evidence gained from studies of diseases of the nervous system and it at once proved useful in giving medical men a deeper understanding than they had formerly had of the physical basis of many types of nervous and mental disorders. Cajal's discoveries constitute the basis of our present-day knowledge of the development and structure of the neuron; of the way in which the nervous impulse is transmitted from sense organ to central nervous system and thence to muscle or gland; of the processes of degeneration and regeneration of nerve fibers; and of the localization of the various sensory and motor areas of the brain.

Carrying his studies of the nerve cells and of the neuroglia of the brain still further, Cajal offered a reasonable hypothesis to explain the phenomenon of sleep and of the loss of consciousness under certain pathological conditions of the body. A series of neurons connect the brain, the physical basis of consciousness, with the external surfaces of the body which receive the stimuli from the outside world. On occasion, these neurons contract—that is, the nerve cells draw in their prolongations, as living protoplasm always does when it is irritated. If the contraction is sufficient to cause the neurons to separate from one another, all consciousness of sensation is lost because the paths of conduction are broken. This occurs naturally in sleep. But the same contraction may result from a blow on the head severe enough to make one lose consciousness, or it may be due to toxic poisons within the body that affect the neurons. The same contraction occurs, too, when a person is fully anesthetized. Sometimes, however, only the more delicate neurons are affected—those through which intellectual processes are accomplished and sensations of pain are felt. These higher neurons are more sensitive to the action of narcotic drugs than are the lower neurons governing the vegetative functions of the body. The higher neurons continue in a state of contraction as long as the influence of the drug lasts, and therefore, by varying the amount given, the depth and length of the anesthesia can be regulated. Similarly, when a person is in a hysterical state, though the paths of conduction may not be interrupted, the neurons may make unusual and unintended connections. Such improper connection may leave parts of the body without sensation or may lead to abnormal sensations.

Cajal's neuron doctrine also helps to explain the mechanism of memory. Recalling one thing may block the pathway to another. It is a common experience for one to forget what he intended to say when his recollection of it is temporarily blocked by another thought that crossed his mind at something he may have just seen or heard. Various sorts of injuries to the nervous system may affect the memory of certain parts of one's past life, as may also the subconscious suppression of painful memories—a phenomenon that lies at the root of the modern treatment of certain nervous and mental disorders through psycho-analysis. Observation of disordered mental states such as illusions and hallucinations have confirmed Cajal's theory as to the contracting and expanding of the branchings of the nerve cells, the blocking of the normal connections, and the occurrence of accidental, unanticipated interconnections that produce abnormal nervous response.

Cajal himself did not fully work out all these hypotheses, but he did hint at many of them. The important thing is that he established the essential anatomical facts underlying them and that his discoveries led other men to do research along these lines—research that proved more fruitful because of the new direction his work had given it.

In evaluating his contributions to human knowledge, one must take into account the diverse fields his discoveries touched and illumined. The new data on the intimate structure of the nervous system that he brought to light are admittedly of greatest interest to the histologist, the physiologist, the pathologist, and the surgeon. But they are of immense concern also to psychologists and psychiatrists, since detailed information about the structure of the nervous system, coupled with observation of its normal and abnormal functioning in health and disease, gives useful suggestions as to ways of coping with nervous and mental disorders. To a considerable degree it was Cajal's work that made modern neurosurgery and neuropsychiatry possible. How important a contribution this was is at once apparent when one considers the vastness of the problem of nervous and mental disorders in the world today. In the United States alone probably more than three million persons are victims of severe nervous or mental disease. It is difficult to determine just how many more are afflicted with the milder form of disorder known as neurosis, but unquestionably it too causes an immense amount of incapacity and misery, representing an enormous economic burden and tragic human waste. Cajal's discoveries have a direct bearing on education because they offer telling hints as to effective methods of teaching and of learning. He has given a valid explanation of how we learn to perform certain acts more easily and quickly through practice and how the faculty of memory can be developed through training. The nerve cells involved in such learning do not increase in number, but the connections between them become more perfect through use. The pathways of interconnection become stronger and the cells may even acquire new branchings by which more diverse connections with other cells are made possible.

Cajal's law of dynamic polarization affirms that the cell body with its dendrites directs the impulse along a oneway course—toward the axon. The question at once suggests itself: What happens when several impulses coming from the dendrites compete with one another for right of way? In such cases, Cajal said, it is the cell body that determines which impulse shall have priority. He suspected that there might be a chemical action of some sort in this selectivity, but did not develop the idea. Years later, Sir Charles Sherrington and his colleagues of the Cambridge School of Physiologists offered a theory of chemical mediation of the nervous impulse.¹ The English physiologists also introduced the modern concept of the synapse, the contact point between the axon of one neuron and the dendrites of the next one in the chain of connection. At the synapse a resistance is set up to the passage of the impulse from one cell to the next. The resistance may vary in degree from an almost imperceptible slowing down to actual blocking (inhibition). However great the resistance may be, the course of the impulse is irreversible; it must go on toward its destination or drain away.

Cajal's theory of nervous conduction has been validated again and again, notably by Cannon's² animal experiments on the reflex arc and Pavlov's famous demonstration that a dog to whom food is given at the same time a bell is rung will learn to salivate when a bell is rung even though no food is offered—through the operation of the now well-known conditioned reflex. These concepts lie at the basis of all modern educational and psychological thought, explaining the mechanisms of animal instinct and habit formation as well as of all human learning. They help to explain, too, the phenomenon of integration, the "oneness" of our consciousness in spite of the fact that it is constantly being bombarded by infinitely diverse stimuli from both inside and outside the body.

THE PERFECTING OF NEW STAINING METHODS

Through the use of Golgi's discarded silver stain—perfected in 1888, so early in his career—Cajal was able actually to see more of the nervous system than had the anatomists before him. It was because of this happy discovery in technique and his idea of applying it to very young or unborn animals whose nerve fibers had not yet myelinated that he was able to add so much in a field that had already been thoroughly worked over by the greatest anatomists of the century—a field so much worked over, in fact, that it seemed almost naïve to expect to find anything more.

Having made a startling beginning with Golgi's stain, Cajal proceeded to perfect Ehrlich's methylene blue and finally to devise new methods that were wholly his own. In 1903 he developed his reduced silver-nitrate stain; in 1913, the gold sublimate, by which the neurofibrils, hitherto elusive to microscopic study, could be clearly visualized and traced. This stain soon yielded valuable data on the structure of the astrocytes, star-shaped cells in the tissue of what Cajal called the "third element" of the nervous system. It was one of his followers, Pío del Rio Hortega, working with various adaptations of Bielschowsky's³ method (staining axons and neurofibrils with ammoniacal silver), who invented the silver-carbonate stain and through its use obtained such clear pictures of the "third element" that he was able to make exhaustive studies of the microglia and Oligodendroglia of which it is, in part, composed.⁴ These researches threw new light on the gliomas, tumors of the glia, or supportive cells of the nervous system, and have been of inestimable help to neurosurgeons in their understanding of these growths and in their efforts to extirpate them.

Another direct medical application of Cajal's investigations—this one the outcome of his studies on nervous degeneration and regeneration and his procedures for producing expertly stained sections—is the modern technique by which the physician is able to aid the regeneration of injured nerve fibers and hasten the healing of a severed nerve. Instead of letting Nature work alone—slowly and often inefficiently—to repair traumatized axons, the doctor now puts them in direct contact with connective tissue or with the cut end of the nerve, if that is possible.

CAJAL'S WRITINGS

Most of Cajal's scientific works were written to serve as textbooks for students and they still rank among the best and the most authoritative. His chief treatises have become classics in histology and give completely original conceptions of cell structure in every part of the nervous system. For many years after his death investigators unfamiliar with his work continued to discover facts Cajal had already unearthed in the 'nineties. The best-known of his scientific writings is his Textura del sistema nervioso (Texture of the Nervous System) (1897-1904), which was revised and amplified in the French edition of 1909. After all the years that have passed since then, this is still the most complete and accurate description ever made of the more delicate nervous structures. His great treatise on the retina completes and supplements the investigations made in this field by such pioneers as Max Schultze, and his encyclopedic work on nervous degeneration and regeneration is the most comprehensive study of the subject to date.

His books and articles—scientific and literary—approximate 286. His literary writings, such works as the Cuentos de vacaciones (Holiday Tales), Psicología de Don Quijote y el quijotismo (The Psychology of Don Quixote and Quixotism), Recuerdos de mi vida (Recollections of My Life), Regios y consejos (Rules and Counsels), Cuando yo era niño (When I Was a Child), Charlas and Chácharas de café (Conversations at the Café), Pensamientos escogidos (Selected Thoughts), La mujer (Woman), El mundo visto a los ochenta años (The World as Seen at Eighty), are of such merit that an honorary degree was given him, in company with another noted Spanish writer, Menéndez Pidal, by no less an institution than the French Sorbonne. Many of his writings have been regarded by competent critics as valuable additions to Spanish literature. Reglos y consejos illustrates his literary style at its best.

THE SPANISH SCHOOL OF HISTOLOGY

One of Cajal's most significant contributions is the school of Spanish histologists he founded and inspired through his teaching and example. To create such a school had been the ambition of his youth. And at that unpropitious time, this must have seemed a project worthy of a second Don Quixote. Even after the school had grown and prospered, he had fears—in the moods of despondency that came upon him with increasing frequency in his later years—that it would shortly cease to exist after he died. Far from it. On the first anniversary of his death, a new Laboratory of Normal and Pathological Histology was established at the University of Madrid. The enrollment of the university increased strikingly in the years to follow, with a large proportion of the students enrolled in medicine. Graduate study of scholarly caliber was made available to promising students under the direction of men who had been trained by Cajal, many of them outstanding figures in the new Spain. Nothing would have given Cajal greater satisfaction than to see how well his disciples, and their disciples, carried on his work.

Throughout all his scientific productivity and in the midst of the many bitter controversies that raged about it during his lifetime, saddening his days, he never forgot the true aim of science as he himself had once trenchantly expressed it in his Charlas de café—"to elucidate the dark mysteries and unknown forces which surround us for the benefit of our children, and to make the world more agreeable and intelligible while we ourselves are forgotten, like the seed in the furrow." He used often to say that the real problem of Spain was a problem of culture. He had once scrawled that thought on a picture of himself hanging in the university laboratory. And he had added: "If we Spaniards are to be numbered with the civilized peoples of the world, we must cultivate the desert of our land and the intellect of our people, thus salvaging through prosperity and mental vigor all those national riches that have been lost in the sea and all those talents lost in ignorance."

DON SANTIAGO THE MAN

Nature had given Cajal many gifts. He was the greatest scientist Spain had ever produced and one of the scientific leaders of the world. He was also an artist of distinction, an authority on color photography, and a precursor in the revival of art that took place in Spain before the outbreak of the Civil War. He was a witty talker, a dynamic teacher, an admirable writer. Among the fortunate faculties he possessed were his ingeniousness, his artist's deftness, and the sharp power of observation the scientist shares with the artist. All these were indispensable to successful work in such a science as histology. So too were his patience, his perseverance, his tirelessness, his urgent drive to do something of note. It is clear that his make-up combined the prime requisites for the work to which, reluctantly at first, he devoted his life.

His capacity for work and the scope of his achievement were immense. Someone of his own land summed it up wittily in the little verse:

A Castilla y Aragón, nuevo mundo dió Colón;A Castilla y Aragón, mundo interno dió Ramón.5

Van Gehuchten once summed it up succinctly too, in more serious fashion: "Cajal has given us the key with which to open up the mysterious caverns of the brain, and with it he himself has unlocked a whole vast world—the world of thinking man."

Dr. Ernesto Lugaro, while professor of psychiatry at the University of Turin, wrote what is perhaps the most apt of all the evaluations of Cajal and his work:

The case of Santiago Ramón y Cajal is certainly unique in history. In a backward environment that was indolent and almost hostile, this man succeeded, by sheer force of talent and will and by inspired, indefatigable work, in a colossal scientific achievement as harmonious as a work of art and solid enough to last for centuries. At the same time, he managed to stir up by his example and his teaching latent, unsuspected energies, creating a school in which the students in their turn were trained to become teachers of the first rank, changing the face of histology and medicine, and shaking the somnolence of the universities in his country. And that was not all. Almost without wishing it, scarcely paying any attention to politics, he exercised a tonic effect on the entire political life of his land, producing changes which, in the opinion of the world, refuted the old commonplaces derogatory to Spain and gave that nation a new faith in its own power. . . .

The work of Cajal is monumental. Without exaggeration it can be said that modern neurology owes to him above all others the enormous progress realized in the last half-century: a gigantic complex of facts and ideas from which present-day neurology derives its characteristic physiognomy. Especially in the field of the morphology of the nerves, it can truly be said that Cajal, by himself alone, has produced more than all the other neurologists together: methods, techniques of inexhaustible fruitfulness, work tools for all; numerous discoveries—even the least of which a scholar might be proud of; penetrating, synthesizing interpretations, both lucid and persuasive, that have worked like ferments on physiology and pathology. No matter what branch of his subject a neurologist chooses, he must always have Cajal's work constantly before him and must invoke his name in the exposition of any facts or ideas whatever. . . .

He has set an example of wholesome nationalism, a nationalism that is not nourished on jealousy of neighboring countries and on blind negation of foreign values but is concerned with raising the repute of one's own country through worth-while work. His was a strong and noble character without taint of self-seeking. [Revista di patologia nervosa e mentale 45:v, 1935.]

Cajal was not only admired by his colleagues and his followers—they loved him too. The very fact that he was known among them simply as "Don Santiago" tells something of their affection. Moreover, his students sensed keenly the greatness of the spiritual heritage he left them. Again and again they mention his endless kindness. They tell how ready he was with quick encouragement whenever the vicissitudes of life had made them downhearted about their own work, how ready he was with his help and protection when they needed it. "And to the greater glory of his spiritual excellence," wrote Fernando de Castro, "he always made it a point not to exert pressure on his pupils by influencing them with any ideas of his in their interpretations of the results they obtained from their own original researches."⁶

Sir Charles Sherrington in the obituary of Cajal that he wrote for the Royal Society of London pays him this warm homage:

He has come to stand in some sort as a symbol of national cultural rebirth. Despite, perhaps partly because of, his retired and simple life and his advanced years, he and his scientific devotion and prestige were taken to typify by many of his fellow countrymen what a new Spain might cherish and accomplish; he was taken as a sort of forecast of what a new Spain should stand for. In this sense he caught the national imagination. Banknotes bore his effigy; a postal issue was to distribute his likeness millionfold as a national emblem. He deprecated the proposal at the time, but after his death it was done. We may well believe that such a memento, at once national and democratic, would have touched Don Santiago's virile heart. It is a tribute which gives evidence of the position accorded him by the Spanish, a position accorded him with the sympathy and applause, indeed, of the civilized world entire. [From Obituary Notices of Fellows, 1935. By permission of Sir Charles S. Sherrington and the Royal Society of London.]

It was also on the occasion of Cajal's death that Dr. Wilder Penfield wrote of him:

Now that the end has come, his life and achievement loom large in the history of neurology. He was a many-sided genius impelled by that mysterious "whisper" that comes to God's chosen few that draws them ever onward to explore beyond the horizons of existing knowledge, without rest and with no need for recompense other than to know that they have entered the promised land of discovery. [From Archives of Neurology and Psychiatry 33:172, 1934. By permission of Dr. Wilder Penfield and the American Medical Association.]

There could be no more fitting epitaph.

NOTES

¹ Two theories compete for general acceptance today: the chemical and electrical. Perhaps both electrical and chemical elements are involved. Both theories postulate the accumulation at the synapse of an active principle—electrical or chemical—which, upon reaching a certain level, will stimulate the dendrites beyond the synapse. The delay at the contact point may be accounted for by the need to build up the required amount of electrical charge or the required concentration of chemical.

It has been observed that in the autonomic nervous system activity is accompanied by the production of chemicals—acetylcholine, sympathin, and related compounds—that stimulate muscles and glands. Acetylcholine is also found here and there in the central nervous system, particularly in those parts containing motor cells and axons.

² Walter Bradford Cannon (born 1871). Boston physiologist. Cannon's discoveries with reference to the physiological basis of emotion constitute one of the greatest contributions to psychology and psychiatry in this century. From studies of x-rays of digestive processes in cats, he found that fear and rage interfere with the normal functioning of the smooth muscles and glands. The bodily changes produced by fear and rage he found to be of a sort that temporarily allow the individual concerned to make greater effort than usual. The heart beats faster, blood pressure is raised, the adrenal glands secrete adrenalin, enabling the body to fight harder or to run away faster—in other words, giving the human machine greater power for a short period. But there are other changes, as, for example, the cessation of the activity of the stomach muscles. The body neglects its usual functions to concentrate its full energies on the emergency that produces the emotion. When such emergencies arise rarely, they do no harm to the healthy body. But in our life today emotional upheaval often becomes chronic, owing probably to the many frustrations modern life imposes, since our society seems to awaken more desire than it is able to satisfy.

³ Max Bielschowsky (1869-1940). German neuropathologist.

⁴ Important today in the diagnosis of nervous disorders are Rio Hortega's glia stain, which tints the cytoplasm of the neuroglia black, and Penfield's glia stain, which renders the Oligodendroglia clearly visible. In studying a microscopic slide for diagnostic purposes, the physician or surgeon must follow an orderly procedure and hold to a definite point of view. After finding out what stain has been used on the tissue, he must look for the special structures that stain shows well. Tissue of the cerebral cortex tinted with Cajal's stain, for instance, shows only the glia cells; tissue stained by Weigert's method shows the myelin sheaths. To obtain a more complete picture, sections treated with different appropriate stains must be studied serially.

⁵ To Castile and Aragon, Columbus gave a new world; To Castile and Aragon, Ramón gave the inner world.

⁶ Translated from the Spanish of the article on Cajal in the volume of Archivos de neurobiología dedicated to his memory: 14:833, 1934. Cajal's last scientific paper had been written for this same journal and appears in 13:217, 1933.