An Interview with Professor Manuel Varela: Santiago Ramón y Cajal – Mapping the Structure of the Nervous system

Jun 29, 2019 by

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Santiago Ramón y Cajal

Michael F. Shaughnessy –

1) Professor Varela – a name that is almost synonymous with the nervous system is a Spaniard- Santiago Ramón y Cajal – where and when was he born and when did he go to school?

Prof. Shaughnessy, I think you will greatly appreciate the life and science of the very famous Santiago Felipe Ramón y Cajal, who is considered by many a biomedical neuroscientist as one of the founding fathers of neuroscience. A great deal of literature has been written about and by Ramón y Cajal. He was a prolific writer in his time, both popularly as well as scientifically.

The famous Dr. Ramón y Cajal is well known for having discovered the neuronal structure called the synapse, the connection between neurons. He is also famous for having formulated the so-called neuron theory, the idea that the brain, the nervous tissue, is composed of discrete, separate neurons, as opposed to the inaccurate theory that the brain is system of fused cells.

Dr. Ramón y Cajal wrote in his best-selling autobiographical memoir “Recollections of my Life” that he was born on the first day of the month of May, in the year 1852, in a small Spanish town called Petilla de Aragon, which was situated in the region called Navarre, in the province of Zaragoza, near the town of Sos del Rey Católico, Spain. Dr. Ramón y Cajal attributes his later successes as a scientist directly to both of his parents.

Santiago’s father, Dr. Justo Ramón Casasús, was a country doctor and surgeon, who later became a professor of applied anatomy. Santiago’s mother was Antonia Cajal, who is described rather fondly by her grateful son. Dr. Ramón y Cajal also wrote that according to her siblings, his mother in her younger days was a beautiful, vibrant, and caring young woman who later as a mother became devoted to her son. He described how she fretted over his safety as he went on his many outdoor hiking excursions. He described his father as possessing an astonishing proclivity for memory recollection, a strong work ethic, a firm believer in perseverance and, from a positive standpoint, ambition. He conveyed that his father could recite entire written works about pathology on command. He also recalled his father having to overcome a profound array of adversity in order to acquire his dream of becoming a surgeon.

Dr. Ramón y Cajal’s childhood education started in a small town called Valpalmas. However, his father homeschooled him on various subjects, such as reading, grammar, French, mathematics, geography and physics. Even while away in Madrid at medical school, his father managed to provide instruction for young Santiago by correspondence. He recounted one terrible day when his elementary school at Valpalmas had been struck by lightning, killing the parish priest, who had been struck directly, and injuring the school mistress. Another event recounted by young Ramón y Cajal was a lunar eclipse of the sun, accurately predicted to occur in 1860. The event transformed young Santiago because it provided an everlasting trust in science which he learned was amazing enough to predict such astronomical phenomena. I think many young beginning scientists share a similar sort of wonderment with the natural world.

At the age of 10, Ramón y Cajal was sent to a boarding school, a college for wayward children and run by Esculapian friars in Jaca, Spain. In 1864, arrangements were made for 12-year old Ramón y Cajal to transfer to another school, this one at Huesca. It was later reported by Ramón y Cajal that his grades at both institutions, while passing in all subjects, were still less than stellar. Thus, in order to focus his idle time on more positive aspects, his father arranged for Ramón y Cajal to begin an apprenticeship under the auspices of a barber, during the third session of his bachelor’s degree program while in secondary school at Huesca. Acquiring failing grades the following year, in 1866, Ramón y Cajal’s father then arranged for entry into an apprenticeship as a shoemaker.

Another intervention by his father at hand, it was decided that, in 1868, young Ramón y Cajal would now take up the subject of osteology, the study of bones. The topic intrigued him, especially when accompanied by midnight excursions to deserted cemeteries in order to acquire the requisite anatomical specimens!

Invoking the “learn-by-doing” method of education, young Ramón y Cajal developed an acumen for anatomical knowledge. Further, he applied his expertise with drawing to conduct his studies. Prior to this, Ramón y Cajal’s zeal for drawing had been a point of conflict between himself and his father. Instead, it was now a point of connection between the father and son collaborators.

Successfully completing the requirements for his bachelor’s degree Ramón y Cajal then enrolled in preparatory school for an additional year, taking courses in natural history, physics, and chemistry, before entry into medical school. It is at this point that the 17-year old Ramón y Cajal became a serious student and successfully completed the necessary prep courses for the study of medicine.

In 1870, he enrolled in medical school at the University of Zaragoza. He devoted himself to the classical study of anatomy, performing dissections on human cadavers guided by open books and making careful drawings during the course of study. During the latter part of his second year he had generated a large anatomy portfolio and became a dissection assistant, which took a great deal of his time. Regarding this, Ramón y Cajal recounted an anecdote.

Apparently, he had been publically chastised for his lack of attendance in a course on obstetrics, taught by Prof. Ferrer, who was put out by Ramón y Cajal’s absences during the lectures. Ramón y Cajal replied that his dissection work had precluded any pleasure of prof. Ferrer lectures, but that he (Ramón y Cajal) was, nevertheless, quite well versed in the course material. Calling his bluff, Prof. Ferrer made Ramón y Cajal actually go to the board in front of the class during the lecture in order to provide for all in attendance the origins of the fetal membranes. As requested, Ramón y Cajal proceeded to do exactly that, clearly drawing on the board every membrane of the blastoderm, complete with their individual stages, umbilical vessels and the allantois, etc., and accurately including the arrows with their physiological explanations, within the diagram. With Ramón y Cajal’s acumen of the topic publically demonstrated for all to see, Prof. Ferrer and the students were astounded. After the incident, Prof. Ferrer had been converted to the ingeniousness of Ramón y Cajal and gleefully excused all future attendance requirements for the duration of the course.

Ramón y Cajal confesses in his memoirs that he had been supremely luck that day. It had been the only topic he had been well-versed in because it had also been covered in during the course of his dissections. He further writes that had prof. Ferrer asked him about any other topic whatsoever from the obstetrics course, the good professor would have discovered his (Ramón y Cajal’s) complete ignorance of the entire remainder of the course material.

Nevertheless, Ramón y Cajal flourished while in medical school, and he took his medical degree in June of 1873, obtaining the title of licensure in medicine, earning honors in the field of anatomy.

2) Apparently, in his youth, Ramón y Cajal was somewhat of a rapscallion. Any interesting early stories?

A self-proclaimed rapscallion, Dr. Santiago Ramón y Cajal wrote in his famous memoirs that when he was young his parents and teachers, with varying degrees of success, had to have an unprecedented amount of patience with him.

At the age of 10 year in boarding school at Jaca, he described bullying by students and dreadful mistreatment by teachers involving beatings, isolation, humiliation, and starvation as various modes of punishment. He further conveyed that school curricula at Jaca was taught by rote memorization. According to Ramón y Cajal, neither the draconian punishments nor the teaching methods produced their respective desired effects upon him at Jaca. He found several ways to escape confinement in order to find food at his uncle’s nearby house, and he figured out how to return to his routine confinement without detection, for a fairly large number of days. Eventually, his scheme was discovered, and talk of permanent disenrollment for young Ramón y Cajal was bandied about, until his father intervened with a letter of reply, imploring the authorities to relax the harshness of their treatment towards his son.

Not surprisingly, considering the interruption in educating Ramón y Cajal with the vicious cycle of behavior-punishment he failed to study effectively. In fact he writes that he had lost interest in learning the subjects. With his professors at Jaca ready to flunk him outright, his father arranged for an independent assessment of his academic performance by professors from the nearby Institute of Huesca, who had not been aware of Ramón y Cajal’s behavioral history at Jaca. Just as readily the Huesca faculty gave him passing marks after having independently graded the same work.

His transfer the next year to school at Huesca was arranged. While his teachers were significantly less draconian than their counterparts had been at Jaca, his fellow students at Huesca were, unfortunately, more harsh in their bullying. Perhaps finding solace in the surrounding beauty of Huesca and its countryside, Ramón y Cajal filled many pages of his sketch book with drawings of butterflies, trees, rocks, streams, and in particular, flowers. Ramón y Cajal reported that he had drawn every flower he could find, but had heard of rare specimens that were not a part of his sketch book portfolio. It is, thus, with his drawings of rare flowers that Ramón y Cajal recalls two memorable incidents at Huesca, both events of which dealt with attempted flower thefts.

The first incident with flower theft occurred when Ramón y Cajal and two of his classmates made a nighttime raid and scaled the wall of a garden containing a coveted specimen, the rose of Alexandria, desirable because of its colors, suitable for drawing, as well as, incidentally, for its fragrance. Almost immediately, the trio of would-be flower thieves were discovered and chased, with Ramón y Cajal eventually making good his escape. His two companions, however, were caught and, consequently, beaten rather severely by their two capturing gardeners.

The second incident transpired when Ramón y Cajal attempted a solo flower heist in another garden, this time in that of a railway station, which harbored another fine flower specimen, tea roses, suitable for drawing because of its shape. This time the raid was made in broad daylight, and having scaled the fence, Ramón y Cajal stole the exquisite flower and scaled back the same wall, where a railway official was waiting. As what occurred with the first attempted flower heist, another chase ensued. Ramón y Cajal lost his chaser but fell in a quagmire of slimy mud while attempting to jump a ditch. Several witnesses who became sympathetic to the hapless young Ramón y Cajal stuck in the mud pulled him out, and, being clothes-washers, proceeded to wash his slimy clothes while he huddled incognito behind a nearby willow tree. It is at this point that the railway chaser finally caught up with the alleged flower thief. With the spectacle of Ramón y Cajal dirty and half-clothed, the official could only burst out laughing, choosing not to pursue the matter, if not also concerned with sliming his own clean uniform. Ramón y Cajal related that his foul-smelling, muddy, and slimy state proved to be an invincible suit of armor against further prosecution.

The next year of school, back at Huesca, this time accompanied by his younger brother, Pedro, the Ramón y Cajal brothers undertook rock throwing with the aid slingshot devices and became proficient, if not accurate, in their aiming. One incident in particular was conveyed in his memoirs regarding a stone-hurtling battle with another group of kids in which police were caught in the crossfire and injured. The story is told that the ringleaders, Ramón y Cajal among them, were hidden for a few days inside the home of a schoolmaster, who had had a prior grudge with the police and chose, thus, not to aid them.

Another rock throwing battle that same year involved a beating of young Ramón y Cajal by another victim caught in the crossfire, this time by a mountaineer who had been herding a train of mules. According to Ramón y Cajal the mountaineer incorrectly attributed a stray stone striking him directly to the visible young boy. Protesting his innocence while the purported real wrongdoers were hiding from view, the disbelieving mountaineer gave young Ramón y Cajal a sound thrashing and then went on his way. Vowing revenge for receiving an unjust punishment, the young Ramón y Cajal shadowed the mountaineer, and when conditions were ripe, delivered a fresh barrage of stones upon him. A complaint that was consequently filed with the police led nowhere, as the identity of Ramón y Cajal was unknown.

Nevertheless, many the local villagers were actually very well aware of Ramón y Cajal and of his stone slinging reputation. School girls his age were aware, too, especially of one girl in particular named Silvería Fañanás García, all of whom would flee for fear of his accurate stone slinging. Ramón y Cajal would recount how this same girl would later marry him, in 1879, having three sons and four daughters together.

3) Apparently one of his major contributions was his study of the structure of the cortex of the brain. How did he become involved in this? 

Dr. Ramón y Cajal was already a full professor at the University of Valencia, having established himself already in the scientific world, dealing with the field of histology, when in 1887, he paid an historic visit to Dr. Luis Simarro, a friend and colleague. Dr. Simarro was himself well established as a noted neurologist and psychiatrist. He was the first investigator to introduce the new silver chromate staining method of Golgi.

Dr. Camillo Golgi was a prominent investigator and professor of histology who was housed at the University of Pavia, where he developed the famous staining technique of nervous system tissue, in1873. Dr. Golgi would share the Nobel with Dr. Ramón y Cajal, in Medicine or Physiology, in 1906.

Dr. Simarro had been using the technique to study brain tissue. During that fateful visit in 1887, when Dr. Simarro showed his Golgi-inspired slides to Dr. Ramón y Cajal, he was immediately impressed with the slides he saw.

Upon returning to his own laboratory back at the University of Valencia, Dr. Dr. Ramón y Cajal immediately invoked the Golgi staining method and instructed his laboratory personnel to do the same. Thus, Dr. Ramón y Cajal’s laboratory began a systematic study of the cerebellum, the cerebrum, the spinal cord, the olfactory bulb, and the retina, among other tissues, of young animals and of embryos. It is at this point where Dr. Ramón y Cajal made a tremendously important discovery.

Using the staining method of Golgi, Dr. Ramón y Cajal found that nervous tissue consisted of individual, discrete, elements that may be in physical contact with one another but were nonetheless separate entities. He further found that long nerve cells had ends, further supporting the notion that nerve cells were distinctive individuals.

Importantly, Dr. Ramón y Cajal had discovered that nervous system cells were not fused with each other, which had been an incorrect notion believed by Dr. Golgi and by virtually all other neuroscientists at the time.

Based on his Golgi staining observations, Dr. Ramón y Cajal went on to postulate the neuron theory, which stated that the brain consisted of individual neurons, and not fused cells. In a sense, Dr. Ramón y Cajal had discovered the neuron, the individual nerve cell. Thus, Dr. Ramón y Cajal established the neuron as a fundamental unit of the brain.

4) Histology seems to have been another area of interest for this Nobel Prize winner- what exactly do scientists mean by this and what were his contributions?

The field of histology has to do with the study of tissues that encompass living beings. In order to visualize cells of living tissue in the microscope the specimen must often be stained with colorful chemicals in order to do so. Such histological work frequently entails acquiring tissue samples from organisms, carving the tissue samples into very thin slices, fixing or embedding the tissue slices onto microscope slides, staining the fixed tissue slices with various chemicals, and using various modes of microscopy to visualize the cells of the tissues.

In modern times, the sophistication involved with histology is incredible, involving the observation of the various cellular activities in tissue that’s still alive or in observing various cellular components as they go about their life-giving activities. Medical histology is an important field devoted to the study of pathology, such as is seen in cancer or other medical diseases.

Dr. Ramón y Cajal can be considered as one of the founding fathers of neuroscience. This is because his main contributions in this realm had to do with his histological studies regarding the neuroanatomy of central nervous system (CNS), which in turn consists of the brain and spinal cord. The CNS relays electrical sensory signals between itself and the peripheral nervous system (PNS) and the body’s muscular system. The CNS receives these external sensory stimuli and interprets them in order to make decisions and instruct the neuromuscular system to conduct behavioral responses.

The CNS represents one of the most complicated biological systems ever known. Although the neuroscientists in modern times regularly make great strides on a routine basis, they nevertheless have much work remaining to do with respect to how the CNS functions at a fundamental level.

5) His artistic talents bode him well – in terms of his drawings. What has he contributed? Professor Varela, in an attempt to get high school students and even college students to delve more deeply into the lives of these famous scientists, I have listed a few YouTube videos- I hope they meet with your approval!

When he was young Dr. Ramón y Cajal had been an aspiring artist, drawing as many subjects as he could, even getting himself into quite serious trouble in order to do so, not only with his father, but also with the authorities, in some cases. As a drawer, he clearly had a burgeoning talent. His interest in drawing as a career was a point of contention between young Santiago and his father. He experienced telling adventures attempting to steal rare flowers in order to draw them for his portfolio. At the point of exasperation the elder Dr. Ramón y Cajal introduced his son to the macabre study of human anatomy, a new interest which young Ramón y Cajal could apply his drawing talent to and of which he took to heart. The new intellectual pursuit changed his life.

As an independent investigator, Dr. Ramón y Cajal produced amazing drawings of neuroanatomical tissues, clearly drawing neuronal branches emerging from the spinal cords of laboratory animals. The artistic and scientific output of drawings by Dr. Ramón y Cajal was legendary, working every day and night, foregoing vacations, etc., in order to continue his work.

The voluminous work of Dr. Ramón y Cajal is inspiring. As your question regarding the YouTube videos attests, young people in modern times have (re)discovered his awe-inspiring work. I think this is a warmly welcomed opportunity for aspiring young scientific investigators. It is especially relevant given that while so much is known regarding the brain and spinal cord, that a tremendous amount of its physiological, cellular, biochemical and molecular knowledge of its basic function is still largely unknown and even unexplored.

Dr. Ramón y Cajal’s drawings also make for great art, and a great deal of microscopic-based images in the scientific realm can certainly be envisaged as artistic. I think this is one of main points to be made regarding Dr. Ramón y Cajal and the YouTube videos that you identified. On many occasions, artists trained as such can be called upon to construct visual graphics depicting biological structures and their cellular mechanisms. Artists are needed to help scientists convey the mechanistic details of various physiological processes, during public presentations or in their publications in the literature. While it is unclear to what extent YouTube as a venue for young people will continue to be an important medium as the current generations continue to age, it is clear that there is a tremendous amount of room for art and science to become linked together. Regarding this linkage, like many great scientists, Dr. Ramón y Cajal was many generations ahead of his time.

6) As I understand he won the Nobel Prize- what was this for?

In short, Dr. Ramón y Cajal earned the Nobel Prize, in 1906, in the category of Medicine or Physiology. He shared the prize with Dr. Camillo Golgi, who had invented a method for staining tissues, using a silver chromate chemical to do so. Dr. Ramón y Cajal used this Golgi technique to study more closely CNS cells and tissue. He discovered that the CNS was composed of separate nerve cells, now called neurons. The implications of the so-called neuron theory were profound. It immediately suggested that the brain and spinal cord were made up seemingly of billions of separate cells. Due to Dr. Ramón y Cajal’s work it now became known that the CNS is an extremely complicated organ from an anatomical perspective. Furthermore, this complicated structural nature of the nervous system, in turn, indicated that there is an extremely complicated functional nature with correspondingly complex sets of cellular and molecular mechanisms associated with it. The profound ramifications of this structural-functional and mechanistic insights would forever change the way neuroscientists would view the nervous system.

Once the concept of the individual neuron had been postulated by Dr. Ramón y Cajal and had become accepted (albeit slowly), then further insightful advances in neuroscience became possible. The study of nerve function was now a possibility. Investigators could now research how nerves work, how signals could be generated, transmitted and received by and between neurons. Due to the pioneering work of Dr. Ramón y Cajal many functional aspects of the brain and spinal cord fell into place. The electrical signals between neurons, called action potentials, became a focal point of study by the neuroscientists. The field of neuroscience exploded. Today, many thousands of scientists have specialized in the field.

7) Can you summarize his contributions to the field of medicine?

In addition to determining the Nobel-winning notion that nerve cells, neurons, are discrete entities and not fused into a giant neuro-filament bundle, he also determined that neurons were connected to each other by forming synapses. That is, one nerve cell consisting of its cell body called a soma and an extended axon structure where its end, called a pre-synaptic terminal will connect to the next (separate) neuron by forming a synapse with the so-called post-synaptic end of that second neuron. Further, Dr. Ramón y Cajal postulated that these pre- and post-synaptic neurons weren’t actually physically connected. Instead, based on his investigative studies in his laboratory, he theorized that these synapses, which he called “connexions” consisted of spaces where these connected nerves weren’t actually touching each other with their respective membranes. He found these connexions throughout the brain and spinal cord and even in peripheral nerves. He showed these various connexions as occurring in so-called Purkinje nerve fibers, which serves inhibitory functions in certain cases.

Later studies of these so-called connexions showed that pre-synaptic nerve terminals would release packets of neurotransmitters, such as small molecules like acetylcholine, or norepinephrine, which would move across the space of the synapse to reach the post-synaptic end of the associated neuron to continue the electrical impulses across the pathway of a particular neuronal system. In some cases, the electrical impulse was excitatory, causing a certain function to occur, or inhibitory, such as seen in Purkinje cells, thus, causing the inactivation of a function. Other studies showed neuromuscular junctions in which a certain type of neuron, called collaterals or reflexomotors by Dr. Ramón y Cajal, would innervate a muscle to cause it to contract or perhaps relax its contraction.

In terms of embryonic development of the brain, Dr. Ramón y Cajal found growing nerve ends, called axonal growth cones. These growth cones had endpoints to them, ends of nerves, which he interpreted as meaning that nerve cells were contiguous and not fused, i.e., not continuous, with each other. In modern times, the growth of nerve endings during brain development is an extensively studied field in neuroscience. He had further postulated that growth cones were guided by gradients of chemicals, showing a behavior called chemotaxis. This area is of particular importance as knowledge of its growth mechanism might pave the way for reconnecting severed spinal cords after traumatic accidents occur in which patients are paralyzed. Severed neurons in the CNS do not reconnect, and knowledge of axonal growth cone making connections between neurons during development is a promising avenue.

Dr. Ramón y Cajal also studied, in his words, the “less important sympathetic system of the intestines.” Later investigators, however, were to find that his studies into the topic were of great importance as it helped explain how the gastrointestinal tract conducts its contractions as regulated by the function of smooth muscle cells. Dr. Ramón y Cajal reported that he studied new types of cells in this arena, and as a tribute to him, one of these cell types has been named interstitial cells of Cajal, each in turn having different sub-categories, such as intramuscular interstitial cells of Cajal, or myenteric interstitial cells of Cajal.

8) What have I neglected to ask?

For aspiring scientists Dr. Ramón y Cajal wrote a popular book, called “Advice for a Young Investigator.” The book is a frank treatise on pragmatic aspects for young scientists. His book is filled with plenty of practical advice on many aspects of scientific research. For example, the book includes instructions on how to write scientific papers or how to be an effective teacher. When he had written also in his personal memoirs about his early education he named not only his teachers’ various mistakes, he named his teachers.

Apparently, in 2005, an asteroid or minor planet, 1.4 km in size, was named after this great scientist: “Ramonycajal asteroid number 117413,” and its orbit has been definitively calculated. I’m not sure if asteroid Ramonycajal 117413 is actually slated to interact with or even come close in any way near to the Earth, but it is most certainly known that Dr. Ramón y Cajal has made a huge impact in the knowledge of our brains.

Dr. Ramón y Cajal’s color drawings have been exhibited in art shows and showcased in museums. His work has been inspirational to artists worldwide. As your YouTube inquiry above indicates, his work will no doubt continue to make influential contributions to generations of artists and scientists alike and to be a positive inspiration for anyone who learns about him.

Dr. Ramón y Cajal passed away in Madrid, Spain, on the 17th day of October, in 1934, at 82 years of age.

1) https://www.youtube.com/watch?v=pBd7AJk1drY

2) https://www.youtube.com/watch?v=x7k6r7AtH3Q

3) https://www.youtube.com/watch?v=72IPPIt5iMw

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