Santiago Ramón y Cajal
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Author: Mr. Abdellatif Nemri, Department of biological sciences, University of Montreal, Canada
Santiago Ramón y Cajal (May 1, 1852 – October 17, 1934) was a Spanish physician and scientist who is considered the founder of modern neurobiology. His masterful use of the staining technique invented by Camillo Golgi, an Italian physician and scientist from the University of Pavia, allowed him to be the first to report with precision the fine anatomy of the nervous system. His work was central in the elaboration of the neuron doctrine: Cajal demonstrated that the nervous system was made up of individual cells connected to each other by small contact zones (synapses, term coined by Sherrington). The 3 distinct anatomical structures described by Deiters, the cell body, the axon and the dendritic arborization (Fig. 2) were thus all part of an individual nerve cell, a conclusion that definitively placed the nervous system within the framework of the cell theory. He also proposed that neurons (the term was coined by Waldeyer to reflect the conceptual advance) were functionally polarized, that is, electrical impulses propagate from dendrites to the cell body to the axon. Part of Cajal's genius was to correctly infer function from observing static images of the nervous tissue on his microscope.
In addition, Cajal discovered the dendritic spines, micron-size structures specialized in cell-to-cell communication in which post-synaptic elements are found. He also described the axonal growth, and proposed that axonal guidance was based on chemical gradients (chemotaxis). Finally, Cajal made contributions to research on color photography, hygiene and on several diseases including cancer and cholera.
Cajal shared the Nobel Prize in Physiology or Medicine in 1906 with Golgi in recognition of their work on the structure of the nervous system.
Early years
Santiago Ramón y Cajal was born in May 1952 in Petilla de Aragón, northeast Spain, where his father was the village surgeon. When Cajal was 6 years old, his father, through sacrifice and determination, obtained the Doctorate of Medicine while supporting his family. Adolescent, Cajal’s inclination was for the arts, especially drawing. His father, however, decided that his son would be a doctor and could always explore the arts on his leisure time after graduating. Some persuasion was necessary, and among other stratagems, our strong-minded and rebellious teenager had to be apprenticed to a barber and to a shoemaker. With a novel interest for the natural sciences, Cajal completed his preparatory year and entered the first year of Medicine. His father who was appointed Professor of Dissection at the University of Zaragoza trained his son in the art of anatomy. His artistic skills finally proved useful in the eyes of his father through anatomical drawings. Cajal received his Licentiate in Medicine in 1873 and shortly after was drafted into the army where he soon joined the Army Medical Service. He served in Cuba during the second insurrection against Spanish rule, and contracted malaria during the expedition (1874-1875). Discharged for health reasons, Cajal returned to Spain. He started his academic career in the end of 1975 as a temporary assistant in the School of Anatomy at the University of Zaragoza while studying for the competitive examinations for professorships.
In 1879 Cajal married Silvería Fañanás García. They had four daughters and three sons.
Academic career
On his return from Cuba Cajal became an assistant in the School of Anatomy in the Faculty of Medicine at the University of Zaragoza (1875) while studying for his doctoral degree and the competitive examinations for professorships. Two years later he obtained the degree of Doctor of Medicine in Madrid but his first attempts at professorship were unsuccessful. It is during this period that Cajal decided to set up his own microscopy laboratory. Cajal eventually succeeded in an examination and became Director of Anatomical Museums of the Faculty of Medicine in Zaragoza (1879). Finally, in 1883 he was appointed to the chair of Anatomy at the Faculty of Medicine in Valencia. In 1887 Cajal was appointed Professor of Histology and Pathological Anatomy at Barcelona and in 1892 he was appointed to the same Chair at Madrid. In 1900-1901 he was appointed Director of the National Institute of Hygiene and Biological Investigations. Cajal continued to work productively in Madrid until his death in 1934.
Scientific contributions
Complete list of published works (with comments and references of recent translations)
"I [...] was led to a conciliatory or compromising solution, erroneous, as are almost all intermediate opinions in science." Ramón y Cajal, Recollections, 1917; p276.
This quote reflects Cajal's perception of his early work (on inflammation) and the subsequent disregard for 'authority' he was to display during his career. In the same spirit, he noted that "hypotheses come and go, but data remain" (Cajal, 1999; p86). To complete this introduction to Cajal's approach of science, let us mention his emphasis on "mastery of technique", which is "so important that [...] it may be stated that great discoveries are in the hands of the finest and most knowledgeable experts on one or more of the analytical methods". In summary, his philosophy was to master technique, focus on facts and challenge theories regardless of the standing of their proponents. A recipe for discovery and success. And controversy too.
Anatomy before Cajal
Theodor Schwann, after realizing the similarities between the animal cells he was studying and plant cells studied by his friend Matthias Schleiden, enunciated that
- "The elementary parts of all tissues are formed of cells in a analogous, though very diversified manner, so that it may be asserted, that there is one universal principle of development for the elementary parts of organisms, however different, and that this principle is the formation of cells." (Schwann, 1839)
Schwann, Schleiden and Virchow further developed these ideas into three principles: 1. All living things are composed of one or more cells. 2. Cells are the basic units of structure and function in living things. 3. New cells are produced from existing cells. The Cell Theory, as Schwann named it, became progressively accepted for all tissues except the nervous system. Technical limitations in association with the complexity of the nervous tissue made its anatomical characterization difficult. The prevalent view at that time was that the nervous system was organized in a reticular way (i.e. nerve fibers forming an anatomically connected network). Some authors (His, Forel, Nansen) argued that cell theory should apply to the nervous system as well, in light of some evidence in the neuromuscular junction and spinal cord, but their demonstration was far from definitive.
On the physiological level, it was known that electrical impulses travel along nerve fibers. The distinction between sensory and motor fibers was also relatively clear.
Cajal's early research
While he was preparing for the competitive examinations for professorships, Cajal had the opportunity to see microscopic preparations. Impressed, he decided to set up his own laboratory in an attic. His first efforts were directed towards the study of inflammation, muscle anatomy and microbiology (1880-1887).
La reazione nera and the ontogenetic method
The achromatic microscope was introduced in the 1820s, yielding results that led to the first formulations of the cell theory. However, no efficient method was available that made the components of the nervous system clearly visible. This changed when Camillo Golgi discovered a histological method to impregnate tissue that was capable of staining the entire nerve cell (Golgi, 1873). Golgi's staining technique involves the immersion of nervous tissue in a solution of potassium dichromate for several days, followed by immersion in a silver nitrate solution for 1-2 days. The nerve cells and processes become filled with a fine opaque precipitate of silver chromate that renders the neuron and neuroglia cells clearly visible against the transparent yellow/orange background.
In 1887 Santiago Ramón y Cajal, then a young anatomist, visited his colleague in Madrid, the psychiatrist Luis Simarro, who showed him some preparations made with the Golgi method. Instantly seduced and impressed by the quality of the preparations, Cajal decided to use the method in his own laboratory. He quickly became aware of the "capriciousness" of the method, and so worked on improving its reliability. He observed that double impregnation gave better results, as well as using different times for different tissues. He also noticed that the myelin sheath made neuronal processes impossible to stain, and thus he started to use preparations from younger animals (the so-called ontogenetic method), a method that was used before by His in developmental studies (His, 1886).
At that moment, Cajal had the right tools, an improved Golgi staining technique and the ontogenetic method, to attack one of the most important questions of his time, the structure of the nervous system. Results were to follow at an amazing pace, forcing Cajal to edit his own journal. In his own words, "1888, my greatest year arrived [...] my year of fortune [...]".
Nerve cells as independent entities
Cajal was like most a reticularist when he started conducting research...
The major proponent of the reticular theory was the German anatomist Josef von Gerlach. Based on observations made with his gold chloride method, he argued that the processes of contiguous nerve cells fuse to create a meshed network (Gerlach 1871). This theory was widely accepted.
Golgi, axon collaterals
--
The neuron doctrine had four tenets:
- The neuron is the structural and functional unit of the nervous system
- Neurons are individual cells, which are not anatomically continuous to other neurons
- The neuron has three parts: dendrites, soma (cell body) and axon. The axon has several terminal arborizations, which make close contact to dendrites or the soma of other neurons
- Conduction takes place in the direction from dendrites to soma, to the end arborizations of the axon (Law of Dynamic Polarization)
In proving that the Cell Theory applied to the nervous system, Cajal made the definitive argument that the Cell Theory provided an accurate description of all tissues in every living things, and thus helped establish this one pillar of modern biology along Schwann, Schleiden and Virchow.
1888 Cajal independent nerve cells
1891 Waldeyer formulates the neuron doctrine.
The Neuron Doctrine had its own merits, especially regarding the physiological characterization of neurons as information processing units
Dendritic spines and synapses
Cajal discovered characteristic structures in dendrites, which he called spines because of their appearance. http://www.cerebromente.org.br/n17/history/neurons3_i.htm
Dendritic spines are sharp thorn-like structures that appear when brain cells are stained with Golgi's method. These were probably observed by other investigators but discarded as artifacts. Cajal...
In order to prove their existence, Cajal reasoned that spines should be demonstrable with an entirely different method. He tried two commonly used variants of Ehrlich’s methylene blue, but failed to see the spines. His third attempt worked.
Concept of synapse introduced by Sherrington in 1897
Law of dynamic polarization
Axonal growth cone, chemotaxis
Degeneration and regeneration of the neurons and axons
Anatomo-pathology and cancer
Less known contributions by Cajal to the study of cancer, rabies….
Summary, timeline and the 1906 Nobel prize
Summary
As we have seen, Cajal was not the first to use the ontogenetic method or the "reazione nera", nor was he the first to propose a hypothesis about the functional polarization of the nerve cells. But he worked with almost unbelievable dedication to improve and adapt those methods to the issues he was interested in. And once the tools were mastered, he applied them relentlessly to describe the fine anatomy of almost every region of the nervous system, giving us new and penetrating insights into the structure of the brain and the spinal cord.
Textura
Timeline
| 1836 | First microscopic image of a nerve cell (Valentin) |
| 1862 | First description of the neuromuscular junction (Kühne) |
| 1873 | Introduction of silver-chromate technique as staining procedure (Golgi) |
| 1888 | Birth of the neuron doctrine: the nervous system is made up of independent cells (Cajal) |
| 1891 | The term “neuron” is coined (Waldeyer). |
| 1892 | Laws of dynamic polarization of neurons (Cajal) |
| 1897 | Concept of synapse (Sherrington) |
| 1903 | Introduction of silver nitrate as staining technique (Cajal) |
| 1904 | Textura del Sistema Nervioso del Hombre y de los Vertebrados: coming-of-age of the neuron theory (Cajal) |
The Nobel prize of 1906
Distinctions
Cajal’s considerable achievements were rewarded by learned societies, academies, and governments from all over Europe and the Americas.
Election to learned societies and academies: Cajal was elected Member of the Royal Academy of Exact, Physical and Natural Sciences of Madrid (1895); of the Royal Academy of Medicine of Madrid (1897); of the Spanish Society of Natural History (1897); Associate Member of the Academy of Medicine, Paris (1906); Member of the Royal Academy of Medicine & Surgery of Madrid (1907); Fellow of the Royal Society (1909); Foreign Member of the Swedish Academy of Sciences (1916); Member Extraordinary of the Royal Academy of Sciences of the Netherlands (1920). In addition, Cajal was Honorary or Foreign Corresponding Member to over 60 learned societies and academies of Europe and the Americas.
Honorary degrees: Doctorate of Medicine from the Universities of Cambridge (1894), Würzburg (1896), Louvain (1909), Mexico (1922) and Guatemala (1925). Doctorate of Laws from Clark University (Worcester, U.S.A., 1899). Honorary Doctorates were also granted to Cajal by the Universities of Bordeaux (1922), Paris (1924) and Strasbourg (1925).
Prizes: Among the prizes won by Cajal are the following: a Medal presented by the International Congress of Hygiene (1892), the Rubio Prize of 1000 pesetas for the publication of the book Elements of Histology, the Fauvelle Prize of 1500 francs of the Society of Biology of Paris (1896); the Moscow Prize of 5000 francs rewarding medical works which, published during the latter three years, have rendered the greatest services to science and humanity was awarded to Cajal by the International Congress of Medicine in Paris (1900).
In 1894, Cajal was invited to give the prestigious Croonian Lecture by the Royal society of London.
The Royal Academy of Sciences of Berlin awarded him the Helmholtz Gold Medal in 1905.
Finally, in 1906, Cajal shared the Nobel Prize in physiology or medicine with Camillo Golgi.
Legacy
Santiago Ramón y Cajal died in Madrid on October 18, 1934. He left all his belongings to the institute he founded in Madrid. Originally named Laboratorio de Investigaciones Biológicas, and founded in 1900 by order of King Alfonso XII on the occasion of the Moscow Prize to Cajal, the institute was renamed after him in 1932 (Instituto Cajal, Madrid). The institute - the largest neuroscience research center in Spain - hosts the collection of his works and other items, including thousands of scientific drawings and illustrations, histological preparations, books, publications, letters, photographs and microscopes in what is known today as the Cajal Museum. The house where he was born in Petilla is also a museum with some original publications and drawings by Cajal as well as photographs and objects from that period.
His most significant and far-reaching legacy is the monumental sum of his published works, with a special mention for his magnum opus, Textura del sistema nervioso del hombre y de los vertebrados, that has been compared in importance to Darwin's Origin of the Species. Cajal's impact on the scientific community of Spain was considerable and is still felt in the 21st century as illustrated by the many scholarly reviews written by Spanish neuroscientists on some aspect of Cajal's work and life.
There is a Santiago Ramón y Cajal monument in Retiro Park, Madrid. In 1977, the Ramón y Cajal university hospital was founded in Madrid. In 2007, the Universidad Politécnica de Madrid and Instituto Cajal became involved in the Blue brain project with an initiative called Cajal Blue Brain that comprises several research groups and laboratories.
The Cajal club (founded 1947) is an international organization of neuroscientists whose goals are to 1) revere Cajal, 2) provide an opportunity for neuroscientists with special interests in the structure and function of the nervous system to confraternize, and 3) contribute to the welfare of neuroanatomy and neuroanatomists.
Cajal-Retzius cells are neurons of the human embryonic marginal zone which display, as a salient feature, radial ascending processes that contact the pial surface, and a horizontal axon plexus located in the deep marginal zone (Meyer et al., 1999).
Interstitial cell of Cajal: Type of cell found in the gastrointestinal tract. It serves as a pacemaker that triggers gut contraction (Sanders & Ward 2006).
Interstitial nucleus of Cajal: Located in the midbrain reticular formation, this nucleus is involved in eye movement control.
Cajal bodies: Spherical sub-organelles found in the nucleus of proliferative cells like tumor cells, or metabolically active cells like neurons.
Petilla Interneuron Nomenclature Group (2008) proposes a standardized nomenclature of interneuron properties. This proposal arose out of a meeting devoted to this topic in Cajal's native town, Petilla de Aragón (Navarra, Spain), and is rooted in the collective work that has been performed in many laboratories (PinG consists of 39 prominent neuroscientists).
The asteroid 117413 Ramonycajal, discovered by Juan Lacruz in 2005, was named in his honour by the Minor Planet Center, the institution responsible for the designation of minor bodies in the solar system. Cajal is a tiny lunar impact crater on the northern part of the Mare Tranquilitatis.
In spanish popular culture: TV series Ramón y Cajal (imdb)
References
- De Carlos, J.A. & Borrel, J. (2007). A historical reflection of the contributions of Cajal and Golgi to the foundations of neuroscience. Brain Res Rev, 55: 8-16.
- Lopez-Munoz, F., Boya, J., Alamo, C. (2006). Neuron theory, the cornerstone of neuroscience, on the centenary of the Nobel Prize award to Santiago Ramon y Cajal. Brain Res Bull, 70: 391-405.
- Meyer G, Goffinet AM, Fairen A. (1999) What is a Cajal–Retzius cell? A reassessment of a classical cell type based on recent observations in the developing neocortex. Cereb Cortex, 9(8):765-75.
- Sanders K, Ward S (2006). Interstitial cells of Cajal: a new perspective on smooth muscle function. J Physiol 576 (Pt 3): 721–6.
- Schwann, Theodor (1839). Microscopic Investigations on the Accordance in the Structure and Growth of Plants and Animals. Berlin. (English translation by the Sydenham Society, 1847)
- The Petilla Interneuron Nomenclature Group (2008). Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat Neurosci, 9(7): 557-68.
- Waldeyer, W. (1891). Über einige neuere Forschungen im Gebiete der Anatomie des centralen Nervensystems. Deutsch Med Wochenschr, 17, 1213–1218, 1244–1246; 1267–1269; 1331–1332; 1352–1356.
Further reading
- Cajal's autobiography: Recollections of my life, MIT Press, 1989. Translation by E. Horne Craigie with Juan Cano.
- Shepherd, G.M. Foundations of the Neuron Doctrine. Oxford University Press, 1991.
External links
- Cajal Institute (Madrid) Largest neuroscience research center in Spain.
- Nobelprize.org: Cajal's Nobel lecture: The Structure and Connexions of Neurons
- Nobelprize.org: biography and life and discoveries
- Nobelprize.org: About the shared Nobel prize between Cajal and Golgi
- Wikipedia: Neuron doctrine, Heinrich Wilhelm Waldeyer, Neuron
See also
Brain, Camillo Golgi, Neuron, Neuron doctrine, Neuroscience,
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