Tech UPTechnologySantiago Ramón y Cajal, the neuron explorer

Santiago Ramón y Cajal, the neuron explorer

It is tradition that those who receive the Nobel prize give a presentation in Stockholm. Nobel prizes began to be awarded in 1901 and, in 1906, the Physiology or Medicine prize was shared for the first time between two people: Camillo Golgi and Santiago Ramón y Cajal . In his presentation, Camillo dedicated the twenty-nine pages of his speech to criticizing the neural theory, which at that time had Santiago Ramón y Cajal as its greatest defender, who gave his own talk the next day.

« It may seem strange that, since I have always been opposed to neuronal theory — although I recognize that its starting point can be found in my own work — , I have decided to choose this question of the neuron as the subject of my paper » ( La doctrina neuronal – theory and facts by Dr. Camillo Golgi. December 11, 1906).

The origin of the Golgi-Cajal confrontation

It is impossible to understand Golgi’s anger and the importance of Cajal without going back a few decades: it is the seventies of the 19th century and the word neuron does not exist. Scientists from all over the world observe the human body under the microscope, thus establishing the bases of Histology and Cell Biology, but there is an organ that is especially elusive to this work: the brain. To see something under the microscope, you have to cut the tissue thin enough for light to pass through it and reach the researcher’s eye, that is, the cuts are so thin that they are transparent. To correct this and to be able to see something, stains are used that color specific tissue structures, whether they are cell types or formations within cells. But the very nature of brain tissue makes it especially difficult to stain: it is a soft tissue that is very difficult to cut where neurons have gigantic ramifications. They are enormous cells of which only the cell body can be stained well, but most of all its ramifications are lost, and without them it is impossible to understand how neurons work and what the basic structure of all nervous systems is. And then came Camillo Golgi with his reazione nera .

In 1873, Golgi finished developing a procedure with silver nitrate that stains whole neurons black, hence the name reazione nera or « black reaction » . Where previous methods showed small protuberances sprouting from the neuron body, or soma, it was now possible to see the full extent of neuronal arborization . This change was so revolutionary that it compensated for the many flaws in the stain, which had a reputation for being extremely complex and unstable. Subtle modifications had to be made to the staining protocols depending on each tissue and even depending on whether the reaction was used in winter or summer. It was, and still is, a difficult stain to do. But the results are spectacular and thanks to it neuroscience, with Golgi at the head, was able for the first time to aspire to understand the cellular structure of the nervous system, the structure of our thoughts, ideas and dreams.

Golgi and his “fuzzy nerve network” model

At the end of the 19th century there were two theories that attempted to explain the structure of the nervous system: the reticular theory and the neural theory . The reticular theory is a model where there is no physical space that separates some neurons from others at any time: they form a continuous network where the cell bodies act as nodes and the branches that grow from them, axons and dendrites, merge. with those of other neurons forming a continuous system through which information flows. In a short time, Golgi became the main defender of this theory, which, based on his observations, he himself qualified in a model of «diffuse nervous network», where the nervous processes were widely distributed among a large number of cells per cell. the entire network. And then Santiago Ramón y Cajal arrived.

In 1887, Cajal’s business trip to Madrid began a series of events that would lead to the birth of modern neuroscience.

Cajal’s encounter with the reazione nera

At that time, Ramón y Cajal was a professor at the University of Valencia and, taking advantage of the trip to Madrid, he visited Dr. Luis Simarro, who in his laboratory showed him some samples of nerve tissue processed with the reazione nera. «… Everything was clear and simple as a diagram. A simple glance was enough. Dumbfounded, I couldn’t take my eyes off the microscope.” Completely absorbed by that technique, from that moment on Cajal’s research work focused on this stain and, therefore, on the nervous system.

When talking about the figure of Cajal, there is a trait that is barely highlighted, but that was key in his career: his chemical expertise with stains . It is no coincidence that he was a great photographer, with all the knowledge in chemical development that this implied at that time. Cajal was a master of histochemistry, that is, the staining of tissues for observation under a microscope. Perhaps the best of its time.

Not only was he able to accurately reproduce one of the most complex stains of the time, but he also refined the method and gained much information on which tissues the stain worked best on. For example, as neurons mature, their axons are covered with successive layers of myelin that improve their conductivity but make it difficult to stain well, so Ramón y Cajal focused a lot on studying nerve samples from very young animals under the microscope where the neurons still they were developing. This, as we shall see later, was essential to one of Cajal’s discoveries.

Santiago Ramón y Cajal himself defines 1888 as his best year as a researcher. He published his results and interpretations, but he soon realized that his work was being ignored, so in 1889 he decided to attend the Congress of the German Anatomical Society where some of the greatest experts in the world were cited, many of whom defended the lattice theory. Among them was Albert Kölliker, the most important figure in German histology at the time.

Kölliker, the perfect godfather

The University of Barcelona refused to financially support Cajal’s trip, who had to pull out savings to attend the congress, where he was largely ignored. Nobody came to observe the samples of that unknown Spanish scientist. Desperate, he finally got Kölliker to look at the stains thanks to the fact that he grabbed him to take him to observe the samples under a microscope. Nothing more was needed. After seeing the results, Kölliker would become one of Cajal’s greatest allies and would also defend what, years later, Cajal would define as neural theory; which, unlike the reticular theory, would end up being proven as the correct interpretation of the cellular structure of the nervous system. After meeting Ramón y Cajal, Albert Kölliker would say: «I have discovered him and I want this discovery to be known in Germany».

The most important point that Cajal’s work demonstrated was the presence of a physical space that separated the end of one neuron and the beginning of the next . Now that gap is known as the synaptic gap and, together, the entire area that encompasses the end of the axon of a neuron, the synaptic gap and the beginning of the dendrites of another neuron is known as a synapse. It is at the synapse where information jumps from one neuron to another through the release of neurotransmitters. After discovering this separation between neurons, Cajal formulated the neuronal theory, according to which nervous systems are made up of a succession of cells, neurons, which are in continuous communication with each other but are physically separated. Therefore, the neuron is the fundamental piece from which the nervous system is built; and this contradicts the reticular theory, according to which neurons are physically fused with each other at their endings.

The Neural Theory

Thus, taking the name created by Waldeyer, Cajal coined the neuronal theory where he defended that the nervous system was a succession of cells (neurons), which communicated with each other, but were physically separated from each other. In addition, Cajal exposed in 1891 the law of dynamic polarization , according to which the information is transmitted within a neuron following this order: the neuron receives the information in its dendrites, from there, it passes to the neuronal body and, later, it travels the entire axon to the axon terminals, where the data is transmitted to the dendrites of another neuron. Both the neuronal theory and the dynamic polarization law are correct and describe the bases of the cellular functioning of the nervous system.

And his discoveries did not stop there. The need to work with animals whose nervous system was still developing, in order to obtain better stains, led to the discovery of the axonal growth cone . During its growth, the axon develops a tip at its end from which it grows and uses to follow a series of chemical signals that guide it to where it must establish a new synapse. With the mere observation of his samples, Cajal was able to intuit this and formulate the chemotropic hypothesis , according to which the growth cones developed following a series of chemical gradients that attract or repel them as they grow. Again, his interpretation was correct, although it would not be until the late 1980s and early 1990s that the first molecules that guide the axonal growth cone during its development were identified.

Scientific support for Cajal

Golgi’s talk on December 11 was not well received by any of those present, least of all by Cajal. However, the next day, in his thirty-four-page talk entitled The structure and connections of neurons , the Spaniard limited himself to going through the most important points of his work, and made references to the contributions of other scientists such as Golgi, Kölliker, Simarro or Waldeyer. Perhaps the contrast between the two speeches is due to the professional gap between the two protagonists: in 1883, Camillo Golgi stopped researching the nervous system to focus on malaria, making great discoveries about the cycle of the parasite that causes the disease, while Santiago Ramón y Cajal entered the world of neuroscience in 1887. At the time of the Nobel Prize, Cajal’s neural theory was unanimously accepted by the entire scientific community, with the exception of Golgi, who had been out of science for more than two decades. neuroscientific vanguard. Cajal himself would write in Memorias de mi vida , referring to Golgi: “What a cruel irony of fate to have paired, like Siamese twins joined at the shoulders, two scientific adversaries with such different characters.”

Cajal always had great confidence that eventually the work bears fruit and the data ends up prevailing over personal biases, errors or prejudices. Time has proved him right.

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