A pair of "enemies" received an award on the same stage - or was it a Nobel Prize?

At the Nobel Prize ceremony in 1906, a pair of "rivals in the same field" with diametrically opposed academic views stood on the podium together. The theme of the older winner's speech was not to introduce his own academic achievements, but to criticize the academic theory of another younger winner. In the end, history made its judgment. This year's Nobel Prize in Physiology or Medicine was fair and just: without the Golgi staining method, there would be no Ramón y Cajal's neuron theory. The former provided a method, and the latter established a theory. It was indeed a successful combination.

Written by Chen Guanrong (City University of Hong Kong)

There is nothing in the world more complex and amazing than the human brain.

The brain is the command center of the body. It controls a person's thinking, emotions, speech and actions, and enables other organs of the body to perform their functions to maintain overall life.

Various external information is transmitted to the brain through the human body's specific sensory functions such as vision, smell, hearing and taste. The brain then receives and processes this information through the sensory nervous system and uses it to direct the corresponding organs of the body to respond. Today, the medical community may have a considerable understanding of the structure and operation mechanism of a single cell in the human brain. However, how hundreds of billions of neurons work together in a cluster remains an unsolved mystery.

Since ancient times, humans have been trying to understand the internal structure of the brain and its internal functions. In ancient China, there is a legend that Hua Tuo (145-208) opened the skull. In Europe, ancient Greece and the Roman Empire left some records about human brain medicine and animal brain structure. The story of Leonardo da Vinci (1452-1519) in the Renaissance dissecting human bodies for painting is well known. However, from the perspective of modern medicine, the first person to open the human brain for medical research may be Belgian doctor Andreas Vesalius (1514-1564). He is considered the founder of modern human anatomy and compiled a relatively complete anatomical work "De humani corporis fabrica" ​​in 1543, which describes many structural characteristics of the brain and nervous system.

Is the function of the brain determined by its structure? Yes, but not completely. There is no definitive answer at present - the brain is too complex. Research in complex network science in recent years has found that the structures of the brain's neural network, the cosmic planetary network, and the artificial Internet are extremely similar. They all have the so-called "small-world network" and "scale-free network" topological characteristics, but the functions of the three are different. However, if we continue to talk about this topic, we will go too far.

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A pair of "enemies" shared the Nobel Prize on the same stage

In the long history of medical and scientific research on the brain, there are countless doctors and scientists who have made outstanding contributions. Here we will introduce only two particularly important figures. They are the "enemies" Italian neuroanatomist, histologist, and pathologist Camillo Golgi (July 7, 1843-January 21, 1926) and Spanish pathologist, histologist, and neurologist Santiago Ramón y Cajal (May 1, 1852-October 17, 1934).

In 1906, the Nobel Prize in Physiology or Medicine was awarded jointly to Golgi and Ramón y Cajal "for their work on the structure of the nervous system."

The main scientific contributions and views of these two winners are as follows:

In 1873, Golgi developed a technique for staining nerve tissue with chromate-silver nitrate: the neurons and glial cells in the stained nerve tissue turned brown-black, making the black cells in the specimen under the microscope clearly visible against the yellow background. This staining technique was later called "Golgi staining". Using this technique, Golgi discovered the organelles in eukaryotic cells in 1898, which were later called "Golgi apparatus".

Golgi has always been a staunch supporter of the reticular theory of the nervous system, which was paved by German neuroanatomist Otto FK Deiters (1834–1863) and established by German anatomist Joseph von Gerlach (1820–1896). The theory holds that the nervous system is composed of a simple continuous network "reticulum", and the Latin word reticulum means net. Golgi believed that the brain is an integrated network of nerve fibers, and it cannot be a combination of discrete cell units. The neural network does not have unidirectional neural signals and does not have any discontinuous characteristics in physiology.

Ramón y Cajal was nine years younger than Golgi and was considered a later generation scholar in the academic world. He improved Golgi's staining method by using a higher concentration of potassium dichromate and extending the immersion time of silver nitrate to obtain more accurate, detailed, complete and reliable staining samples. Based on a large number of detailed and meticulous experimental observations, Ramón y Cajal believed that the brain's nervous system is composed of many independent neurons (rather than reticulum), and that neurons are the basic units of the nervous system. Signal conduction within neurons is unidirectional, and activity between neurons is discontinuous. Nerve signals can cross unconnected tissue structures and be transmitted through the mutual contact of neurons.

Obviously, the academic views of these two Nobel Prize winners are diametrically opposed.

Figure 1 Winners of the 1906 Nobel Prize in Physiology or Medicine: Maxim Golgi (left), Ramón y Cajal (right)

Now let’s go back to the Nobel Prize ceremony in 1906.

At the award ceremony, Golgi was scheduled to speak first. To the surprise of the attendees, Golgi's speech was not to explain his own research results, but to criticize Ramón y Cajal's theory. The theme of his speech was "The neuron doctrine". In his speech, he clearly opposed Ramón y Cajal's "discrete" neuron theory and defended his own "continuous" neural system circuit theory. He said:

"Oddly enough, I have always been against the neuron theory, but it was only because of my work that it began to gain acceptance. I chose the neuron as the subject of my lectures, but now the view is generally unpopular. ... Although this [circuit theory] runs counter to the trend of individual components, I still cannot give up the idea that the nervous system acts as a whole, so don't blame me for clinging to old ideas."

Gorky believed that there was no sufficient evidence to prove that the neuron theory was correct. He concluded by quoting a sentence from Nobel: "Every new discovery will leave a seed in the human brain, enabling a new generation of people to think about greater scientific ideas."

It was Ramon Cajal's turn to speak. He responded:

“Yes, from the analytical point of view it would be very convenient and economical if all nerve centres consisted of a continuous network of intermediaries between motor nerves… and sensory nerves. Unfortunately, nature seems to be unaware of our intelligence’s need for convenience and uniformity, and often welcomes complexity and variety.”

Science does not care about the personality of scientists, and history does not draw conclusions based on human will. With the support of sophisticated instruments and advanced technology, later generations have proven that Ramón y Cajal's theory is correct. Today, Ramón y Cajal is known as the "Father of Neuroscience."

Many years later, Ramón y Cajal humorously said in his autobiography: "What a cruel irony of fate, to pair together such distinct scientific rivals, side by side like conjoined twins!" However, he was calm: "The other half (of the Nobel Prize) was very rightly awarded to Camilo Gorky, the outstanding professor at Pavia (University). He is the inventor of the methods used to achieve my amazing discoveries."

The 1906 Nobel Prize in Physiology or Medicine was considered fair and just: without the Golgi staining method, there would be no Ramón-Cajal neuron theory. The former provided the method, and the latter established the theory, which was indeed a successful combination.

Camillo Gorky

Biography

Golgi was born on July 7, 1843 in Corteno, Brescia, Italy. His father, Alessandro Golgi, was a physician and the head of a local medical institution. After graduating from high school, Golgi entered the medical school of the University of Pavia in Italy. The University of Pavia was founded in 825 AD, with a history of more than a thousand years. There, Golgi had the honor of being taught by Giulio Bizzozero (1846-1901), a pioneer in histology who was only three years older than him, as well as the famous pathologist, physiologist, and anthropologist Paolo Mantegazza (1831-1910) and histologist and physiologist Eusebio Oehl (1827-1903). In 1865, Golgi graduated and worked as an intern at St. Matteo Hospital, where he began to study diseases of the nervous system.

In 1867, Gorky returned to the Medical School of the University of Pavia and continued to study medical theory under the guidance of Cesare Lombroso (1835-1909), a professor of mental illness and anthropology. The following year, he completed his graduation thesis on the "Etiology of Mental Disorders" and received a doctorate in medicine. Gorky engaged in medical teaching and scientific research throughout his life, and held some administrative positions, but never actually practiced clinical medicine.

In 1872, Gorky came to a chronic disease hospital near Milan as Chief Medical Officer. During this period, he established and led the Pavia Institute of Serum Therapy, Vaccine and Antigen Detection.

In 1875, Gorky returned to the University of Pavia as a distinguished professor, and concurrently served as professor of general pathology and honorary dean of St. Matteo Hospital, where he was known as a good teacher and his laboratory was open to anyone who wanted to do research.

In 1879, Gorky moved to the University of Siena as a professor of anatomy. In 1881, Gorky returned to the University of Pavia Medical School and succeeded his mentor Bizzozero as a professor of general pathology. He worked at the University of Pavia for the rest of his life until his retirement. From 1893 to 1896 and from 1901 to 1909, Gorky served as the president of the University of Pavia. He married Bizzozero's niece Donna Lina Aletti. They had no children, but adopted a daughter, Carolina.

During World War I, Gorky, at the age of 70, was still the head of the Borrmeo Military Medical College in Pavia, where he also founded a center for neuropathology and physical therapy, studied and treated nerve damage, and was responsible for caring for the wounded.

contribute

In Golky's time, the study of the central nervous system was extremely difficult because people could not identify individual cells. The rough tissue staining technology of the time was powerless against delicate neural tissue. Golky changed history: he explored a new staining method that completely changed the way people observed the brain. It was during his work at the Chronic Disease Hospital. Since this small hospital had no laboratories and research equipment, Golky set up a simple laboratory in the small kitchen of the apartment, put a microscope on it, and did experiments at night under candlelight.

Although Golgi was not the first person to try to stain cells, he made great improvements on the traditional method. His method of staining nerve tissue can stain a limited number of cells as a whole. He first treated a small piece of brain nerve tissue with potassium dichromate to harden it, and then soaked it in silver nitrate. Under the microscope, the outlines of a small number of neurons (less than 3%) became distinct from the surrounding tissue and cells: silver chromate particles formed a bright black deposit on their surface, highlighting the cell body (soma) and axon (axon) of the nerve cell and all the dendrites (dendrites), thus providing a fairly clear picture of the neuron, and in sharp contrast with the yellow background, showing the basic structure of the brain's nerve cells. Because the cells were selectively stained black, Golgi called this process "black reaction". On August 2, 1873, he published this staining method in the Italian medical journal Gazzeta Medica Italiani. Today, this method is called "Golgi staining."

Figure 2 Golgi's manuscript showing neurons (left) and hippocampus (right) using his staining method

Golgi next used his staining method to make a series of important observations about the human nervous system.

He discovered receptors that detect muscle tension, now called the Golgi tendon organ. In 1878, he discovered the Golgi-Mazzoni corpuscles, which transmit pressure. In 1879, he discovered the myelin annular apparatus, also known as the Golgi-Rezzonico horny funnel.

In 1885, Golgi discovered that there are two basic types of neurons in the brain: one with very long axons extending from the cerebral cortex to other parts, and the other with very short axons or no axons at all. These two types of neurons were later named "Golgi type I" and "Golgi type II", respectively. He was also the first to clearly describe the structure of the cerebellum, hippocampus, spinal cord, olfactory lobe, and striatal and cortical lesions in chorea.

Another major contribution of Golgi was the discovery and detailed description of the organelles in cells responsible for protein and lipid packaging, which are now called "Golgi bodies" in biology textbooks. The main function of the Golgi body is to process, sort, and transport synthesized proteins, and then send them to specific parts of the cell or secrete them outside the cell in different categories. This process includes glycosylation of proteins, participation in cell secretion activities, membrane transformation functions, protein hydrolysis into active substances, participation in the formation of lysosomes, and participation in the formation of plant cell walls. Other functions include participating in regulating the fluid balance of cells in some protozoa.

In addition, Golgi also studied human kidney function and malarial parasites in the human body. He was the first to completely dissect the nephron and discovered that the nephrons of the distal renal tubule (Henle loop) would return to the glomerulus. In 1885, he discovered that different types of malaria were caused by different types of malarial parasites. The following year, he discovered that the fever of malaria patients was related to the red blood cell cycle in human blood. It turned out that malarial parasites parasitize in red blood cells, and patients have fever when red blood cells lyse. This law is called "Golgi's law."

Behind

In 1918, Gorky retired from the University of Pavia and became an emeritus professor. But he did not stop his lifelong love of medical research and observation experiments. On January 26, 1926, Gorky passed away and was buried in the Pavia Memorial Cemetery at the age of 82. The University of Pavia built a monument for him on the campus, which reads in Italian:

“Camilo Gorky (1843-1926), an outstanding histologist and pathologist, a pioneer and a master. Through his painstaking efforts, the secret structure of the nervous tissue was discovered and clearly described. Here he worked, here he lived, and here he also guided and inspired future scholars.”

Figure 3 Statue of Gorky on the campus of the University of Pavia

The University of Pavia has also opened a special exhibition hall in the school history museum, named "Golky Hall", to showcase his achievements in neuroscience, and display more than 80 of his awards and honorary degree certificates. Gorky's major honors include: in 1900, he was appointed as a senator by King Umberto I of Italy; in 1913, he was selected as a foreign academician by the Royal Netherlands Academy of Arts and Sciences; he received honorary doctorates from Cambridge University, Geneva University, Christiania College University, Kapodistrian University of Athens and Sorbonne University in Paris.

In 1994, the European Communities issued a commemorative stamp in Italy dedicated to Camillo Gorky.

In 1956, Gorky's birthplace, Corteno, was renamed Corteno Golgi. In addition, the asteroid No. 6875 in the sky is now called "Golgi Star".

Santiago Ramón y Cajal

Biography

Ramón y Cajal was born on May 1, 1852, in the town of Petilla de Aragón in northern Spain. His father, Justo Ramón Casasús (1822-1903), was a surgeon and professor of applied anatomy at the University of Zaragoza, Spain. Ramón y Cajal later recalled that his father believed that the human mind was born to acquire knowledge, "he despised and criticized everything in literature, and rejected everything that was purely for appreciation or entertainment." His father believed that art was a terminal disease, and he only allowed medical books in the house, and literary novels were absolutely not allowed. However, Ramón y Cajal's mother, Antonia Cajal, was a romanticist. She often hid cheap fantasy novels at the bottom of the box and secretly gave them to Ramón y Cajal, his younger brother Pedro, and his younger sister Paula, so the children all loved their mother.

Ramón y Cajal was very naughty and stubborn since he was young. He was a "problem teenager" and a headache for his parents and teachers. In order to make him sit down and study hard, his father transferred him to several elementary schools. However, his grades in school were very poor and he often skipped classes. So his father simply made him drop out of school and learn a craft from a barber and a leatherworker, but he was not successful. Later, the "problem teenager" finally went to middle school after much tugging.

Fortunately, Ramón y Cajal was not completely useless. He loved to draw and take photos, and he dreamed of becoming an artist. Once, his father took him to a cemetery to inspect an ancient tomb, guessing that he might find it interesting to draw bones. Unexpectedly, his son not only liked to draw human skeletons, but also became very interested in anatomy. In fact, Ramón y Cajal had been deeply attracted by the metaphors of some literary works when he was reading relevant materials. He found the famous saying of German pathologist Rudolf LC Virchow (1821-1902) very interesting: "The whole body is a country, and each cell is its citizen." Ramón y Cajal confirmed this statement when he used a microscope for the first time - he "discovered fascinating scenes from infinitely small lives." He later recalled that he was so fascinated that he watched the movement of white blood cells for 20 hours in a row.

In 1868, at the age of 16, Ramón Čajal entered the Medical School of the University of Zaragoza, where his father taught. Under his father's supervision and guidance, he performed better and better, especially in anatomical techniques. Three years later, he won the honors award and was hired as an assistant in anatomy. In 1873, he graduated from the medical school and obtained a medical license.

That same year, Ramón y Cajal was drafted into the army. After serving in the army for a few months, he successfully applied to join the medical corps. In 1874, the unit he served in moved to Cuba, a Spanish colony. The following year, he was sent back to Spain from Cuba, having contracted dysentery and malaria, especially malaria, which almost killed him. After leaving the army, Ramón y Cajal returned to school and received a doctorate in medicine from the University of Madrid in Spain in 1877. He then obtained professorships at the University of Barcelona and the University of Madrid.

In 1879, Ramón y Cajal married and later raised four daughters and two sons with his wife. In the same year, he became the director of the Zaragoza Museum. In 1881, he became a professor at the University of Valencia in Spain. In 1899, he was appointed director of the Spanish National Institute of Health.

In 1932, Ramón y Cajal founded the Cajal Institute, an institution affiliated with the Spanish National Research Council.

Ramón y Cajal's wife died in 1930, and he died on October 17, 1934, at the age of 82. The couple were buried together in Madrid.

Figure 4 Ramón y Cajal’s tomb in Madrid

contribute

In 1887, at the age of 35, Ramón y Cajal visited Luis Simarro Lacabra (1851-1921), a neurologist and psychiatrist from the University of Valencia, and witnessed for the first time a specimen of neural tissue stained using the Golgi method. Ramón y Cajal later wrote in his autobiography that at the time, "the vast majority of neurologists did not know or underestimated" the Golgi stain. He recalled observing the impregnated elements at the time, describing it as like seeing "a painting with India ink," which left a "flash in his life."

However, using the Golgi staining method, only the cell bodies of nerve cells and a small number of proximal processes, as well as some unclearly colored nerve fibers, can be seen. Because of this, Golgi believed that nerve cells were fused together to form a vague overall network.

But Ramón y Cajal made a key improvement to the Golgi staining method by using "double immersion". He conducted staining experiments on different parts of the nervous system of many different species. Among the approximately 1,500 sections of the nervous system that he left to future generations, more than 800 were obtained using the Golgi staining method. The nervous system map he drew included almost all brain regions in some animals' brains, and various neural tissues from development to adulthood, normal and pathological, as well as degenerative and regenerative. It was under such a large number of observations, comparisons and analyses that Ramón y Cajal felt that what he saw was by no means an exception to the neural cell network theory that everyone believed in at the time. He saw and determined that the nervous system is composed of independent nerve cells, not an uninterrupted loop network as Golgi believed.

Figure 5 Ramón y Cajal's map of the cerebellum's Purkinje fibers

Ramón y Cajal published his breakthrough in 1888. He reported on the nervous system in the brains of birds and mammals, showing that it was composed of many interconnected but independent neurons. He was able to show this very clearly because the proportion of cells that could be stained in the bird brain was quite high.

In October 1889, Ramón y Cajal attended the German Anatomy Society Congress in Berlin, where he presented many of his experimental images, which won the approval and support of some of the attendees, especially the Swiss histologist Rudolf A. von Kölliker (1817-1905).

In 1891, another supporter of Ramón-Cajal, German anatomist Heinrich WG von Waldeyer-Hartz (1836-1921), summarized the experimental evidence provided by Ramón-Cajal and others, defined chromosomes, and perfected the neuron doctrine. Since then, the neuron doctrine has become the theoretical basis of modern neuroscience.

In 1894, Ramón y Cajal gave a speech at the Royal Society of London, reporting his observations of the ultrastructure of dendritic spines of neurons and speculating that dendritic spines could receive signals from axons. He also proposed the "dynamic polarization law", pointing out that nerve cells are "polarized", they receive information on the cell body and dendrites, and transmit information to distant places through axons. These discoveries and descriptions greatly refined Golgi's original observations many years ago.

In 1904, Ramón y Cajal further elaborated his ideas in the book "Histology of the Nervous System of Man and Vertebrates" (Textura del Sistema Nervioso del Hombre y los Vertebrados), in which he described in detail the characteristics of the nerve cell organization of the central and peripheral nervous systems of many animals, and presented these characteristics in detail with his exquisite painting skills.

In 1913, Ramón y Cajal published the book Degeneración y Regeneración del Sistema Nervioso, which detailed his observations on the development of the nervous system and its response to injury. Based on this research, Ramón y Cajal first used the word "plasticity" for the brain to describe the pruning and connection of the nervous system during development, as well as structural changes during the learning process and self-reconstruction after trauma. He even promoted "brain gymnastics" to improve intelligence.

Figure 6 Ramón y Cajal in the laboratory

In summary, Ramón y Cajal contributed three basic components to modern neuroscience.

First, Ramón y Cajal verified the concept of "neuron" with exquisite and detailed observations and contributed to the establishment of the "neuron theory". He pointed out that the nervous system is not a continuous network structure, but is composed of many independent nerve cells - neurons - connected by contact with each other. In 1897, British neurophysiologist Sir Charles S. Sherrington (1857-1952) named this contact point "synapse".

In fact, Ramón-Cajal was not the first person to have this "dispersion" concept. In 1886, Swiss-born German anatomist and embryologist Wilhelm His Sr (1831-1904) had observed nerve fibers at different developmental time points and believed that nerve cells did not fuse with each other, but could transmit information to each other without tight connections. In the same year, Swiss neuroanatomist and psychiatrist Auguste-Henri Forel (1848-1931) also noticed that motor nerves were not directly connected to muscle fibers, and thus speculated that nerve cells in the central nervous system did not need to be connected to each other. However, there is no doubt that Ramón-Cajal was the first neuroscientist to verify this view with a large number of experimental results. This concept overturned the mainstream thinking at the time, led by Golgi, that the brain was an integrated network of nerve fibers, and was contrary to Golgi's cognition that "brain nerves are not a combination of discrete cell units." Later, advanced detection technology proved that Ramón-Cajal was right.

Second, Ramón-Cajal accurately verified and clarified Golgi's earlier vague observations. He found that all neurons have an asymmetric polar structure: one end is a very long fiber-like axon, and the other end is a dendrite with many branches. He thus proposed a "Law of Dynamic Polarization". He believed that nerve cells are "polarized", the axon is the output structure of the neuron that transmits information to a distant place, and the dendrite is the input structure that receives signals from other neurons, and the signal flows unidirectionally from the dendrite to the axon in the neuron. This assertion runs counter to Golgi's view that there is no unidirectional conduction of nerve signals inside neurons. Ramón-Cajal's theory was later confirmed to be the basic principle of neural connection function.

Third, Ramón y Cajal discovered that there is a "growth cone" at the front end of the axon in the growth phase. It will seek a growth path under the induction of chemicals secreted by the target cells, eventually find its target cells, and then form synaptic connections.

Figure 7 Ramón y Cajal's diagram of neuron fiber-like axons and dendrites

Behind

For more than a hundred years since Ramón y Cajal, the neuroscience community has always recognized him as the most outstanding neuroanatomist. He correctly interpreted the structure and function of the nervous system and provided a large amount of valuable neuroanatomical data. Many of his neuron and nervous system maps have been adopted by modern neuroscience textbooks. These are his unparalleled contributions to neuroscience.

However, the neural network circuit school led by Golgi had been resolutely criticizing and stubbornly resisting Ramón y Cajal's "heretical" theory. Ramón y Cajal's debate with the mainstream theory of neuroscience during his lifetime was quite difficult and outstanding. Ramón y Cajal's works "On the Structure of the Nervous System of Man and Vertebrates" and "New Views on the Histology of the Nervous System" reflect his arduous struggle. In order to spread and defend his own theory, Ramón y Cajal fought until the last moment of his life. In 1933, a year before his death, he was still writing the book "Neuronismo ó Reticularismo". The manuscript was officially published by the Cajal Institute in 1952, and its English translation was published in 1954.

In addition to monographs, Ramón y Cajal also wrote several advanced scientific research books for young people. In his works such as "Reglas y consejos sobre investigación científica" written in 1899 and "Advice for a Young Investigator" written in 1897, he repeatedly emphasized the independence, concentration and persistence of scientific research. He believed that intelligence was not the most critical factor, and even scientists with average qualifications could make significant scientific achievements. He said: "I am really not a genius. I am just... a tireless worker." He left a great advice to future generations: "The attitude towards failure can be as simple as four words: keep trying."

Figure 8 Selected Works of Ramón y Cajal

Ramón y Cajal is the second Spanish scientist to win the Nobel Prize. The first was José Echegaray (1832-1916), a civil engineer, mathematician, politician, and playwright, who won the 1904 Nobel Prize in Literature.

Ramón y Cajal left a huge legacy to neuroscience, but he did not receive much honor during his lifetime. Perhaps this "problem teenager" did not care.

In any case, it is worth mentioning that in 2017, the entire Ramón y Cajal archive (including manuscripts, drawings, paintings, photographs, books and letters) was permanently inscribed on the UNESCO Memory of the World Register.

Figure 9 The Beauty of the Brain: A Collection of Illustrations by Santiago Ramón y Cajal, edited by Eric A. Newman et al., translated by Yan Qing, edited by Fu He, published by Hunan Science and Technology Press in October 2020

This article is supported by the Science Popularization China Starry Sky Project

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

Produced by: Science Popularization China

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