Shulou(Shulou.com)11/24 Report--

This article comes from the official account of Wechat: ID:fanpu2019, author: Chen Guanrong

At the Nobel Prize presentation ceremony in 1906, a pair of "peer enemies" with opposing academic views stood on the podium together. The theme of the speech of the older winner was not to introduce his academic achievements, but to attack the academic theory of another young winner. In the end, history made its verdict that the Nobel Prize in Physiology or Medicine was fair and just: without Golgi staining, there would be no Ramon-Kakhar neuron theory. The former provides a method, while the latter establishes a theory, which is indeed a successful combination.

Written by Chen Guanrong (City University of Hong Kong)

Nothing in the world is more complex and magical than the human brain.

The brain is the command center of the body. it controls people's thoughts, emotions, words and actions, and allows other organs of the body to perform their duties to maintain life as a whole.

All kinds of information from the outside world is transmitted to the brain through the specific sensory functions of the body, such as vision, smell, hearing and taste, and then the brain receives and processes the information through the sensory nervous system, which is then used to direct the corresponding organs of the body to respond. Nowadays, the medical community may have a good understanding of the structure and operation mechanism of the single cell (cell) in the human brain. However, how hundreds of billions of neurons (neuron) cooperate in clusters is still an unsolved mystery.

Since ancient times, human beings have been trying to understand the internal structure and function of the brain. In ancient China, there is a legend of Hua Tuo (145Mal 208) who opened his skull. In Europe, the ancient Greek and Roman empires left some records about the structure of human brain medicine and animal brains. The story of Renaissance Leonardo da Vinci,1452-1519 dissecting the human body for painting is well known. However, from a modern medical point of view, the first person to open the human brain for medical research may be the Belgian doctor Andreas Visarius (Andreas Vesalius,1514-1564). He is considered to be the founder of modern human anatomy. In 1543, he wrote a relatively complete anatomical book, the structure of the Human body (De humani corporis fabrica), which describes many structural features of the brain and nervous system.

Is the function of the brain determined by its structure? Also, not exactly, there is no final conclusion-the brain is too complicated. In recent years, the scientific research of complex network has found that the structures of brain neural network, cosmic planet network and artificial Internet are very similar, which have the topological characteristics of so-called "small world network" and "scale-free network". But the three functions are different from each other. However, if we go on to this topic, we will go too far.

A pair of "friends" share the Nobel Prize together in the long history of medical and scientific research of the brain, there are countless doctors and scientists who have made outstanding contributions. Here are only two particularly important people. They are "enemies" Italian neuroanatomist, histologist and pathologist Camilo Gorky (Camillo Golgi,1843.7.7-1926.1.21) and Spanish pathologist, histologist and neurologist Santiago Ram ó n y Cajal,1852.5.1-1934.10.17 (Santiago Ram ó n y Cajal,1852.5.1-1934.10.17).

In 1906, the Nobel Prize in Physiology or Medicine was awarded to Gorky and Ramon Kakhar "for their work on the structure of the nervous system".

The main scientific contributions and viewpoints of the two winners are as follows:

Gorky developed a chromate-silver nitrate staining technique for nerve tissue in 1873: neurons and glial cells in the stained nerve tissue turned brown and black, making the black cells in microscopic specimens clear against a yellow background. This staining technique was later called "Golgi staining" (Golgi staining). Using this technique, Golgi discovered the organelle (organelle) in eukaryotic cells (eukaryotic cell) in 1898, which was later called "Golgi apparatus" (Golgi apparatus).

Gorky has always firmly supported the nervous system loop theory (reticular theory) established by German neuroanatomist Otto F. K. Deiters,1834-1863 and German anatomist von Grah (Joseph von Gerlach,1820-1896). The theory holds that the nervous system is made up of a simple continuous network "reticulum", and the Latin word reticulum means net. Gorky believes that the brain is a whole network of nerve fibers, not a combination of discrete cell units, and that the neural network does not have one-way conduction of neural signals and does not have any physiological discontinuity characteristics.

Ramon Cahar is nine years younger than Gorky and can be regarded as a later generation of scholars in academia. He improved the Golgi staining method by using a higher concentration of potassium dichromate and prolonging the immersion time of silver nitrate to obtain more accurate, more complete and reliable staining samples. Based on a large number of detailed and detailed experimental observations, Ramon-Kakhar believes that the cerebral neural system is composed of many independent neurons (not reticulum). Neurons are the basic unit of the nervous system, the signal transmission within neurons is unidirectional, the activity between neurons is discontinuous, and neural signals can be transmitted through unconnected tissue structures and through the contact of neurons.

Obviously, the academic views of the two Nobel laureates are tit-for-tat.

Fig. 1 winners of the 1906 Nobel Prize in Physiology or Medicine: Gorky (left) and Ramon Kakhar (right) are now back at the 1906 Nobel Prize ceremony.

At the award ceremony, Gorky was arranged to speak first. To the surprise of the participants, Gorky's speech was not to explain his research results, but to criticize Ramon-Kakhar's theory. The theme of his speech turned out to be "neuron theory" (The neuron doctrine). In his speech, he explicitly opposed Ramon-Kakhar's "discrete" neuron theory and defended his "continuous" nervous system loop theory. He said:

"it's strange that I've always been opposed to neuron theory, but it began to be recognized because of my work. I chose neurons as the theme of my speech, but now this view is generally unpopular. Although this [loop theory] runs counter to the trend of individualization of constituent elements, I still can't give up the view that the nervous system acts as a whole, so don't blame me for clinging to old ideas. "

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

Ramon Kakhar is next to speak. He responded:

"Yes, from an analytical point of view, if all nerve centers are made up of motor nerves... and sensory nerves, it would be very convenient and economical. Unfortunately, nature does not seem to realize the need for convenience and unity in our wisdom, but often welcomes complexity and diversity."

Science does not pay attention to the personality of scientists, and the conclusion of history is not based on man's will. With the support of precision instruments and advanced technology, later generations proved that Ramon-Kakhar's theory is correct. Today, Ramon Kakhar is known as the father of neuroscience.

Many years later, Ramon Kakhar said humorously in his autobiography: "what a cruel irony fate is to pair scientific opponents with such distinct characters side by side like Siamese twins!" However, he was calm: "the other half very correctly awarded Camilo Gorky, a distinguished professor at Pavia [university]. He is the inventor of the method I used to make those amazing discoveries."

The 1906 Nobel Prize in Physiology or Medicine was considered fair: without Golgi staining, there would be no Ramon-Kakhar neuron theory. The former provides a method, while the latter establishes a theory, which is indeed a successful combination.

Camilo Gorky was born on July 7, 1843 in the town of Corteno, Brescia province, Italy. His father, Alessandro Golgi, was a physician and a director of local medical institutions. After graduating from high school, Gorky entered the Medical College of the University of Pavia (University of Pavia) in Italy. The establishment of Pavia University can be traced back to 825 AD and has a history of more than a thousand years. There, Gorky was fortunate to be taught by a histology pioneer, Giulio Bizzozero (1846, 1901), who was only three years his senior, as well as by the famous pathologist, physiologist, and anthropologist Paolo Mantegazza (1831, Mak 1910) and histologist and physiologist, Eusebio Oehl (1827, Mel 1903). In 1865, Gorky graduated and worked as an intern at St. Matteo Hospital, where he began to study neurological diseases.

In 1867, Gorky returned to Pavia University School of Medicine and continued to study medical theory with Professor of Psychiatry and Anthropology Cesare Lombroso (1835 ~ 1909). The following year, he completed his graduation thesis on the theme of "Etiology of Mental Disorders" and received his MD. Gorky engaged in medical teaching and scientific research all his life, and held some administrative positions, but never really practiced medicine.

In 1872, Gorky came to a chronic hospital near Milan as chief physician (Chief Medical Officer). During this period, he established and led the Pavia Regional Institute for Serum Therapy and Vaccine and Antigen testing.

In 1875, Gorky returned to Pavia University as a distinguished professor, as well as professor of general pathology and honorary dean of St. Matteo Hospital. There, he is a famous good teacher, and his laboratory is unconditionally open to anyone eager to do research.

In 1879, Gorky moved to the University of Siena (University of Siena) as professor of anatomy. In 1881, Gorky returned to Pavia University School of Medicine to replace instructor Bizzozero as professor of comprehensive pathology, and then worked at Pavia University until his retirement. Gorky served as president of Pavia University from 1893 to 1896 and from 1901 to 1909. He married Bizzozero's niece Donna Lina Aletti, who had no children but adopted a daughter, Carolina.

During World War I, Gorky was still in charge of the Borrmeo military Medical School in Pavia in his twenties. There, he also established a neuropathology and physiotherapy center to study and treat nerve injuries and to care for the wounded.

At the time of Gorky, the study of the central nervous system was extremely difficult because people could not recognize individual cells. The rough tissue staining technique of that year was powerless to fine nerve tissue. Gorky changed history: he explored a new staining method that revolutionized the way people look at the brain. That was when I was working in the chronic Disease Hospital, and because the small hospital had no laboratory and research equipment, Gorky set up a simple laboratory in the kitchenette of the apartment, put a microscope on it, and experimented by candlelight at night.

Although Gorky was not the first person to try to dye cells, he made great improvements to traditional methods. His nerve tissue staining method can stain a limited number of cells as a whole. He first treated a small piece of brain nerve tissue with potassium dichromate, hardened it, and then soaked it in silver nitrate. Under the microscope, the contours of a small number (less than 3%) of neurons become distinct from those of surrounding tissues and cells: silver chromate particles form bright black deposits on their surfaces, highlighting the soma and axon of nerve cells and all dendrite, thus providing a fairly clear picture of neurons in sharp contrast to the yellow background. It shows the basic structure of nerve cells in the brain. Because cells are selectively stained black, Gorky calls this process a "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.

Fig. 2 the manuscript of nerve cells (left) and hippocampus (right) shown by Gorky using his staining method. Next, Gorky used his staining method to make a series of important observations on the human nervous system.

He discovered receptors that detect muscle tension, now known as the Golgi tendon organ (Golgi tendon organ). In 1878, he discovered the Golgi-Mazoni body (Golgi-Mazzoni corpuscles) that conducts pressure. In 1879, he also discovered the myelin annular organ (myelin annular apparatus), also known as the Gorky-Rizonico horny funnel (Golgi-Rezzonico horny funnel).

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

Another major contribution of Golgi is the discovery and detailed description of the organelles responsible for the packaging of proteins and lipids in cells, which are now called "Golgi apparatus" in biology textbooks. The main function of Golgi apparatus is to process, sort, transport synthetic proteins, and then send them to specific parts of the cell or secrete them outside the cell. This process includes glycosylation of proteins, participation in cell secretion, transformation of membranes, hydrolysis of proteins into active substances, participation in the formation of lysosomes and the formation of plant cell walls. Other functions include participation in regulating the liquid balance of cells in some protozoa.

In addition, Gorky has also studied human kidney function and malaria parasites in humans. He was the first to fully dissect the nephron (nephron) and found that the nephron of the distal renal tubule (Henle ring) returns to the glomerulus (glomerulus). In 1885, he discovered that different types of malaria were caused by different types of malaria parasites. The following year, he found that fever in malaria patients was associated with the cycle of red blood cells in human blood. It turns out that Plasmodium parasites in red blood cells, red blood cells when the patient has a fever, this law is known as the "Golgi law."

In 1918, Gorky retired from Pavia University and became professor emeritus. But he did not stop medical research and observation experiments that he loved all his life. On January 26, 1926, Gorky died and was buried at Pavia Memorial Cemetery at the age of 82. The University of Pavia built a monument for him on campus, which read:

Camilo Gorky (1843Mir 1926), an outstanding histologist and pathologist, pioneer and master. The secret structure of nerve tissue was discovered and clearly described through his hard work. He works here, he lives here, and he guides and inspires future scholars here. "

Fig. 3 the statue of Gorky on the campus of Pavia University Pavia University has also opened a special exhibition hall in the school history museum, named "Gorky Hall", to showcase his neuroscience achievements and display more than 80 awards and honorary degrees. Gorky has received major honors including: he was canonized as a member of the House of Lords (senator) by King Umberto I of Italy in 1900; he was selected as a foreign fellow by the Royal Dutch Academy of Arts and Sciences in 1913; and he received honorary doctorates from the University of Cambridge, the University of Geneva, the University of Kristiania, the National Kapodistrian University of Athens and the Sorbonne University of Paris.

In 1994, the European Community (European Communities) issued a Camilo Gorky commemorative stamp in Italy.

In 1956, Gorky's birthplace, Corteno, was renamed Corteno Golgi Town. In addition, the 6875 asteroid in the sky is now called Gorky Star.

Santiago Ramon-Kakhar was born on May 1, 1852, in the town of Petilla de Arag ó n in northern Spain. His father, Justo Ram ó n Casashost s (1822 ~ 1903), was a surgeon and professor of applied anatomy at the University of Zaragoza (University of Zaragoza) in Spain. Ramon-Kakhar later recalled that his father believed that human thought was born to acquire knowledge. "he despised and criticized everything in literature and rejected everything purely for appreciation or entertainment." My father thought that art was a terminal disease. He was only allowed to have medical books at home, but literary novels and the like absolutely could not exist. But Ramon Kakhar's mother, Antonia Cajal, is a romantic. She often hides cheap fantasy novels at the bottom of her box and secretly slips them to Ramon Kakhar and his brother Pedro and sister Paula, so the children like their mother.

Ramon Kakhar has been very naughty and stubborn since he was a child, and he is a "troubled teenager", which makes his parents and teachers have a headache. In order for him to sit down and study hard, his father transferred him to several primary schools. But he got very poor grades at school and often skipped classes. So his father simply asked him to drop out of school and went to learn from a barber and a cobbler, but without success. Later, the "problem boy" pulled and pulled or went to middle school.

Fortunately, Ramon Kakhar is not useless. He likes painting, taking pictures and fantasizing about becoming an artist. Once, his father took him to the cemetery to inspect an ancient grave, guessing that he might have some novel pleasure in drawing bones. Unexpectedly, my son not only likes to draw human bones, but also has a great interest in anatomy. In fact, Ramon-Kakhar has already been deeply attracted by the metaphors in some literary works when reading relevant materials. He found the famous words of the German pathologist Rudolf L. C. Virchow (1821 Mel 1902) interesting: "the whole body is a country, and every cell is its citizen." Ramon Kakhar confirmed this when he first looked at it under a microscope-he "found fascinating scenes in his infinitesimal life". He later recalled that he was so fascinated that he watched the movement of white blood cells for 20 hours on end.

In 1868, 16-year-old Ramon Kakhar entered the medical school of the University of Zaragoza, where his father taught. Under the supervision and guidance of his father, he became more and more excellent, especially in anatomical techniques. Three years later, he won the top student award and was hired as an assistant professor of anatomy. In 1873, he graduated from medical school and was qualified to practice medicine.

In that same year, Ramon Kakhar was drafted into the army. After several months of service in the army, he successfully applied to join the medical team. In 1874, the troops he served moved to the Spanish colony of Cuba. The following year, when he was sent back to Spain from Cuba, he was already suffering from dysentery and malaria, especially malaria, which almost killed him. After leaving the army, Ramon Kakhar returned to school and received his medical doctorate from the University of Madrid in Spain in 1877. Next, he won professorships at the University of Barcelona and the University of Madrid.

Ramon Kakhar married in 1879 and later raised four daughters and two sons with his wife. In the same year, he became the curator of the Zaragoza Museum, a professor at the University of Valencia (University of Valencia) in 1881 and the director of the Spanish National Institutes of Health in 1899.

In 1932, Ramon Kakhar founded the Kakhar Institute (Cajal Institute), which belongs to the Spanish National Research Council (Spanish National Research Council).

Ramon Kakhar, whose wife died in 1930, died on October 17, 1934, at the age of 82. The couple were buried together in Madrid.

Fig. 4 Ramon-Kakhar couple's Tomb contribution in Madrid in 1887, 35-year-old Ramon Kakhar visited Luis Simarro Lacabra, a neurologist and psychiatrist from the University of Valencia, and witnessed for the first time nerve tissue specimens stained with Golgi method. Ramon Kakhar later wrote in his autobiography that "most neuroscientists did not know or underestimated" Golgi staining. He recalled his observation of the impregnation elements at that time, describing it as seeing a "painting painted in Indian ink", leaving a "flash in his life".

However, Golgi staining can only see the cell bodies and a small number of proximal processes of nerve cells, as well as some nerve fibers that are not obviously stained. It is because of this that Gorky believes that nerve cells fuse with each other to form a fuzzy whole network.

However, Ramon-Kakhar made a key improvement to Golgi staining with "double impregnation". He stained different parts of the nervous system of many different species. Of the about 1500 sections of the nervous system he left to posterity, more than 800 were obtained by Golgi staining. His map of the nervous system includes almost all areas of the brain of some animals, and has a variety of nerve tissues from development to adulthood, normal and morbid, and degenerative and regenerated. It was under such a great deal of observation, comparison and analysis that Ramon Kakhar felt that what he saw was by no means an exception to the neural network theory that people believed in at that time. He saw and determined that the nervous system was made up of independent nerve cells, rather than an uninterrupted network of loops as Gorky thought.

Fig. 5 Ramon-Kakhar's Purkinje fiber map of the cerebellum. Ramon-Kakhar officially published his breakthrough in 1888. He reported on the nervous system in the brains of some birds and mammals, pointing out that it was made up of many independent neurons that were in contact with each other. He was able to show this clearly at the time because there was a high proportion of stained cells in the brains of birds.

In October 1889, Ramon Kakhar attended the academic Conference of the German Anatomical Society (German Anatomy Society Congress) in Berlin. At the meeting, he showed many of his experimental images, which were approved and supported by some participants, especially the Swiss organizer Rudolf A. von K ö lliker (1817mur1905).

In 1891, German anatomist Heinrich W. G. von Waldeyer-Hartz, another supporter of Ramon Kakhar, summed up the experimental evidence provided by Ramon Kakhar et al., defined the chromosome (chromosome) and perfected the neuron theory (neuron doctrine). Since then, neuron theory has become the theoretical basis of modern neuroscience.

In 1894, Ramon Kakhar gave a speech at the Royal Society of London, reporting that he had observed the ultrastructure of neuronal dendritic spines (dendritic spine) and speculated that dendritic spines could receive signals from axons. He also proposed the "law of dynamic polarization", which points out that nerve cells are "polarized". They receive information on cell bodies and dendrites and transmit information to a distance through axons. These discoveries and descriptions have greatly refined Gorky's original observations many years ago.

In 1904, Ramon Kakhar further clarified his point in the histology of the nervous system of humans and vertebrates (Textura del Sistema Nervioso del Hombre y los Vertebrados). In this book, he describes in detail the nerve cell tissue characteristics of the central and peripheral nervous systems of many animals, and presents these characteristics in detail with his own exquisite painting techniques.

In 1913, Ramon Kakhar published the book Degeneraci ó n y Regeneraci ó n del Sistema Nervioso, which summarized in detail the development of the nervous system and its response to injury. Based on this research, Ramon-Kakhar first applied the word "plasticity" to the brain to describe the pruning and connection of the nervous system during development, the structural changes in the learning process and self-reconstruction after trauma, and he even promoted "brain gymnastics" to improve intelligence.

Fig. 6 Ramon-Kakhar summed up in the laboratory that Ramon-Kakhar contributed three basic components to modern neuroscience.

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

In fact, Ramon Kakhar is not the first person to have this concept of "fragmentation". In 1886, Wilhelm His Sr, a German anatomist and embryologist born in Switzerland, had observed nerve fibers at different developmental points and believed that nerve cells did not fuse with each other, but could transmit information to each other without a tight connection. In the same year, Auguste-Henri Forel, a Swiss neuroanatomist and psychiatrist, also noted that motor nerves are not directly connected to muscle fibers, thus speculating that nerve cells in the central nervous system do not need to connect to each other. However, there is no doubt that Ramon Kakhar is the first neuroscientist to use a large number of experimental results to verify this view. This idea subverts the mainstream idea led by Gorky at that time that the brain is a whole neural fiber network, and runs counter to Gorky's cognition that "the brain nerve is not a combination of discrete cell units". Later, advanced testing technology proved Ramon-Kakhar to be correct.

Second, Ramon-Kakhar accurately verified and clarified Gorky's early fuzzy observations. He found that all neurons have asymmetrical polar structures: a long fibrous axon at one end and many dendrites at the other. He thus proposed a "law of dynamic polarization" (Law of Dynamic Polarization). He believes that nerve cells are "polarized", axons are the output structures of neurons that transmit information to the distance, while dendrites are input structures that receive signals from other neurons, and the signals flow unidirectionally from the dendrites to the axons within the neurons. This argument runs counter to Gorky's view that there is no one-way transmission of nerve signals inside neurons. Ramon-Kakhar's theory was later proved to be the basic principle of neural connection function.

Third, Ramon-Kakhar found that there is a "growth vertebra" (growth cone) at the front of the axon during the growth period, which will find the growth path induced by the chemicals secreted by the target cells, and finally find its own target cells, leading to synaptic connections.

Fig. 7 Ramon-Kakhar's map of neuronal fibrous axons and dendrites behind Ramon-Kakhar has been recognized by the neuroscience community as the most outstanding neuroanatomist for more than a century. He correctly interpreted the structure and function of the nervous system and provided a large number of valuable neuroanatomical data. Many of his maps of neurons and nervous system have been used in modern neuroscience textbooks. These are his unparalleled contributions to neuroscience.

However, at that time, the neural network loop school led by Gorky has been firmly criticizing and tenaciously resisting Ramon-Kakhar's theory of "apostasy". The debate between Ramon Kakhar and the mainstream theory of neuroscience at that time was quite difficult in his lifetime. Ramon Kakhar's books on the structure of the nervous system of humans and vertebrates and the New View of nervous system Histology reflect his arduous struggle. In order to spread and defend his doctrine, Ramon Kakhar fought until the last moment of his life. The year before his death, in 1933, he was still writing Neuronismo ó Reticularismo (Neuron Theory or Loop Theory). The manuscript was officially published by the Kakhar Institute in 1952 and its English translation was published in 1954.

In addition to the monographs, Ramon Kakhar has also written several advanced books on scientific research for young people. He repeatedly emphasized the independence, concentration and persistence of scientific research in his works Reglas y consejos sobre investigaci ó n cient í fica (1899) and to Young Scholars (English translation: Advice for a Young Investigator) in 1897. He believes that intelligence is not the most critical, and even moderately qualified scientists can make great scientific achievements. "I'm really not a genius," he said. I'm just. Tireless worker. " He left an excellent piece of advice to future generations: "there are only four simple words in your attitude towards failure: keep trying."

Fig. 8 Ramon Kakhar selected by Ramon Kakhar is the second scientist in Spanish history to win a Nobel Prize. The first was a civil engineer, mathematician, politician and playwright Jos é Etchegaray, winner of the Nobel Prize for Literature in 1904.

Ramon Kakhar left great wealth to brain neuroscience, but he did not receive many honors in his lifetime. Maybe the "troubled teenager" doesn't care.

However, it is worth mentioning that in 2017, all of Ramon Kakhar's archives (including manuscripts, drawings, paintings, photographs, books and letters) were permanently deposited in UNESCO's memory of the World Register (Memory of the World Register).

Figure 9, the Beauty of the brain: San Diego Ramon-Kakhar Pictures, Eric A. Edited by Newman et al., translated by Yan Qing, Fu he School, published by Hunan Science and Technology Publishing House in October 2020.

Welcome to subscribe "Shulou Technology Information " to get latest news, interesting things and hot topics in the IT industry, and controls the hottest and latest Internet news, technology news and IT industry trends.