Horse of Swords: RAFAEL LORENTE DE NÓ, the last and most precocious direct disciple of Cajal, four-time Nobel candidate

It is very likely that, if you are not a doctor or neuroscientist, the name of Rafael Lorente de Nó will be as unknown to you as those of Nicolás Achúcarro and Pío del Río-Hortega before reading the Horse of Wands entry 😅. The wars (civil in Spain from 1936 to 1939 and world war in Europe from 1939 to 1945) truncated the scientific progress and international projection of our researchers promoted by the Board of Expansion of Studies and the Spanish Neurological School of Cajal. But perhaps in the case of Lorente de Nó, the fact that he developed most of his scientific career in the United States, where he moved in 1931 and where he died in 1990, has also contributed to the lack of knowledge about him.

Perhaps you will also not know that Lorente de Nó was proposed on four occasions (1949, 1950, 1952 and 1953) to receive the Nobel Prize in Medicine or Physiology, nor that after the Second World War he was part of the dozen experts who illuminated the birth of cybernetics. You are probably also unaware that, in addition to his deep knowledge of medicine and biology, he was an excellent chemist and mastered mathematics, and that he trained with two Nobel Prize winners: Cajal (in 1906) and Bárány (in 1914). Impressive, right?
Born in 1902 in Zaragoza and Aragonese like Cajal, unlike Cajal, he was a brilliant and very precocious student. His incredible academic record (he published his first scientific article at the age of 15) [1] caught the attention of Pedro Ramón y Cajal, in whose Zaragoza laboratory he learned histological techniques to study the nervous system. Pedro recommended him to the laboratory of his brother Santiago, where he arrived at the age of 18, ready to continue his medical studies in Madrid, and research under the direction of Cajal with frog larvae, rodents and rabbits.
At the Biological Research Laboratory—where he formed a solid friendship with Cajal’s other brilliant young disciple, Fernando de Castro Rodríguez—he published his first works in 1921 and 1922 on neuronal regeneration in frog larvae. At the age of 21 (in 1923) he received his doctorate with a thesis on histophysiology of the inner ear. That same year in Zaragoza he met Robert Bárány, an Austrian doctor of Hungarian origin – who in 1914 had received the Nobel Prize in Physiology or Medicine for his work on the physiology and pathology of the vestibular apparatus (in the inner ear) – and who , impressed by the knowledge of Rafael Lorente de Nó, invited him to train with him in Upsala (Sweden) [6].
From 1924 to 1927 Rafael remained with Bárány at the University of Uppsala thanks to a scholarship from the Board of Further Studies. There his interest will shift from histology to the physiology of vestibular reflexes. He interrupted his stay in Sweden a couple of times to travel to Utrecht and Berlin (in 1925). In Utrecht he trained with Rudolf Magnus, an expert in pharmacology and animal reflexes who died before receiving the Nobel Prize for his work with De Kleyne, and at the Institute for Brain Research in Berlin he worked with Oskar and Cecile Vogt when this brilliant marriage. who directed the work of Brodmann, who would end up describing the brain histological areas that bear his name, tried to locate the brain functions that occurred in the cerebral cortex.
With such scientific background behind him, upon returning to Spain, he however found that the lack of financial means for research forced him to practice as a private otorhinolaryngologist. In 1928 he was appointed head of the first otorhinolaryngology service in Spain, at the Casa de Salud de Valdecilla (Santander) [8], where he set up the best otorhinolaryngology laboratory in the world thanks to his training with the leaders of the specialty in Königsberg, Frankfurt and Berlin. However, the overload of clinical and surgical work prevents him from continuing with his research and, frustrated by the few research opportunities in Spain, Lorente de Nó, who is already admired by the international neuroscientific community and enjoys the endorsement of Bárány and the couple, In 1931, Vogt accepted the assignment to become director of the Institute of Deafness (Central Institute for the Deaf) in Missouri (USA).
It was upon arriving in St. Louis, Missouri that Lorente de Nó converted to Electrophysiology, realizing the incredible power that the cathode ray oscilloscope provided for research in the new specialty. Furthermore, it was there where he met Joseph Erlanger and Herbert Gasser, two scientists who in 1944 would obtain the Nobel Prize in Medicine or Physiology for their discoveries about different types of nerve fibers and their action potentials.
From then on, Lorente de Nó would develop his entire career in the US, and as research director of the Institute of Deafness – where he carried out work that continues to enjoy current recognition on neuro-otology, histophysiology of the cochlear complex and of The vestibular reflex—he went on to work in 1935 at the University of Washington School of Medicine and, in 1936, became a principal investigator at the Rockefeller Foundation—the best institute in the world at the time. After retiring in 1970 he worked at the University of California, Los Angeles as professor emeritus of the Brain Research Institute. From the US he continued to correspond with his teacher Cajal, but also with his friend Fernando de Castro, although he never considered returning to Spain.
In 1981 he retired to live in Tucson, Arizona, where he published a synthesis of his major research—on brain localization and cytoarchitecture, functional organization of the neocortex, electrophysiology, and basic physiology of nerve conduction—before dying in 1990.  

In total, Lorente de Nó spent four decades at the pinnacle of international neurophysiological research. It can be said that he was the one who achieved the perfect combination of neuroanatomy techniques and knowledge and the electrophysiological approach. Erudite, brilliant and innovative, his conceited character earned him many enmities and made him rise up against the chemical nature of the action potential, a discovery for which Eccles, Hodgkin and Huxley received the Nobel Prize in Physiology or Medicine in 1963. But this It is something that should not make us forget the very great contributions to neurophysiology, mainly in three areas, the organization of the cerebral cortex of mammals (elucidating the function that is based on a certain structure of the cerebral cortex), the organization of the vestibular and auditory and the basic physiology of neuronal functioning (physiology of dendrites, soma and axon, and theory of electrical potential in volume conductors) [3][4][5].
Although his work has been scarcely disseminated and appears in few studies on the history of neuroscience, Rafael Lorente de Nó made some of the most important neuroscientific contributions of the last century and formulated new concepts [2] [5] [7]:
– He discovered neocortical neural circuits and coined the term cortical “module” or “elementary unit.”
– He described the vestibular nucleus, the acoustic nucleus, and the anatomy of the VIII cranial nerve.
– He studied oculovestibular reflexes and their anatomical pathways.
– In nerve conduction at the axonal level he contributed to the knowledge of the nervous impulse thanks to the characterization of the synaptic delay and the temporal and spatial sum of nervous impulses,
– He made the first description of a biological negative feedback system.
– He synthesized tetraethalimonium (TEA)—a quaternary ammonium compound—used by modern neurobiology as a selective blocker of potassium channels in excitable tissues.
Although he was a rather solitary scientist who signed most of his publications as the sole author, due to his brilliance and global prestige he trained many young doctors from different countries who collaborated at different times and places with Lorente de Nó: the Chinese T. P. Feng and H. T. Chang, the Spanish A. Galledo, L. M. Hernando de Larramendi, F. de Castro and V. Honrubia, the Frenchman Y. Laporte, the Italian Cazullo, the Uruguayan Soriano and the Mexican García Ramos, as well as Lundberg from the Karolinska in Stockholm [8]. We cannot fail to mention, among his last disciples, Jorge Larriva-Sahd, who met Lorente de Nó at the University of California Los Angeles and became his personal friend, today custodian of the Rafael Lorente de Nó Archive that is located in Mexico [9].

“He who discovers something new will have to confront something more mundane: that his truth is now supported by those who assume the opposite.” Rafael Lorente de Nó [2]

For Larriva-Sahd, “the way the image of Lorente de Nó evolved is paradoxical [2]; from having been considered the most important researcher in the United States of America in the neurosciences of the 1940s, until, after a few decades, becoming an author poorly cited in the literature, despite the valuable contributions of he “. As you can see, the Spanish ignorance of such illustrious Spanish scientists as Lorente de Nó and the rest of the gentlemen of the neurodeck is incomprehensible, but perhaps after reading these lines you will change your mind and want to join the team of those who know and recognize the genius of Spanish science.

Have you been curious and want to know more?

SOURCES CITED

[1] Rafael Lorente de Nó published his first scientific article at the age of 15 (in 1917): “Temperature”, Revista del Ateneo Científico Escolar, pp. 1 to 14. In this article he made a mathematical treatment of thermodynamics.
[2] LARRIVA-SAHD, Jorge A. (2005). Reminiscence of Rafael Lorente de Nó (1902-1990). Bol Mex His Fil Med 2005; 8 (2): 53-58 https://www.medigraphic.com/pdfs/bmhfm/hf-2005/hf052e.pdf
[3] LARRIVA-SAHD, Jorge A. (2014). Some predictions of Rafael Lorente de Nó 80 years later. Frontiers in Neuroanatomy, vol. 8  https://www.frontiersin.org/article/10.3389/fnana.2014.00147
[4] LARRIVA-SAHD, Jorge A. (2002). Some contributions of Rafael Lorente de Nó to neuroscience: A reminiscence, Brain Research Bulletin,Volume 59(1): 1-11. https://www.sciencedirect.com/science/article/pii/S0361923002008389
[5] RODRÍGUEZ, J.J. and VERKHRATSKY, A. Rafael Lorente de Nó (1902-1990): The pioneer of Physiologycal Neuroanatomy   https://www.feps.org/yuklemeler/famous_european_physiologists/RafaelLorentedeNo.pdf
[6] Biography of Rafael Lorente de Nó the SENChttps://www.senc.es/wp-content/uploads/2017/11/biografi%CC%81a-Rafael-Lorente-de-No.pdf
[7] FERNÁNDEZ DE MOLINA, Antonio. Royal Academy of History: Electronic Biographical Dictionary (DB-e), entry Rafael Lorente de Nó https://dbe.rah.es/biografias/12374/rafael-lorente-de-no
[8] BALCELLS, M. (2016). Rafael Lorente de Nó: biography of an almost unknown neuroscientist. Neurosciences and History 2016; 4(4): 164-167 https://nah.sen.es/vmfiles/abstract/NAHV4N42016164_167ES.pdf
[9] A Hombros de Gigantes (RNE), Series about Santiago Ramón y Cajal, his school and his legacy. Podcast from 04/24/2022 (LISTEN MINUTES 28:00 to 39:22): Manuel Seara interviews Fernando de Castro Soubriet, who reveals the profiles of some of the disciples of Lorente de Nó: Antonio Gallego, Yves Laporte, Luis Manuel Hernando by Larramendi, Vicente Honrubia and Jorge Larriva-Sahd, among others https://www.rtve.es/play/audios/a-hombros-de-gigantes/hombros-gigantes-tp53-egfr-apoe-pokemon-asterix-quien -how-genes-are-named-24-04-22/6501333/
ESPINOSA-SANCHEZ J. M., ESPINOSAS-CAMPOS L., BATUECAS-CALETRÍO, A. (2020). Lorente de Nó: From Neuroanatomy to Neurophysiology. Anat Rec (Hoboken), 303(5):1221-1231. doi:10.1002/ar.24190. https://anatomypubs.onlinelibrary.wiley.com/doi/abs/10.1002/ar.24190
A Hombros de Gigantes (RNE), Series about Santiago Ramón y Cajal, his school and his legacy. Podcast from 07/21/2021 (LISTEN MINUTES 31:20 to 41:50): Manuel Seara interviews Fernando de Castro Soubriet, who reveals the profile of Rafael Lorente de Nó https://www.rtve.es/play/audios/ a-shoulders-of-giants/giant-shoulders-mechanobiology-influence-physical-forces-cells-25-07-21/6010218/
YouTube Channel Friends of the Museum of Natural Sciences. Series of lectures on the exhibition of Santiago Ramón y Cajal at the MNCN: If ever a scientist was a school, it was Cajal: the Spanish Neurological School. In just three decades, Cajal trained a series of disciples who, following in his footsteps, shone with their own light. His brother Pedro Ramón y Cajal, Francisco Tello, Domingo Sánchez, Nicolás Achúcarro, Pío del Río-Hortega, Gonzalo R. Lafora, Fernando de Castro and Rafael Lorente de Nó illuminated fundamental discoveries. Fernando de Castro Soubriet delves into the trajectories and contributions of what we know as the Spanish Neurological School, January 28, 2022 https://youtu.be/4wwbi4IvbrM?t=2516

El País: news of the death of Rafael Lorente de Nó https://elpais.com/diario/1990/04/09/agenda/639612001_850215.html
Google Scholar profile of Rafael Lorente de Nó https://scholar.google.com/citations?user=Wq8JpmIAAAAJ
Great Aragonese Encyclopedia, entry Rafael Lorente de Nó. http://www.enciclopedia-aragonesa.com/voz.asp?voz_id=8185