Xavier REZAI J.M.N. 2007 BIOGRAPHY OTTO LOEWI SCIENTIFIC CONTEXT MAIN WORK The end of the 19th century was the starting point of many discoveries in the field of the neurophy- siology. At that time, only basic technical approaches were available, and new discoveries depended on few results and lots of deductions. Furthermore, the scientific com- munity was often debating on theoretical speculations and was often divided. I have chosen to present a German neurophysio- logist, Otto Loewi, as he witnessed lots of debates of the late 19th century, and since he had solved the major question of synaptic transmission with quite simple ex- periments. BIOGRAPHY 1873 3rd June, birth of Otto Loewi, in Frankfurt- am-Main (Germany). His father is Jacob Loewi, a merchant, and his mother is Anna Willstätter. 1891 He starts medical studies at the universities of Munich and Strasbourg (at that time part of Germany). 1893 He just manage to pass his first examina tion although he was more interested in the philosophy lectures. 1896 He finally brilliantly obtains his doctor’s 1921 He proves, the chemical transmission of the degree with a thesis about “techniques of nerve impulses. isolations of frog’s heart”. 1936 He receives the Nobel price, with Henri Dale. 1898 He becomes an assistant of Pr Hans Horst Meyer, a pharmacologist. 1938 He is forced to leave Austria, invaded by the Germans and moves to London. 1902 In London, in Starling’s laboratory, he meets for the first time Henri Hallet Dale, who was 1940 He travels from England to America, where to become a lifelong friend. he is invited to join the College of Medicine of New-York, as a Research Professor in 1904 He starts teaching at the University of Vien Pharmacology. na, as a Professor in Pharmacology. 1946 He becomes an American citizen. 1909 He is appointed to the Chair of Pharmaco logy in Graz. 1961 25th December, death. SCIENTIFIC CONTEXT 35 years before Otto Loewi ‘s birth, Gabriel Gustav Valentin was the first to describe the nucleus and nucleolus of The neuronal theory had four tenets: cells present in the brain. The name « neuron » was used for the The neuron is the structural and first time in 1891, when Otto Loewi en- functional unit of the nervous ters the university. He was 33 years old system; when Santiago Ramon Y Cajal and Camil- lio Golgi shared the 1906 Nobel Price for Neurons are individual cells, their contribution in neurophysiology, which are not continuous to This theory was supported by S.R. y although having a completely different other neurons, neither anatomi Cajal, R. A. von Kölliker, W. von Wal- point of view about brain organisation. cally nor genetically; deyer and of course was the good Actually, the scientific community was at one. that time divided about the brain organi- The neuron has three parts: den sation between reticularist and neuronal drites, soma (cell body) and axon. Having established that neurons theory. The axon has several terminal do not fuse together at any level of arborizations, which make their ramifications, a question be- The reticularist doctrine was supported close contacts to dendrites or the came important. How is the contact by C.Golgi : soma of other neurons; between neurons? How the trans- mission of an electrical impulse « There is certainly to be found a very Conduction takes place in the wave occurs between two neurons? widespread network of filaments anas- direction from dendrites to soma, This «neuronal junction», was too tomosing one with the other throughout to the end arborizations of the small to be observed by the micros- the gray matter of the brain. » axon copes of that time. SCIENTIFIC CONTEXT The problem of the nature of trans- purely electrical synapse conveying exci- Sherrington gave the name, «synapse», mission from one neuron to another was tation or inhibition. which, in Greek, means «to clasp» and he also a point of major consideration and was one of the first to discover that the inquiry among neurophysiologists at the The third was based on the observed delay interplay of central excitation and inhibi- turn of the 20th century. Back to 1846, in the transmission of impulses through a tion are fundamental for information in- Emil DuBois-Reymond proposed the exis- simple proprioceptive reflex. An electrical tegration. tence of synapses that could be either transmission should have no delay. The same concepts of excitation electrical or chemical. He had no support and inhibition appeared again in the study for this speculation, and thid idea was of the peripheral nervous system, particu- abandoned. Many of the experiments supporting these larly in the Autonomous Nervous System data were carried out in the laboratory of (ANS). Many neurophysiologists defended the the great British physiologist Sir Charles For example, the force of contraction and idea that the transmission should be S. Sherrington (1852-1952), who investi- heart rate increase when the so-called electrical, just like the propagation wave gated in the late 1890s the physiology of sympathetic division is activated (by elec- along the axon. It was actually making simple and complex motor reflexes. trically stimulating the ganglionar nerves sense to imagine electrical synapses. Un- which innervate the heart, for example). fortunately there were three important ar- In contrast, they are decreased when the guments against such simple picture of vagus nerve, which conduits the so-called the nervous system. parasympathetic division, is activated. The first is the unidirectional flow of in- How electrical transmission in the same formation in a neural chain: this flow is postsynaptic element could achieve total- always in the axo-dendritic or axo-soma- ly opposite effects. The answer, of course, tic way, and must be mediated by the sy- was again a chemical transmission. napse. All these evidences have convinced neu- roscientists in the beginning of the 20th The second is that scientists were accu- century that most synapses had chemical mulating evidence that there were exci- transmission. However the fundamental tatory as well as inhibitory synapses. Sin- proof came only in 1921, as we will see, ce it was already known that the action with the crucial experiments carried out potential has always the same polarity, by Otto Loewi. it would have been difficult to imagine a MAIN WORK After working 12 years on the pharmaco- However, when he perfused the second logy of the Autonomous Nervous System, heart with the outflow of the perfusion in the University of Graz, he designed his of the first one, he achieved exactly the most famous experiment, which provided same effect (D), with a small delay provo- the first evidence for the existence of che- ked by the pump action and the chemical mical transmission in a synapse. action. The legend tells that he had the idea of the experiment in a dream and that he ran to the lab in the middle of the night. It was therefore concluded that some The experiment was very simple and be- substance produced at the parasympa- came a prototype for all investigations of thetic synapse level in heart R, was able chemical factors in the nervous system. to induce a similar response in the mus- cles of heart D. Loewi believed that it was He cut out two hearts from frogs and per- acetylcholine, and it was actually demons- fused them with a warm physiological trated later. solution (Ringer). In this condition, the frog´s hearts continue to beat for some hours. He then stimulated the vagus ner- After using the same preparation to study ve to one of the hearts. the effects of stimulating the sympathetic As a consequence, there was a strong in- nerves, he obtained an opposite effect: hibition in this heart beats (R). The second Loewi´s original kimographic record of heart D accelerated its pace, as observed heart was unaffected. the experiment. following adrenaline injection. CONCLUSION & REFERENCES «If a nerve by a stimulus gets an impulse this impulse is propagated within the nerve and is transmitted to the respective effecti- Loewi doubted that such neurotransmitters ve organs (heart, muscle, gland) innervated by the nerve. The question arose by which also operated in the somatic nervous sys- means the impulse coming from the nerve tem. is transmitted to the effector organ. I was able to solve this question by proving Research in this area was much more difficult that the impulse running down within the to carry out, but Sir Henry Dale again came nerve liberates from its endings chemical to rescue, by proving, in a series of elegant substances (Acetylcholine or Adrenaline respectively) which in their turn influence experiments between 1929 and 1936, that the effector organ exactly like the stimula- acetylcholine was also a neurotransmitter in tion of the nerve. With other words: the influence of nervous the neuromotor synapse, and that pregan- stimulation on an organ is not a direct one glionic synapses in the ANS are all choliner- but an indirect one mediated to the organ by chemical substances released by the gic, in contrast to the postganglionic ones, nerve stimulation in its endings.» which can be either cholinergic or adrener- gic, as Loewi had demonstrated. Otto Loewi Dale also was the first to isolate acetylcholi- ne from mammalian organs, and to propose the terms «cholinergic» and «adrenergic» sy- http://nobelprize.org/nobel_prizes/medicine/laureates/1936/index.html napses. http://www.cerebromente.org.br/n17/history/neurons4_i.htm Loewi and Dale, who were friends since 1906, http://ura1195-6.univ-lyon1.fr/articles/savenir/genie/loewi.html continued their efforts on clarifying the role http://www.answers.com/main/ntquery?s=loewi&gwp=13 of neurotransmitters.