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June 3, 1873 marks Otto Loewi’s birthday. This German born pharmacologist is known for his discovery of acetylcholine, a neurotransmitter found in both the peripheral and central nervous systems of many organisms including humans. For his discovery, he was awarded the 1936 Nobel Prize in Physiology or Medicine with Sir Henry Dale. Loewi is also known as the “Father of Neuroscience.”
The problem of Neuron Transmission
Between 1836 and 1838, scientists were first able to describe the first cells in nervous tissue. Gabriel Gustav Valentin (1810-1863) was the first to describe the cell, nucleus and nucleolus of neurons, in 1836. By the time Otto Loewi enters university in 1891, the term neuron is being used the cells in the brain. In 1906, both Santiago Ramón y Cajal and Camillo Golgi are awarded the Nobel Prize in Medicine “in recognition of their work on the structure of the nervous system”. Both men had completely different points of view regarding brain organization with the scientific community divided between the reticularist doctrine and neuronal theory.
The reticularist doctrine, supported by C. Golgi, believe that the widespread network of filaments seen in the brain fused into each other. This view was challenged by y Cajal applied the concept of cell theory and said that each neuron is an individual entity and the basic unit of neural circuitry. Neuronal theory eventually won and having established that neurons do not fuse together at any level, the questions of how neurons maintained contact and transmitted signals remained. The neuronal junction was too small to be observed by the microscopes of the time.Many neurophysiologists defended the idea that transmission should be electrical, just like the propagation wave along the axon. While the idea made sense, there were important arguments against this simple picture of the nervous system.
- Information flow along a neural chain is unidirectional — this either occurs between the synapse between one neuron and the dendrite of another (axodendritic) or the synapse between the axon of one neuron and the cell body of another.
- Scientists observed evidence that there were both excitatory and inhibitory synapses. A purely electrical synapse conveying excitation and inhibition would be difficult given that action potentials always have the same potential.
- Scientists also observed a delay in the transmission of impulses through a simple proprioceptive reflex. Electrical transmission should see no delay. A common example of this is the standard knee-jerk response when visiting the doctor.
By the beginning of the 20th century, neuroscientists were convinced that most synapses used chemical transmission. The fundamental proof came in 1921 with experiments carried out by Otto Loewi.
Discovery of Acetylcholine
Before the 1920s, it was unclear whether signalling across synapses were electrical or chemical but in 1921, Loewi designed an experiment to answer that question. Loewi claimed that the idea for his experiment came to him in a series of dreams. He took the beating hearts of two frogs. One heart had the vagus nerve attached which acts to lower heart rate while the other had it removed. By electrically stimulating the vagus nerve, Loewi made the first heart beat slower. Loewi then took some of the liquid bathing the first heart and applied it to the second heart causing it to beat slower. This proved that some soluble chemical released by the vagus nerve was controlling and slowing heart rate and not the electrical impulse itself. Loewi called this chemical Vagusstoff and it was later found to be acetylcholine.
Loewi further tested this effect by stimulating the sympathetic nerves to accelerate heart rate. When Loewi bathed the heart with the liquid, it also accelerated the rate of the other heart. This chemical was discovered to be adrenaline.
The Nobel Prize
Loewi doubted that these neurotransmitters also acted in the somatic nervous system — the nervous system associated with the voluntary control of body movements via skeletal muscles. Research in this area proved much more difficult to carry out but Sir Henry Dale proved this through a series of elegant experiments between 1929 and 1936.
Loewi and Dale, were friends since 1906 and continued their research on neurotransmitters. They shared the Nobel Prize in 1936 for their discoveries.