This article was first published in 听
The banging on the door at 3 in the morning of March 12, 1938, by Gestapo agents was fierce. They were rousing Otto Loewi out of bed to drag him off to jail. His crime? Loewi was Jewish. It didn鈥檛 matter that two years earlier he had been awarded the Nobel Prize for a landmark experiment that was destined to change the course of medicine.
By the 18th century, anatomists had developed expertise in dissecting cadavers and had identified two sets of nerves that stemmed from the spinal cord and connected to the heart, lungs and kidneys. Since we don鈥檛 consciously control these organs, these nerves were termed 鈥渁utonomic,鈥� as opposed to the 鈥渟omatic鈥� nerves that control our voluntary muscular movements. The first clue as to how the autonomic nerves work came from Luigi Galvani鈥檚 classic discovery in the 1780s that a spark from an electrostatic generator made the severed leg of a frog twitch. This suggested that electricity passed down a nerve.
Then in the 1840s, German anatomist Eduard Weber used a battery, recently developed by Alessandro Volta, to stimulate the vagus nerve in dogs. Stimulation of the vagus, part of the autonomic nervous system, slowed the activity of the heart. A few years later, Moritz Schiff, in a similar experiment, stimulated another set of nerves that caused the heart to speed up. It was now clear that a message travelled down a nerve via an electric current, but there was a conundrum. In the 1880s, Spanish neuroscientist Santiago Ramon y Cajal had looked at stained nerve cells under a microscope and surmised that the cells were separated by a tiny gap that British neurophysiologist Charles Sherrington later named the 鈥渟ynapse,鈥� from the Greek for 鈥渏oin together.鈥� How did the electrical message pass from one nerve cell to another? The theory that seemed rational was that an electrical spark somehow jumped across the gap.
The dismantling of this theory began with Japanese chemist Jokichi Takamine鈥檚 extraction of adrenalin from adrenal glands in 1901. John Langley at Cambridge then made the fascinating observation that injecting adrenalin into the body had the same effect as stimulating the nerve that speeds up the heart. This led his student Thomas Elliott to theorize that maybe the message between the nerve cells that causes the heart to speed up is transmitted by one nerve cell releasing adrenalin that stimulates the next nerve cell and so on. Then in 1907, pharmacologist Walter Dixon, also at Cambridge, stimulated the vagus nerve in a frog, removed the heart, ground it up and made an extract that he then applied to the beating heart of another frog and showed that it slowed down. But significantly, he did not connect this observation to nerve activity. Around the same time, Henry Dale showed that acetylcholine, a compound that occurs naturally in the ergot fungus, and had also been synthesized by Adolf von Baeyer in 1867, slowed the heart exactly like vagus nerve stimulation.
The stage was now set for Loewi to dream up his groundbreaking experiment. Loewi had given up practicing clinical medicine in favour of biochemistry and pharmacology and had achieved a fair degree of recognition with his demonstration that the body could use amino acids from the metabolism of proteins in the diet to build the proteins it needs. In 1909, Loewi accepted a position at the University of Graz in Austria, where he focused on understanding the nervous system. His appetite had been whetted by his travels in England where he met Elliot and Dale and learned about their work.
Now we turn to the famous dream episode, as discussed in detail in Loewi鈥檚 autobiography. On April 2, 1921, he woke up in the middle of the night and jotted down some notes about a dream in which he had carried out a pioneering experiment. In the morning, he could not remember the dream; nor could he read the note he had scrawled. The next night he woke up again at 3 in the morning, having dreamed of designing an experiment to test a theory he had formulated about chemical transmission between nerves. He jumped out of bed and rushed to the lab.
It was well known at the time, as Dixon had found, that a frog鈥檚 heart will continue to beat for a short time if it is immersed in a solution that supplies the ions needed to sustain electrical and mechanical activity. Loewi removed the heart of a frog but left part of the vagus nerve attached. He placed the heart of a second frog in a separate container, but in this case he completely detached the vagus nerve. Then he stimulated the heart of the first frog by applying a current from a battery and after a few minutes transferred some of the solution in which this heart was immersed to the second heart. The beat of the second heart slowed down just as if it had experienced vagal stimulation. This astounding experiment clearly demonstrated that nerves do not influence the heart directly, since the second heart had no nerves attached. In Loewi鈥檚 words, 鈥淣erves must liberate from their terminals specific chemical substances, which, in their turn, cause the well-known modifications of the function of the heart characteristic of the stimulation of its nerve.鈥�
Loewi had discovered the first 鈥渘eurotransmitter,鈥� a chemical that an electrically stimulated nerve cell releases into the synapse that then fits into a receptor on an adjacent cell, much like a hand fits into a glove. When there is an exact fit, the cell 鈥渇ires,鈥� meaning that an electrical signal scoots down to its end, where more neurotransmitter is released, when then stimulates the next cell and the signal is thus propagated. The neurotransmitter in Loewi鈥檚 experiment turned out to be acetylcholine, the same chemical that Dale had found slows the heart鈥檚 activity when injected into an animal. Dale and Loewi shared the 1936 Nobel Prize in Medicine 鈥渇or their discoveries relating to chemical transmission of nerve impulses.鈥�
The concept of neurotransmitters changed the practice of medicine by presenting the possibility of drugs that can enhance, block or mimic the action of neurotransmitters. Parkinson鈥檚 disease is caused by a shortage of dopamine in the brain and can be countered with levodopa, a drug that can cross the blood-brain barrier and release dopamine. Specific serotonin ieuptake Inhibitors (SSRIs) increase the concentration of the mood-elevating neurotransmitter serotonin in the synapse, and atropine blocks receptors for acetylcholine and can speed up an ailing heart. Today, over a hundred neurotransmitters have been identified, many having therapeutic significance.
After spending months incarcerated by the Nazis, during which time he suffered extreme weight loss, Loewi was released with the stipulation that he relinquish all his possessions, including the Nobel Prize money, to the Nazis. He ended up in America as an immigrant who continued to contribute to science until his death in 1961. Many others who heard the Gestapo knocking in the middle of the night, including all four of my grandparents, were not so lucky.
