Serotonin Research & Three Great Scientists’ Contributions

Vittorio Erspamer MD, Photo credit: Unknown; Public Domain, Wikipedia Commons

 

Dr. Vittorio Erspamer (1909-1999), the well-known discoverer of serotonin and octopamine, was an Italian pharmacologist and chemist, known for the identification, synthesis and pharmacological studies of more than sixty new chemical compounds, most notably serotonin and octopamine.

 

Erspamer was born in 1909 in the small village of Val di Non in Malosco, a municipality of Trentino in northern Italy. He attended school in the Roman Catholic Archdiocese of Trento and then moved to Pavia, where he studied at Ghislieri College, graduating in medicine and surgery in 1935. He then took the post of assistant professor in anatomy and physiology at the University of Pavia – one of the oldest universities in Europe, founded in 1361. In 1936, he obtained a scholarship to study at the Institute of Pharmacology at the University of Berlin. After returning to Italy in 1939, he moved to Rome where he took up the position of professor in pharmacology. In Rome, the focus of his research shifted to drugs and he used his past biological experience to focus on compounds isolated from animal tissues. In 1947 he became professor of pharmacology at the Faculty of Medicine at the University of Bari. In 1955, he moved from Bari to Parma, to assume an equivalent position of professor of pharmacology at the Faculty of Medicine, University of Parma. Erspamer was one of the first Italian pharmacologists to realize that fruitful scientific research benefits from building a relationship with the chemical and pharmaceutical industries. In the late 1950s, he established a collaboration with chemists at the Farmitalia company. The collaboration was useful, not only for the analysis of the structure of new molecules which he isolated and characterized pharmacologically, but also for the subsequent industrial synthesis of these chemicals and their synthetic analogs.

 

Thanks to funding received from Farmitalia, over the years Erspamer collected more than five hundred species of marine organisms from all around the world, including amphibians, shellfish, sea anemones and other species. For this purpose, he spent much time in traveling, and was known among his colleagues for his careful preparation of expeditions and knowledge of geography. Using these world-wide observations he developed a theory of geo-phylogenetic correlations among the different amphibian species of the world, which was based on analysis of the peptides and amines in their skin.

 

The research activities of Erspamer spanned more than 60 years and resulted in the isolation, identification, synthesis and pharmacological study of more than sixty new chemical compounds, especially polypeptides and biogenic amines, but also some alkaloids. Most of these compounds were isolated from animals, predominantly amphibians. In the late fifties his research shifted to peptides. In the laboratories of the Institute of Medical Pharmacology, University of Rome, he isolated from amphibians and mollusks more than fifty new bioactive peptides. These became the subjects of numerous studies in other laboratories in Europe and North America. In 1979, he focused on opioid peptides specific to Phyllomedusa, a genus of tree frog from Central and South America. These were used by the native Indians in initiation rites, to increase their prowess as “hunters” and make them feel “invincible”. They applied secretions from the skin of these frogs that resulted in euphoric and analgesic effects. The peptides studied by Erspamer have become essential to characterize the functional role of opioid receptors.

 

Erspamer retired from administrative positions in 1984 because of the age limits, but continued his research and writing until his death in Rome in 1999. His last, unfinished review was completed by his collaborators and published in 2002. During his lifetime he was twice nominated for the Nobel Prize.

 

Between 1933 and 1934, while still a college student, Erspamer published his first work on the histochemical characteristics of enterochromaffin cells using advanced techniques, not normally used at that time, such as diazo reactions, Wood’s lamp and fluorescence microscopy. In 1935, he showed that an extract prepared from enterochromaffin cells made intestinal tissue contract. Other chemists believed the extract contained adrenaline, but two years later Erspamer demonstrated that it was a previously unknown chemical, an amine, which he named enteramine and which was renamed, later as serotonin. In 1948, Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum, and since it was a serum agent affecting vascular tone, they named it serotonin. In 1952 it was shown that enteramine was the same substance as serotonin. Another important chemical, also an amine, was discovered by Erspamer in 1948, in the salivary glands of the octopus, and therefore named by him octopamine.

 

Maurice Rapport (1919-2011) was a biochemist who is best known for his work with the neurotransmitter serotonin. Rapport, Irvine H. Page, and Arda A. Green worked together to isolate and name the chemical. Alone, Rapport identified its structure and published his findings in 1948. Research since its discovery has implicated serotonin with mood regulation, appetite, reproductive drives, and sleep as well as gastrointestinal roles. After his work with serotonin, Rapport did important research with cancer, cardiovascular disease, connective-tissue disease and demyelinating diseases.

 

Maurice Rapoport was born on September 23, 1919 in Atlantic City, New Jersey. His mother changed the spelling of the family name to Rapport. His father was a furrier from Russia who left the family when Rapport was a small child. Rapport graduated from DeWitt Clinton High School in the Bronx, New York and went on to earn a bachelor’s degree in chemistry from the City College of New York in 1940. He obtained his doctorate in organic chemistry in 1946 from California Institute of Technology. In 1946, Maurice Rapport began working in the Cleveland Clinic Foundation which was directed by Irvine H. Page. Since the 1860s, a substance was known about, in the serum of blood vessels, that promoted clotting. Rapport was assigned the project of isolating this serum. They enlisted the help of Arda A. Green, a physical biochemist. The substance was acquired by leaving a test tube of the reagents in a cold room while Rapport went on vacation. When he returned he isolated the crystals of the desired substance. In a paper published in 1948, they gave it a name: serotonin, derived from “serum“ and “tonic“.

 

In 1948, Rapport left the Cleveland Clinic for a position at Columbia University and continued searching for serotonin’s structure. In May 1949, the structure of serotonin was discovered to be 5-hydroxytryptamine (5-HT). Serotonin was found to be the same substance that Dr. Vittorio Erspamer had been studying since the 1930s called “enteramine“. Enteramine had a substantial place in scientific literature due to Erspamer’s research into its role in smooth muscle constriction and intestinal tracts. Erspamer’s research contributed to Rapport’s discovery of serotonin’s structure and allowed other researchers to synthesize the substance and further study its role in the body.

 

The structure of serotonin was given to Upjohn Drug Company where researchers focused on the role of serotonin in the bodily processes such as blood vessel constriction. In 1954, Betty Twarog discovered the distribution of serotonin in the brain. Further research illustrated how serotonin plays a major role in the central nervous system and digestive tract. The understanding of serotonin has led to a progression in our view of mental illness and allowed the development of antidepressants and other drugs for hypertension and migraines. After his work with serotonin, Rapport worked at the Sloan-Kettering Institute for Cancer Research. His contributions involved the activity and structures of lipids in relation to immunological activity. Specifically, he isolated cytolipin H from human cancer tissue in 1958. This led to a better understanding of our immune system. He also was a professor at the Albert Einstein College of Medicine. There he isolated two glysosphingolipids and studied antibodies to gangliosides. These findings were useful to further pharmacological studies relating these substances to demyelinating diseases such as Amyotrophic Lateral Sclerosis (ALS).

In 1968, Rapport returned to Columbia University as chief of pharmacology and professor of biochemistry. The next year, he became the chief of the new neuroscience division which combined the chemistry, pharmacology, and bacteriology divisions. He retired in 1986 and remained in the neurology department of the Albert Einstein College of Medicine as a visiting professor.

 

Betty Mack Twarog (1927 – 2013) was an American biochemist who was the first to find serotonin in the mammalian brain.. She attended Swarthmore College from 1944 to 1948, focusing on mathematics. While studying for an M.Sc. at Tufts College she heard a lecture on mollusc muscle neurology and in 1949 enrolled under John Welsh in the PhD program at Harvard to study this area. By 1952 she had submitted a paper showing that serotonin had a role as a neurotransmitter in mussels. In Autumn 1952 Twarog moved for family reasons to the Kent State University area , and chose the Cleveland Clinic as a place to continue her study of her hypothesis that invertebrate neurotransmitters would also be found in mammals. Although her supporter there, Irvine Page did not believe serotonin would be found in the brain, he nevertheless gave Twarog a laboratory and technician. By June 1953 a paper was submitted announcing the isolation of serotonin in mammalian brain. Twarog left the Cleveland Clinic in 1954 and continued to work on invertebrate smooth muscle at Tufts, Harvard and SUNY at Stony Brook. In later years, at the Bigelow Laboratory for Ocean Sciences in Boothbay Harbor, Maine she worked on how shellfish evade phytoplankton poisons. Twarog died on February 6, 2013, at the age of 85 in Damariscotta, Maine.

 

Twarog’s isolation of serotonin in brain established its potential as a neurotransmitter and thus a modulator of brain action. Her discovery was an essential precursor to the creation in 1978 of the antidepressant SSRI medicines such as fluoxetine and sertraline.

 

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