Severo Ochoa

• Born: September 24, 1905
• Birthplace: Luarca, Spain
• Died: November 1, 1993
• Place of death: Madrid, Spain

Spanish-born biochemist

Although Ochoa made significant discoveries about the metabolism of glucose, he is best known for his discovery of polynucleotide phosphorylase (PNP), which led to the deciphering of the genetic code. He won a Nobel Prize in 1959 for his work on the synthesis of ribonucleic acid (RNA).

Areas of achievement: Science and technology

Early Life

Severo Ochoa de Albornoz (seh-VEH-roh oh-CHOH-ah) was born on September 24, 1905, in Luarca, Spain, to Severo Manuel Ochoa and Carmen de Albornoz. He attended grade school in Málaga and then went to Málaga College, a state school equivalent to an American high school, from which he received a bachelor’s degree in 1921.

Ochoa’s interest in the biomedical sciences was stimulated by Santiago Ramón y Cajal, a Spanish biologist and 1906 Nobel laureate. To further his knowledge of the biomedical sciences, Ochoa attended medical school at the University of Madrid, from which he received an M.D. degree in 1929. As a medical student, Ochoa worked with Juan Negrín y López, a physician and head of the department of physiology. Working with Negrín, Ochoa and another student, José Valdecasas, developed a method to assay small amounts of creatinine and subsequently isolated creatinine from urine. In the summer of 1927, after his fourth year of medical school, Ochoa worked with Diarmid Noël Paton at the University of Glasgow. There, he discovered that the compound guanidine stimulated the contraction of melanophores (pigment cells) in frog skin.

After medical school, Ochoa held several positions that gained him considerable expertise in experimental biochemistry. From 1929 to 1930, he worked with Nobel laureate Otto Fritz Meyerhof in Germany, where he studied muscle metabolism and biochemistry. Upon returning to Madrid in late 1930, Ochoa collaborated with Francisco Grande Covián to study the effect of the adrenal gland on muscle contraction. These studies formed the basis of his thesis, which was a requirement for the M.D. degree. After completing his thesis in 1931, Ochoa was appointed lecturer in physiology at the University of Madrid. Also in 1931, he married Carmen García Cobián. From 1932 to 1933, Ochoa studied with Harold Ward Dudley and Henry Hallett Dale at the National Institute for Medical Research in London. When Ochoa returned to Madrid in 1933, he again joined the Negrín laboratory as an assistant professor in biochemistry and investigated glycolysis in the heart muscle.

Life’s Work

In 1934, Ochoa was appointed lecturer in physiology and biochemistry; he later was appointed head of the physiology division of the Institute for Medical Research at the University of Madrid. When the Spanish Civil War erupted in 1936, Ochoa left Spain and returned to the laboratory of Meyerhof to pursue research focusing on carbohydrate metabolism.

Before Meyerhof fled Nazi Germany for France, he arranged a six-month fellowship for Ochoa with Archibald Vivian Hill at the Plymouth (England) Marine Biological Laboratory. From 1938 to 1941, Ochoa worked on vitamin B1 with biochemist Rudolph Albert Peters at Oxford University, where he became interested in oxidative phosphorylation—a metabolic pathway that uses energy released from nutrients to produce adenosine triphosphate (ATP), a coenzyme used in cells. During his tenure in the Peters laboratory, Ochoa discovered the coupling of phosphorylation to the oxidation of pyruvic acid and demonstrated that three phosphates were fixed for each oxygen atom consumed.

Ochoa left for the United States in August, 1940, and was appointed instructor and research associate in pharmacology at Washington University School of Medicine in St. Louis. There, he worked with Carl Cori and Gerty Cori. Under the tutelage of the Coris, Ochoa pursued studies involving the isolation, purification, and characterization of enzymes. In 1942, Ochoa was appointed research associate in medicine at New York University (NYU) School of Medicine. He spent time in the Department of Biochemistry and in the Department of Pharmacology, but by 1954 he was professor of biochemistry and chairman of this department. Ochoa became a U.S. citizen in 1956. He remained at NYU until he retired in 1974.

Through the early 1950’s, Ochoa’s research focused on various aspects of intermediary metabolism and oxidative phosphorylation and culminated with the isolation of nicotinamide adenine dinucleotide (NAD), a coenzyme found in living cells. By the mid-1950’s, his attention had turned to the synthesis of nucleic acids. In 1955, while studying the mechanism by which the energy of glucose is stored as ATP, he and Marianne Grunberg-Manago discovered an enzyme known as polynucleotide phosphorylase (PNP), which could polymerize (unite molecules in a chemical reaction to form three-dimensional networks or polymer chains) ribonucleoside diphosphates into a polynucleotide chain without a deoxyribonucleic acid (DNA) template. This was the first enzyme discovered that could polymerize ribonucleotides into ribonucleic acid (RNA), and although it was subsequently shown that within living organisms the enzyme degraded RNA, under laboratory conditions PNP ran in the reverse direction and synthesized RNA.

The discovery of PNP was instrumental in the synthesis of synthetic messenger RNAs (mRNAs) used in the unraveling of the genetic code. In separate laboratories, Ochoa, Marshall Nirenberg, and Har Gobind Khorana used PNP to synthesize a variety of synthetic mRNAs, including copolymers consisting of two or more different nucleotides. In 1961, Ochoa, Peter Lengyel, and Joseph Speyer discovered that copolymers such as those made with uracil and cytosine promoted the synthesis of polypeptides consisting of phenylalanine, serine, and leucine. It only took five years for the laboratories of Ochoa, Khorana, and Nirenberg to completely decipher the genetic code.

Ochoa’s later research contributed to the understanding of the mechanisms of replication of RNA viruses and the translation of mRNA into polypeptides. Upon his retirement from NYU School of Medicine in 1974, Ochoa became a distinguished member of the Roche Institute of Molecular Biology. There, he studied protein biosynthesis and the replication of RNA viruses. In 1985, he returned to Madrid as a professor of biology at the Autonomous University of Madrid.

Ochoa published more than two hundred scientific articles during his distinguished career and received numerous honorary degrees and awards. In 1959, Ochoa shared the Nobel Prize in Physiology or Medicine with Arthur Kornberg. In 1961, he was elected president of the International Union of Biochemistry, a position he held until 1967. Ochoa died on November 1, 1993, in Madrid.

Significance

Although Ochoa’s work on carbohydrate metabolism and oxidative phosphorylation contributed significantly to the understanding of energy transfer between glucose and ATP, it was Ochoa’s discovery of PNP and his work on the genetic code for which he is best known. The use of PNP by Ochoa, Nirenberg, and Khorana to synthesize synthetic mRNAs of known composition significantly contributed to the elucidation of the genetic code, one of the most important accomplishments in the history of science.

Bibliography

Garretson, Gregory. Severo Ochoa. Chicago: Heinemann/Raintree, 2005. Aimed at young adult readers, this book summarizes the life and work of Ochoa.

Grunberg-Manago, Marianne. “Severo Ochoa.” Biographical Memoirs of Fellows of the Royal Society 43 (November, 1997): 351-365. This obituary of Ochoa was written by one of his postdoctoral students, with whom he discovered polynucleotide phosphorylase.

Kornberg, Arthur. “Severo Ochoa.” Proceedings of the American Philosophical Society 141, no. 4 (December, 1997): 478-491. Obituary of Ochoa written by Kornberg, who shared the 1959 Nobel Prize in Physiology or Medicine with Ochoa.

Ochoa, Severo. “Pursuit of a Hobby.” Annual Review of Biochemistry 49 (1980): 1-30. Autobiographical sketch describing Ochoa’s early life and scientific career.