Severo Ochoa de Albornoz was a biochemist and medical doctor who made groundbreaking discoveries that were important for understanding RNA synthesis and deciphering the genetic code. He was awarded the Nobel Prize in Physiology or Medicine in 1959 together with Arthur Kornberg “for their discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid.”
1 Ochoa’s Life and Career
Severo Ochoa de Albornoz was born on September 24, 1905 in Luarca, Spain [1–3]. After the death of his father when Severo was seven years old, he and his mother moved to Málaga, Spain. Ochoa studied medicine at the University of Madrid, Spain, starting in 1923. During his studies, he spent the summer of 1927 at the University of Glasgow, UK, working with the Scottish physician Diarmid Noël Paton. Ochoa completed his undergraduate medical degree in 1929, and then moved to Berlin, Germany to join the 1922 Nobel Laureate in Physiology or Medicine Otto Fritz Meyerhof at the Kaiser Wilhelm Institute for Biology in Berlin-Dahlem.
Severo Ochoa returned to Madrid in 1930 and finished his M.D. degree with a thesis on the role of the adrenal glands in muscular contraction. He married Carmen García Cobián in 1931. For postdoctoral studies, Ochoa moved to the National Institute for Medical Research in London, UK, where he worked with Henry Hallett Dale (1936 Nobel Laureate in Physiology or Medicine together with Otto Loewi). He returned to Madrid in 1933, and was soon offered the position of Director of the Physiology Section at the Institute for Medical Research of the University of Madrid Medical School.
However, the Spanish Civil War erupted just a few months later, and Ochoa decided to leave Spain. In September 1936, he and his wife left for Heidelberg, Germany, where Meyerhof had moved earlier. Meyerhof, who was Jewish, had to leave the country in 1938 due to the Nazi regime and emigrated to Paris. The Ochoas moved to Plymouth, UK, where Severo had received a fellowship to work for six months at the Marine Biological Laboratory (MBL), then on to Oxford, UK, to work with Rudolph Albert Peters. The time in Oxford was, again, cut short, this time by the start of World War II, and Ochoa left in 1940 to join Carl and Gerty Cori at Washington University in St. Louis, MO, USA.
In early 1942, Severo Ochoa moved again, this time to join New York University (NYU), USA, as a research associate in medicine. Arthur Kornberg was one of his first postdoctoral students there. At NYU, Ochoa was appointed Assistant Professor of Biochemistry in 1945, Chair of the Department of Pharmacology in 1946, and Chair of the Department of Biochemistry in 1954. He stayed there until his retirement in 1974. Severo Ochoa passed away in Madrid on November 1, 1993. His life and work have been honored widely. For example, the asteroid 117435 Severochoa is named after him, and both the Spanish General Post Office and the United States Postal Service issued stamps featuring Ochoa.
2 Ochoa’s Research
When Ochoa was still in medical school, Juan Negrín (Spanish physician and politician) encouraged Ochoa and his fiend José Valdecasas to isolate creatinine from urine [4]. The two students developed a method to measure levels of muscle creatinine [5], which marked the beginning of Ochoa’s research career. His postdoctoral research in London involved the enzyme glyoxalase, which was the start of his lifelong interest in enzymes. In Heidelberg, he worked on, e.g., glycolysis in the heart and isolated nicotinamide adenine dinucleotide (NAD) from skeletal muscle. At the Marine Biological Laboratory in Plymouth, Ochoa worked together with his wife, who had no prior laboratory training, on transphosphorylation reactions and NAD distribution in invertebrate muscle. The couple published a joint paper in Nature [6].
In Oxford, Ochoa worked on vitamin B1 (thiamine) and cocarboxylase [7], as well as oxidative phosphorylation, a process in cells that generates adenosine triphosphate (ATP), work he continued at NYU [8,9]. He then studied some of the enzymes of the citric acid cycle, such as isocitric dehydrogenase. This work also had additional impacts: Ochoa thought that a reversed isocitric dehydrogenase reaction could provide a mechanism for CO2 fixation. He observed this proposed reversibility using a spectrophotometer [10]. This device had been obtained through a grant from the American Philosophical Society, which was valid for one year, with the instrument to be returned to the society at the end of this time. The success of the experiments led the society to allow Ochoa to keep the instrument.
2.1 Polynucleotide Phosphorylase and the Genetic Code
In 1954, Ochoa returned his focus to oxidative phosphorylation, searching for enzymes that can convert adenosine diphosphate (ADP) to ATP. He and his postdoc Marianne Grunberg-Manago found such an enzyme in extracts of Azobacter vinelandii. It promoted the incorporation of 32P into ADP, but also into other nucleoside diphosphates. The researchers then also found that the enzyme also catalyzed the formation of polynucleotide products.
The group had discovered the first nucleic-acid-synthesizing enzyme, polynucleotide phosphorylase (PNPase) [11,12]. Initially, it was thought that the new enzyme was an RNA polymerase used by E. coli cells to make RNA chains from separate nucleotides [13]. However, while the enzyme can link nucleotides together, the reaction is highly reversible and it later became clear that the enzyme usually catalyzes the breakdown of RNA, not its synthesis.
The discovery of PNPase happened shortly after James Watson and Francis Crick discovered the double helix structure of DNA in 1953. How exactly the sequence of nucleobases can be translated into an amino acid sequence—i.e., the genetic code—was not known at the time. It was found that not the DNA itself, but a single-stranded messenger RNA (mRNA) copy is used to translate the genetic information during protein synthesis outside of the nucleus. PNPase was used to prepare polyribonucleotides, which could then be used in protein synthesis in E.coli bacteria to find out which amino acids they encode—thus, helping to crack the genetic code. So even though PNPase catalyzes the reverse reaction in vivo than Ochoa’s team first thought, its use in the in vitro synthesis of polyribonucleotides contributed to a groundbreaking discovery in biochemistry.
Severo Ochoa is the answer to Guess the Chemist (138).
References
[1] Severo Ochoa (24 September 1905 – 1 November 1993),
Arthur Kornberg,
Proc. Am. Philos. Soc. 1997, 141, 478-491.
[2] Severo Ochoa (1905–1993): The Changing World of Biochemistry,
Marı́a Jesús Santesmases,
Trends Biochem. Sci. 2001, 26, 140–142.
https://doi.org/10.1016/S0968-0004(00)01751-5
[3] Severo Ochoa. 24 September 1905 – 1 November 1993,
Marianne Grunberg-Manago,
Biogr. Mems Fell. R. Soc. 1997, 43, 351–365.
https://doi.org/10.1098/rsbm.1997.0020
[4] A Pursuit of a Hobby,
Severo Ochoa,
Ann. Rev. Biochem. 1980, 49, 1–31.
https://doi.org/10.1146/annurev.bi.49.070180.000245
[5] A Micromethod for the Estimation of Total Creatinine in Muscle,
Severo Ochoa, José Valdecasas,
J. Biol. Chem. 1929, 81, 351–357.
https://doi.org/10.1016/S0021-9258(18)83817-0
[6] Cozymase in Invertebrate Muscle,
S. Ochoa, C. G. Ochoa,
Nature 1937, 140, 1097.
https://doi.org/10.1038/1401097a0
[7] Pyruvate oxidation in brain: The active form of vitamin B1 and the role of C4 dicarboxylic acids,
Ilona Banga, Severo Ochoa, Rudolph Albert Peters,
Biochem. J. 1939, 33, 1109–1121.
https://doi.org/10.1042/bj0331109
[8] “Coupling” of Phosphorylation with Oxidation of Pyruvic Acid in Brain,
Severo Ochoa,
J. Biol. Chem. 1941, 138, 751–773.
https://doi.org/10.1016/S0021-9258(18)51399-5
[9] Efficiency of Aerobic Phosphorylation in Cell-Free Heart Extracts,
Severo Ochoa,
J. Biol. Chem. 1943, 151, 493–505.
https://doi.org/10.1016/S0021-9258(18)44922-8
[10] Biosynthesis of Tricarboxylic Acids by Carbon Dioxde Fixation. III. Enzymatic Mechanisms,
Severo Ochoa,
J. Biol. Chem. 1948, 174, 133–157.
https://doi.org/10.1016/S0021-9258(18)57383-X
[11] Enzymatic Synthesis and Breakdown of Polynucleotides,
Marianne Grunberg-Manago , Severo Ochoa,
J. Am. Chem. Soc. 1955, 77, 3165–3166.
https://doi.org/10.1021/ja01616a093
[12] Enzymic Synthesis of Polynucleotides. I. Polynucleotide Phosphorylase of Azotobacter vinelandii,
Marianne Grunberg-Manago, Priscilla J. Ortiz, Severo Ochoa,
Biochim. Biophys. Acta 1956, 20, 269–285.
https://doi.org/10.1016/0006-3002(56)90286-4
[13] Enzymatic Synthesis of Nucleic Acidlike Polynucleotides,
Marianne Grunberg-Manago, Priscilla J. Ortiz, Severo Ochoa,
Science 1955, 122, 907–910.
https://doi.org/10.1126/science.122.3176.907
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