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Ochoa, Severo

OCHOA, SEVERO

(b. Luarca [province of Asturias], Spain, 24 September 1905; d. Madrid, Spain, 1 November 1993)

biochemistry, enzymology, molecular biology.

Ochoa’s contributions to modern biology were significant and involved many problems central to twentieth-century biochemistry, including bioenergetics, enzymology, intermediary metabolism, and the foundation of molecular biology. Through a series of fortunate contingencies, he was able to follow biochemistry’s disciplinary migration from Germany to Britain and, ultimately, to the United States. His diverse career bridged the flourishing of biochemistry during the twentieth century’s middle decades—a period that Marianne Grunberg-Manago called “The Golden Age of Intermediary Metabolism” (1997, p. 353)—and helped establish early concepts of molecular biology. In her Ochoa obituary, Grunberg-Manago accurately summarized Ochoa’s career as “a résumé of the history of contemporary biochemistry and the foundation of molecular biology.”

Early Life and Education Ochoa, named after his father, was one of seven children. His father, a lawyer and businessman, died when Ochoa was seven years old. His mother, the former Carmen Albornoz, moved the family to Málage on the Mediterranean coast “in search of a milder climate.” Ochoa completed his baccalauréat in 1921 at a local Jesuit private high school. Inspired by the Nobel Prize–winning neurobiologist, Santiago Ramón y Cajal, he developed an interest in the natural sciences, especially biology. In 1923 he began medical studies at Madrid University; he did not intend to practice medicine, but chose this course of study because it was the best route to the study of biology. Ramón y Cajal had retired from working with students, and Ochoa was mentored by the “young, bright, and inspiring teacher, Juan Negrín.” Negrín trained at the University of Leipzig, and he (as Ochoa described) “opened wide, fascinating vistas to my imagination, not only through his lectures and laboratory teaching, but through his advice, encouragement, and stimulation to read scientific monographs and textbooks in languages other than Spanish” (Ochoa, 1980, p. 2).

Negrín, who was interested in reactions of creatine, phosphocreatine, and creatinine, introduced Ochoa to experimental research and encouraged him and another student, José Valdecasas, to use his laboratory. The medical school lacked a research facility; thus Ochoa lived and worked at an institution that he described as the equivalent of an Oxford or Cambridge college. The environment was a rich intellectual experience; the Spanish dramatist and poet Federico García Lorca, the painter Salvador Dalí, and the film director Luis Buñuel were also working or studying at “La Residencia.”

To learn laboratory practice, Negrín suggest that Valdecasas and Ochoa attempt to isolate creatinine (a biological “waste product” of phosphocreatine) from urine. After initial difficulties, the two succeeded, and a few months later they developed an easy micromethod to measure creatinine levels in muscle. In 1927, to improve his English skills, Ochoa spent the summer in Glasgow with D. Noel Paton, Regius Chair of Physiology, working on creatine metabolism, where he further refined the assay procedure. Returning to Madrid, Ochoa and Valdecasas submitted their work to the Journal of Biological Chemistry, which rapidly accepted the paper (Ochoa, 1980, p. 4), thus beginning Ochoa’s biochemistry career.

In summer of 1928, his bachelor of medicine completed, Ochoa began to think about going abroad for further training. At the time, biochemists were increasingly interested in the metabolic role of phosphocreatine. Ochoa’s previous work on creatine and creatinine led to an interest in Otto Meyerhof’s work on the chemical processes of muscle contraction. In 1929 Ochoa began work in Meyerhof’s laboratory at the Kaiser Wilhelm Institute for Biology in Berlin-Dahlem. The institute was rapidly becoming an international center for biochemistry, with distinguished scientists such as Meyerhof, Otto Warburg, and Carl Neuberg, and was fertile ground for the expansion of Ochoa’s scientific growth. After a brief visit to Madrid to take required examinations for the MD degree, Ochoa returned to Meyerhof’s lab, which had moved from Berlin to Heidelberg. His work with Meyerhof was by and large confirmatory of earlier work, Ochoa claimed, and indeed he published little during this period.

While his work in Heidelberg may have been largely “confirmatory,” Ochoa found the Meyerhof laboratory to be a “hot bed” of new biochemical ideas. In 1930 Einar Lundsgaard traveled from Denmark to Heidelberg to personally demonstrate that Meyerhof’s ideas about energy generation, for which he received the 1922 Nobel Prize in Physiology and Medicine, were wrong and that phosphocreatine was involved in muscle contraction. Fritz Lip-mann, who was in Meyerhof’s lab at the time, commented that Lundsgaard’s work was a “truly great discovery … [that] changed our concepts of metabolic energy transformation” (1969, pp. 246–247). Both Lundsgaard’s demonstration and Meyerhof’s acceptance of his error impressed Ochoa.

In late 1930 Ochoa returned to Madrid, where he and Francisco Grande Covián collaborated to study the role of adrenal glands in muscle contraction, which eventually became his MD thesis. After completing his medical education, Ochoa married Carmen García Cobián and in 1931 began postdoctoral study at the National Institute for Medical Research (NIMR) in London, directed by Sir Henry Dale. His research involved glyoxalase, an enzyme that catalyzes the conversion of methylglyoxal to lactic acid. The enzyme was important, because biochemists speculated that methylglyoxal might be an intermediate in glucose oxidation to lactic acid. Studying glyoxalase influenced Ochoa’s career in two ways. First, the work was at the forefront in the rapidly evolving study of intermediary metabolism (i.e., the sequence of chemical reactions whereby foodstuffs are converted to compounds that are biologically useful for energetic and synthetic purposes). Second, the project initiated what became a lifelong interest in enzymology.

After two years in London, Ochoa returned to Madrid and began to study glycolysis in heart muscle. In 1935 the University of Madrid Medical School created a new Institute for Medical Research, and Ochoa became director of the Physiology Section. Unfortunately, within months the Spanish civil war erupted, and the Ochoas decided to leave Spain; in September 1936 they began what he later called the “wander years.”

Wander Years Once he decided to leave Spain, Ochoa contacted Meyerhof, who found him a place at Heidelberg. Ochoa noted that scientifically Meyerhof’s laboratory had changed radically since his 1930 visit. In 1930 the primary focus was on physiology; “one could see muscles twitching everywhere” (Ochoa, 1980, p. 8). In 1936 the laboratory work was biochemical and focused on glycolysis and fermentation. The lab was beginning to purify and characterize enzymes that catalyzed these processes in muscle or yeast extracts.

Although the Meyerhof lab was scientifically vigorous, Ochoa observed that Meyerhof was in a precarious position; his family had left Germany, and Meyerhof himself planned to leave for Paris. Ochoa wryly noted that he had left one troubled country for another. Meyerhof arranged, through his friend Archibald Vivian Hill, for Ochoa to obtain a six-month Ray Lankester Investigator fellowship at the Marine Biological Laboratory (MBL) in Plymouth, England, which began in July 1937.

Ochoa’s brief time at the Plymouth MBL was productive and happy, except for concerns about relatives still in Spain. He continued work begun in Meyerhof’s lab on the metabolic role of “cozymase” (which came to be known as nicotinamide adenine dinucleotide, NAD), which he isolated in pure form. Support staff was not readily available, and Ochoa’s wife, who had no prior laboratory training, helped on a variety of projects. Her assistance on NAD distribution in invertebrate muscle was such that the two coauthored a Nature paper (1937). More important, for Ochoa’s long-term career, was a friendship with William Ringrose Gelston Atkins, who helped him secure a Nuffield Foundation fellowship. In December 1937 the Ochoas departed for Oxford, where Ochoa began a rich collaboration with Rudolph Albert Peters, who was Whitley Chair of Biochemistry.

During the 1920s Peters had established the concept that the B vitamin complex consisted of individual chemicals with specific physiological properties. His work increasingly focused on vitamin B1 (thiamine) and its role in alleviating neurological beriberi symptoms. When Ochoa joined his laboratory Peters was beginning work on the chemical mechanism of thiamine action, a goal in which Ochoa played a central role. Over the next two years Ochoa and Peters successfully isolated various enzymes and demonstrated the role of thiamine (in addition to various other cofactors) in enzyme action (Thompson and Ogston, 1983).

Ochoa understated his relationship with Peters when he described it as “a very happy and productive one.” During the two years in Oxford, Ochoa published more than eighteen papers, eleven coauthored with Peters, two of which (Ochoa and Peters, 1938; Ochoa, et al., 1939) are seminal to Ochoa’s career. Both papers explored connections between various cofactors and pyruvate metabolism in brain tissue. In addition to confirming many aspects of intermediary metabolism, the work established the role of both vitamin B1 and “adenine nucleotides” (i.e., now known as adenosine triphosphate or ATP) as cofactors in pyruvate oxidation. Marianne Grunberg-Manago has suggested that the ATP involvement led to Ochoa’s later interest in oxidative phosphorylation (1997, p. 353). More importantly, the two papers demonstrated both Ochoa’s developing biochemical skills and his ability in the rapidly evolving field of enzymology.

Unfortunately, warfare again intervened; and the “happy and productive” period was short-lived as the laboratory’s focus increasingly shifted to war support. Because of Ochoa’s status as an alien, he was excluded from this work and increasingly began to consider a move to the United States. He wrote to Carl and Gerty Cori in St. Louis and was readily accepted to work in their Washington University laboratory. In August 1940 the Ochoas “sailed for the New World, not without sadness, but full of hope and expectations” (Ochoa, 1980, p. 9).

The move to the United States was, arguably, the most important event in Ochoa’s career, so a reasonable question might arise about why the Coris were so willing to accept him into their lab. However, by 1939 Ochoa’s resume must have been impressive. He had worked with two Nobel Prize recipients, and his Oxford work demonstrated his biochemical maturity. In 1938 Dale, recipient of the 1936 Nobel Prize in Physiology or Medicine, wrote a letter supporting Ochoa’s application for a lectureship in biochemistry at University College, Dundee. Dale noted that Ochoa was “a man of exceptional promise in Biochemical research … a keen, enterprising, and well-qualified research worker in Biochemistry” (Dale, 1938). Clearly such letters would carry great impact in a lab even as sophisticated as that of Carl and Gerty Cori.

Although Ochoa had studied enzyme actions since his NIMR work, the previous work mostly involved crude, cell-free extracts. The Cori lab focus, however, was on purified enzymes free of potentially contaminating

reactions. Although the Coris were not the first to study metabolism by isolating purified enzymes, Hugo Theorell called their in vivo synthesis of glycogen using crystalline enzymes an “astounding feat” (1947).

For Ochoa, the St. Louis lab was both exciting and frustrating. Excitement arose from enzymology’s central role in the research as well as the stream of visitors, such as Herman Kalckar and Earl Sutherland, and graduate students such as Sidney Colowick, who brought in new ideas and techniques. Frustration arose from his research work. Cori suggested that Ochoa attempt to study fructose conversion to glucose, which both men thought “ought to have been a cinch” (Ochoa, 1980, p. 10). Unfortunately, the problem was far more refractory and was not resolved for many years. Although he had been in the Cori lab for less than two years, apparently the research difficulties were sufficiently frustrating that Ochoa decided to once again move, a decision that ultimately led to his career’s major work.

Career Stability and “The Golden Age of Intermediary Metabolism.” During his brief time at Oxford, Ochoa developed a strong friendship with Robert Stanley Good-hart, a New York University (NYU) nutritionist. Good-hart persuaded Ochoa to move to NYU, which he did in early 1942. His appointment as a Department of Medicine research associate began a long career at NYU, which Ochoa described as both “fruitful and happy.” At age thirty-seven, Ochoa was now an independent investigator with his own graduate and postdoctoral students.

Although his initial NYU appointment was in medicine, two years later he moved to the Department of Biochemistry as assistant professor (his first faculty position). In another two years he was named chair of pharmacology. Ochoa noted that he was only the second biochemist to chair an American Medical School pharmacology department. However, he decided that he “was in good company” because “Cori was the first” (Ochoa, 1980, p. 11). Ochoa spent nine “exciting and productive” years (1946–1954) in pharmacology; in the summer of 1954 he was made chair of biochemistry, a position he held for twenty years until his retirement at age sixty-nine.

Ochoa’s scientific career was varied and complex; he published more than five hundred papers on a variety of topics. Several general themes, which can be merely highlighted in this entry, run through his work. As noted earlier, Ochoa developed an early interest in enzymes, and at NYU he established one of the most powerful enzymology laboratories in the world. His enzymology work focused on processes of oxidative phosphorylation, CO2 fixation, and enzymes involved in the tricarboxylic acid (TCA) cycle. Ochoa was a major contributor to elucidating the detailed steps of the TCA cycle (Kresge, et al., 2005). However, his work on oxidative phosphorylation led to what some biochemists believe to be his major contribution, RNA synthesis and the genetic code.

Oxidative Phosphorylation From his undergraduate work on creatine phosphate, Ochoa was interested in cellular energetics, which arguably was one of the twentieth century’s most difficult and contentious biochemical problems. While at Oxford he demonstrated that biological oxidations were “coupled” to phosphorylation reactions, often forming ATP. At NYU he demonstrated that the ratio of oxygen consumed to phosphate bonds formed (the P/O ratio) was three, the standard value soon adopted by other investigators (Ernster, 1993).

Shortly after completing this work, Ochoa abandoned the area of energetics to begin an enzymology program that achieved international distinction. The shift in research focus was apparently pragmatic.

Grunberg-Manago observed that: “After completing this work on the P/O ratio, it appeared to Severo that the mechanism of oxidative phosphorylation was not likely to be understood without further knowledge of the enzymatic reactions involved in oxidation and particularly those coupled to phosphorylation” (1997, p. 354). Ochoa believed that if he was to understand energetics, he needed to understand the underlying enzymology.

CO2 Fixation and the TCA Cycle When Ochoa made this research shift, the central pathway for carbohydrate oxidation—and source of cellular energy—the TCA (or Krebs) cycle, had been sketched out and biochemists were beginning to fill in the details. In 1937 Hans Adolf Krebs and W. H. Johnson established that carbohydrates were oxidized to a two-carbon “active acetate” intermediate, which “condensed” with oxaloacetic acid to form a six-carbon tricarboxylic acid, citrate. Citrate was then sequentially oxidized to two molecules of CO2 and oxaloacetate, which repeated the cycle. Ochoa decided to focus on an early suspected reaction, the conversion of isocitrate to α-ketoglutaric acid.

Previous work demonstrated that citrate was converted to isocitrate via cis-aconitate; the reactions leading to α-ketoglutarate, however, were only hypothetical, and “oxalo-succinic acid” was a postulated intermediate. Ochoa started with oxalo-succinic acid and observed α—ketoglutarate formation. Thus, he concluded that oxalosuccinic acid was indeed a reaction intermediate; decarboxylation of this compound led to CO2 and α—h;ketoglutarate. The process, he believed, was as follows (note that, in modern use, TPNox and TPNred are referred to as NADP and NADPH):

Isocitric acid + TPNOX ⇆ oxalosuccinic

acid + TPNred (Reaction 1)

Oxalosuccinic acid ⇆ α-ketoglutaric acid

+ CO2 (Reaction 2)

Ochoa then made an interesting intellectual leap. By the 1940s, Harland Goff Wood and Chester Werkman had established that CO2-fixation was not exclusive to plants and specialized bacteria (called the “Wood-Werkman Reaction”) (Singleton, 1997). The reaction, however, had no mechanism. Ochoa reasoned that if the decarboxylation process in Reaction 2 was reversible, CO 2 would be “fixed,” thereby providing a mechanism to explain the Wood-Werkman reaction. The easiest way to test this hypothesis was to use isotopic carbon as a tracer, but at the time Ochoa’s lab lacked the ability to use isotopes (Grunberg-Manago, 1997, p. 355).

In October 1944 Ochoa purchased a Beckman DU spectrophotometer using a $1,200 American Philosophical Society grant. Ochoa thought that he might use the instrument to measure CO2-fixation via the reverse of Reactions 1 and 2 by measuring TPNox production when the enzymes were incubated in the presence of α-ketoglutarate and CO2. However, he viewed the hypothesis as “too good to be true” and procrastinated doing the experiment until persuaded to do so by his good friend Efraim Racker. When he ran the experiment and the spectrophotometer indicated TPNox production, Ochoa was so excited he ran out of the room calling for everyone to “come and watch this.” No one came, and Ochoa realized that the time was past 9 p.m. (Ochoa, 1980, p. 15). The experiment, which confirmed an important aspect of the TCA cycle, was Ochoa’s first with a spectrophotometer. Nevertheless, he rapidly “became a virtuoso of coupled spectrophotometric assays of oxidative enzymes” (Grunberg-Manago, 1997, p. 355) and influenced generations of biochemists.

In 1948 Ochoa began to work on what he called “the most elusive enzyme of the citric acid cycle.” The enzyme, referred to as the “condensing enzyme,” catalyzed the reaction of oxaloacetate, a four-carbon dicarboxylic acid, with “active acetate,” an unknown two-carbon compound, to form the six-carbon tricarboxylic citric acid. He assigned a new postdoctoral student, Joseph Stern, who had trained with Krebs, to work on the problem.

Stern’s early attempts to study the enzyme in animal tissues were unsuccessful; thus, in a move that Grunberg-Manago (1997, p. 355) calls “characteristic of Severo,” he turned to a bacterial system. Ochoa, Stern, and another student combined extracts from Escherichia coli and pig heart that synthesized citrate from acetyl phosphate and oxaloacetate but also required small amounts of coenzyme A (CoA). From this system, the group crystallized the condensing enzyme, the first crystalline TCA cycle enzyme.

Further work demonstrated that the E. coli extract contained an enzyme, transacetylase, which catalyzed acetyl CoA formation from acetyl phosphate and CoA. This observation confirmed Feodor Lynen’s prediction that acetyl CoA was the “active acetate” in the TCA cycle. Ochoa’s lab joined with Lynen’s lab to demonstrate that the condensing enzyme catalyzed the reversible reaction (Ochoa, 1980, p. 17):

Oxalosuccinic acid + Acetyl CoA⇄ CoA + Citrate (Reaction 3)

The two studies discussed here provided major descriptions for two major sections of the TCA cycle. Further work in Ochoa’s lab helped to clarify other portions of the cycle while showing how the cycle was part of the broader intermediary metabolism scheme (Grande and Asensio, 1976, p. 4). Arguably, Ochoa completed the work that Krebs began. Based on this work alone, Ochoa would be considered a major figure in the history of biochemistry.

RNA Synthesis and the Genetic Code In 1954 Ochoa returned to the oxidative phosphorylation problem and began looking for enzymes capable of converting ADP to ATP. Like most biochemistry labs at the time, the Ochoa lab now worked with radioisotopes, and Ochoa decided to approach the problem by looking for reactions that incorporated radioactively labeled phosphate

32 PO4= (32 Pi) into ATP. A new postdoctoral student from Paris, Grunberg-Manago, picked up the problem (Ochoa, 1980, p. 18).

Using bacterial extracts from Azobacter vinelandii, Grunberg-Manago quickly demonstrated an active exchange reaction between 32Pi and ATP and partially purified the activity. In early experiments, she had used amorphous ATP. She later repeated the experiment with crystalline—and thus purer—ATP, and the reaction no longer worked. She discovered that the amorphous ATP was contaminated with ADP; this observation led her to believe that the reaction she observed was:

ADP⇄ AMP + (PO)4 - (Reaction 4)

Ochoa did not believe Grunberg-Manago’s initial data and offended her by saying that “it was impossible.” Later, “regretting his first reaction,” Ochoa came to Grunberg-Manago’s lab, where she was easily able to convince him that ADP was indeed the reaction substrate. As Grunberg-Manago noted, Ochoa became “very excited, because no known enzyme was able to catalyse such an exchange.” Within a short time Grunberg-Manago had characterized the reaction further and demonstrated that other nucleotide diphosphates (i.e., UDP, CDP, GDP, and IDP) were substrates in addition to ADP (Grunberg-Manago, 1997, p. 359).

Up to this point, Grunberg-Manago had studied the process as an “exchange” reaction; she incubated bacterial extracts with (32 PO)4= and nucleotide diphosphate and looked for radioactivity incorporated into the nucleotide. Consequently, the true products in Reaction 3 were ambiguous. In the summer of 1954 she began a series of experiments to more precisely characterize the enzymatic reaction. In one set of experiments she had difficulty isolating the product, which seemed to be of high molecular weight. Further work demonstrated that the product was a nucleotide polymer identical to ribonucleic acid, and that the true reaction was:

(XMP)n⇄ n XDP + n (PO)4 = (Reaction 5) [where X is a nucleotide base (adenine, uracil, etc)].

Grunberg-Manago and Ochoa debated what to call the new enzyme. Ochoa, hoping that it might be involved in polynucleotide synthesis, wanted to name the enzyme “RNA synthetase.” Grunberg-Manago, however, thought the activity involved RNA degradation and favored calling it phosphorylase. Ochoa yielded, saying “Marianne, because I like you very much, I will adopt the name you suggested,” and the enzyme was called “polynucleotide phosphorylase” (Grunberg-Manago, 1997, p. 360). Regardless of name, the enzyme was the first in vitro synthesis of a large molecular weight biological compound and launched Ochoa’s research in a new direction.

The period between 1951 and 1961 was one of the most exciting in biological research. Consider that during the decade Alfred Hershey and Martha Chase confirmed that DNA was indeed the genetic material, James D. Watson and Francis Crick demonstrated DNA’s structure, Matthew Meselson and Franklin Stahl demonstrated the nature of DNA replication, Arthur Kornberg isolated DNA polymerase, and the role of messenger RNA (mRNA) was clarified. By 1961 François Jacob and Jacques Monod were able to sketch out what became known as the “central dogma” of modern biology: that is, that information flows from DNA to RNA to protein (Thieffry and Sarkar, 1998). An organism’s genotype resided in its DNA; protein was responsible for expressing the organism’s phenotype. As the discipline of molecular biology began to evolve out of biochemistry, research focus shifted to understand the mechanisms driving those processes; a central problem of this research program was to understand the nature of the “genetic code.” How was information contained in four DNA nucleotides converted into a functional sequence of twenty amino acids in a protein? Polynucleotide phosphorylase played an important role in answering that question.

In 1959 Marshall Nirenberg and coworkers at the National Institutes of Health (NIH) began experimental attempts to understand how DNA information was expressed as protein function. Nirenberg synthesized RNA molecules consisting of a single base (e.g., poly-U was an RNA molecule made up entirely of the nucleoside uridine). This synthetic mRNA was introduced in an E. coli protein synthesis system containing a mixture of amino acids, one of which contained a radioactive label. Incorporation of the labeled amino acid into protein indicated that the base in the polynucleotide coded for that amino acid. At the 1961 International Congress of Biochemistry in Moscow, Nirenberg and Heinrich J. Matthai reported that a poly-U mRNA was translated into polyphenylalanine; thus, the RNA code for phenylalanine was uracil (or thymine in DNA).

Peter Lengyel and Joseph Speyer, in Ochoa’s lab, started to work with cell-free protein synthesis systems in early 1961. Their hypothesis was that synthetic polyribonucleotides, of known base composition, generated with polynucleotide phosphorylase would act as mRNA and incorporate amino acids into protein depending upon the polyribonucleotide base composition (Ochoa, 1980, p. 20). The hypothesis was highly successful, and very shortly the Ochoa and Nirenberg labs were engaged in a tight, and highly competitive, race to solve the genetic code.

Initially, Nirenberg was unaware of the competition. He had given a talk on his work (accounts of this incident differ as told by Ochoa and Nirenberg) and was in the process of answering audience questions. He was surprised when Peter Lengyel from Ochoa’s laboratory told the audience that he had done similar work. Nirenberg said that after the meeting he returned to Washington “feeling very depressed,” because he had not realized that Ochoa’s lab was working the “important problem of deciphering the genetic code.” He “clearly … had to either compete with … Ochoa … or stop working on the problem” (Nirenberg, 2004, p. 49). After a brief 1961 attempt to collaborate rather than compete, Nirenberg concluded that collaboration was out of the question. Later he concluded that, to his horror, he enjoyed the competition, which stimulated him to be more focused, and he “accomplished far more than I would have in its absence” (2004, p. 50).

In approximately two years (1961–1963) the two laboratories published almost twenty full-length papers in the Proceedings of the National Academy of Sciences of the United States of America alone, in which they fully defined all aspects of the genetic code. Ochoa noted that the results between the two labs “agreed beautifully.” Har Gobind Khorana confirmed and expanded upon much of this work by chemically synthesizing deoxyribonucleotides polymers, of known base composition, and demonstrated that they directed incorporation of specific amino acids into proteins. Thus, what appeared to be a difficult problem was completely resolved in a relatively short period. Furthermore, solving the genetic code arguably opened the way for the disciplinary expansion of molecular biology.

Recognition and Maturity Ochoa remarked: “Polynucleotide phosphorylase may be considered to have been the Rosetta Stone of the genetic code” (1980, p. 20), a statement recognized, in part, by his receipt, with Kornberg, of the 1959 Nobel Prize in Physiology or Medicine. In his Nobel Prize presentation speech, Theorell commented that their work would have far-reaching impact in fields such as “biochemistry, virus research, genetics, and cancer research.” He concluded that Ochoa’s work had “helped us to advance quite some distance on the road to understanding the mechanism of life” (Theorell, 1959).

In 1974, after twenty years as chair of biochemistry at NYU, Ochoa retired and accepted an offer to join the Roche Institute of Molecular Biology at Nutley, New Jersey. The move was apparently rewarding, and Ochoa wrote to Krebs: “I cannot tell you how happy I am here with splendid facilities for work, and with the feeling that I now have time to do what I most like to do” (Krebs, 1976, p. 419). While at Roche, Ochoa maintained an active and productive research program for another decade.

In 1985 he and his wife, Carmen, returned to Spain, where he was already a national hero. Although he spent more than half his life in the United States, and had become a U.S. citizen in 1956, he retained his love of Spain. The love was reciprocal; Grunberg-Manago commented that “Ochoa was indisputably one of the best-known people in his home country” (Grunberg-Manago, 1997, p. 363). Many Spanish streets are named after him, and his portrait is displayed in Madrid restaurants that he visited.

Coda During his career, Ochoa authored or coauthored more than five hundred papers. Of these, Science Citation Index (SCI) lists almost three hundred papers from 1945 to 1990; the lab published as many as sixteen papers per year and had a three-year “running average” publication rate of six papers per year. This publication record is impressive; however, publication volume and rate are not the only measures of scientific influence; the scientific community’s use of an individual’s work is equally important (Hull, 1988). By this indicator as well, Ochoa’s career was influential. Almost 20 percent of Ochoa papers listed in the SCI database were cited more than a hundred times by other workers. Because a significant majority of papers published are never cited, this citation frequency is remarkable. These data clearly indicate Ochoa’s significant scientific impact.

Perhaps the ultimate recognition of a scientist’s contribution is in his or her peers’ estimation. Ochoa was awarded virtually every public award a scientist can receive; however, perhaps one of the most significant honors was a celebration of his seventieth birthday. In September 1975 Ochoa’s former students and colleagues held an international symposium in Barcelona and Madrid and presented papers in six colloquia that covered various fields in which Ochoa had worked: energy metabolism, lipids and saccharides, regulation, nucleic acids and the genetic code, protein biosynthesis, and cell biology. Such celebrations and published Festschrifts for distinguished scientists are not unusual. Few, however, reflect such a tremendous diversity of contributions as the above list indicates or such a distinguished list of speakers. Of the almost fifty papers published, eleven were by Nobel Prize recipients; every author was a member of at least one honorary national scientific academy or society. In addition to the distinguished contributors list, the Festschrift is remarkable in that its dust jacket features a reproduction of a Dalí painting, titled “My Homage to Severo Ochoa.” Figures in the painting “symbolize the genetic code messengers, or molecules of polynucleotides, which were synthesized for the first time in Severo Ochoa’s laboratory” (Dalí, 1976, p. 445).

Biochemistry’s history was written by many great scientists; F. Grande and Carlos Asensio observed, “Severo Ochoa’s scientific biography condenses the history of contemporary biochemistry and connects events which have significantly affected the development of the science” (1976, p. 1). Arguably, Ochoa’s career reached further than many of his contemporaries. His career began in Germany in what Grande and Asensio call “the golden age of European Biochemistry.” As the disciplinary power increasingly swept westward, first to Britain, and then to the United States, life circumstances forced Ochoa to follow that migration. One cannot help but wonder what paths that migration might have followed if a critical friendship or mentor had not provided support. David Hull notes the important role of contingency in both scientific discovery and in individual careers (1988). Severo Ochoa’s life and career certainly illustrate the validity of this point.

BIBLIOGRAPHY

The biographical article by Marianne Grunberg-Manago, cited below, includes a complete list of Ochoa’s publications.

WORKS BY OCHOA

With José G. Valdecasas. “A Micro Method for the Estimation of Total Creatinine in Muscle.” Journal of Biological Chemistry81 (1929): 351–357.

With Carmen G. Ochoa. “Cozymase from Invertebrate Muscle.” Nature 140 (1937): 1019.

With Rudolph Albert Peters. “Vitamin B1 and Carboxylase in Animal Tissues.” Biochemical Journal 32 (1938): 1501–1515.

With Ilona Banga and Rudolph Albert Peters. “Pyruvate Oxidation in Brain. VII. Some Dialysable Components of the Pyruvate Oxidation System.” Biochemical Journal 33 (1939): 1980–1996.

“Coupling of Phosphorylation with Oxidation of Pyruvic Acid and Brain.” Journal of Biological Chemistry 138 (1941): 751–773.

With Marianne Grunberg-Manago. “Enzymatic Synthesis and Breakdown of Polynucleotides: Polynucleotide Phosphorylase.” Journal of the American Chemical Society 77 (1955): 3165–3166.

“Enzymatic Synthesis of Ribonucleic Acid.” Nobel Lecture, 11 December 1959. Available from http://nobelprize.org/medicine.

“The Pursuit of a Hobby.” Annual Review of Biochemistry 49 (1980): 1–30.

OTHER SOURCES

Dale, Henry. NIMR Archives, Box PF15. 30 March 1938. Letter, Henry Dale to Andrew Bennett. National Institute for Medical Research, Mill Hill, London.

Dalí, Salvador. “My Homage to Severo Ochoa.” In Reflections on Biochemistry: In Honour of Severo Ochoa, edited by A. Kornberg et al., 445. New York: Pergamon Press, 1976.

Ernster, Lars. “P/O Ratios: The First Fifty Years.” FASEB Journal 7 (1993): 1520–1524.

Garfield, Eugene. “The 1,000 Contemporary Scientists Most-Cited, 1965–1978. Part I. The Basic List and Introduction.” Current Contents, no. 41 (12 October 1981): 5–14.

Grande, F., and Carlos Asensio. “Biographical Introduction: Severo Ochoa and the Development of Biochemistry.” In Reflections on Biochemistry: In Honour of Severo Ochoa, edited by Arthur Kornberg et al., 1–14. New York: Pergamon Press, 1976.

Grunberg-Manago, Marianne. “Severo Ochoa: 24 September 1905–1 November 1993.” Biographical Memoirs of Fellows of the Royal Societ y 43 (1997): 350–365. The standard Ochoa biography, written by one of his major scientific collaborators. The essay contains a complete list of Ochoa’s publications.

Hull, David. Science as a Process. Chicago: University of Chicago Press, 1988.

Kornberg, Arthur. “Severo Ochoa (24 September 1905–1 November 1993).” Proceedings of the American Philosophical Society141 (1997): 479–491. _____. Remembering Our Teachers.” Journal of Biological Chemistry 276 (2001): 3–11.

_____. —, Bernard L. Horecker, Luis Cornudella, et al., eds. Reflections on Biochemistry: In Honour of Severo Ochoa. New York: Pergamon Press, 1976. Festschrift for Ochoa’s seventieth birthday, the collection contains many personal reflections on Ochoa.

Kresge, Nicole, Robert D. Simoni, and Robert L. Hill. “Severo Ochoa’s Contributions to the Citric Acid Cycle.” Journal of Biological Chemistry 280 (2005): e8–e10.

Lane, M. Daniel. “The Biotin Connection: Severo Ochoa, Harland Wood, and Feodor Lynen.” Journal of Biological Chemistry 279 (2004): 39187–39194.

Lipmann, Fritz. “Einar Lundsgaard.” Science 164 (1969): 246–247.

Nirenberg, Marshall. “Historical Review: Deciphering the Genetic Code—A Personal Account.” Trends in Biochemical Sciences 29 (2004): 46–54.

Santesmases, María Jesús. “Enzymology at the Core: Primers and Templates in Severo Ochoa’s Transition from Biochemistry to Molecular Biology.” History and Philosophy of the Life Sciences24 (2002): 193–218.

_____. Severo Ochoa and the Biomedical Sciences in Spain under Franco, 1959–1975.” Isis 91, no. 4 (December 2000): 706–734. _____. —, and Emilio Muñoz. “Scientific Organizations in Spain

(1950–1970): Social Isolation and International Legitimation of Biochemists and Molecular Biologists on the Periphery.” Social Studies of Science 27, no. 2 (1997): 187–219.

Singleton, Rivers, Jr. “Harland Goff Wood: An American Biochemist.” In Comprehensive Biochemistry: History of Biochemistry, Vol. 40, edited by Giorgio Semenza and Rainer Jaenicke. Amsterdam: Elsevier, 1997.

Theorell, Hugo. “The Nobel Prize in Physiology or Medicine 1959, Presentation Speech.” Available from http://nobelprize.org/nobel_prizes/medicine/laureates/1959/press.html.

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Rivers Singleton Jr .

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Severo Ochoa

Severo Ochoa

Spanish-born biochemist Severo Ochoa (1905-1993) spent his life engaged in research into the workings of the human body. In the 1950s, he was one of the first scientists to synthesize the newly discovered ribonucleic acid (RNA) in the laboratory.

Severo Ochoa's ability to synthesize RNA in the laboratory marked the first time that scientists managed to combine molecules together in a chain outside a living organism, knowledge that would later prove to be an essential step in enabling scientists to create life in a test tube. For this work, Ochoa received the Nobel Prize in 1959. In addition to his laboratory work, Ochoa, who was trained as a physician in Spain, taught biochemistry and pharmacology to many generations of New York University medical students.

Severo Ochoa was born on September 24, 1905, in Luarca, a small town in the north of Spain. Named after his father, a lawyer, Ochoa was the youngest son in the family. He lived in this mountain town until the age of seven, when his parents decided to move to Málaga, Spain. The move gave young Severo access to a private school education that prepared him for entrance into Málaga College, which is comparable to an American high school. By this time, Ochoa knew that he eventually would enter a career in the sciences; the only question in his mind was in which field he would specialize. Because Ochoa found mathematics at Málaga College very taxing, he decided against pursuing an engineering career, in which such skills would be essential. Instead, he planned to enter biology. After Ochoa received his B.A. from Málaga in 1921, he spent a year studying the prerequisite courses for medical school, at that time physics, chemistry, biology, and geology. In 1923 he matriculated at the University of Madrid's Medical School.

At Madrid, Ochoa had dreams of studying under the Spanish neurohistologist Santiago Rámon y Cajal, but these were quickly dashed when he discovered that the 70-year-old histology professor had retired from teaching, although he still ran a laboratory in Madrid. Ochoa hesitated to approach Cajal even at the lab, however, because he thought the older man would be too busy to be bothered by an unimportant student. Nonetheless, by the end of his second year in medical school, Ochoa had confirmed his desire to do biological research and jumped at one of his professor's offers of a job in a nearby laboratory.

The Medical School itself housed no research facilities, but Ochoa's physiology teacher ran a small research laboratory under the aegis of the Council for Scientific Research a short distance away. Working with a classmate, Ochoa first mastered the relatively routine laboratory task of isolating creatinine—a white, crystalline compound—from urine. From there he moved to the more demanding task of studying the function and metabolism of creatine, a nitrogenous substance, in muscle. The summer after his fourth year of medical school he spent in a Glasgow laboratory, continuing work on this problem. Ochoa received his medical degree in 1929.

In an attempt to further his scientific education, Ochoa applied for a postdoctoral fellowship working under Otto Meyerhof at the Kaiser-Wilhelm Institute in a suburb of Berlin. Although the Council for Scientific Research had offered him a fellowship to pursue these studies, Ochoa turned down their offer of support because he could afford to pay his own way. He felt the money should be given to someone more needy to himself. Ochoa enjoyed his work under Meyerhof, remaining in Germany for a year.

On July 8, 1931, he married Carmen García Cobian, a daughter of a Spanish lawyer and businessman, and moved with his newlywed wife to England, where he had a fellowship from the University of Madrid to study at London's National Institute for Medical Research. In England Ochoa met Sir Henry Hallett Dale, who would later win the 1936 Nobel in medicine for his discovery of the chemical transmission of nerve impulses. During his first year at the Institute, Ochoa studied the enzyme glyoxalase, and the following year he started working directly under Dale, investigating how the adrenal glands affected the chemistry of muscular contraction. In 1933 he returned to his alma mater, the University of Madrid, where he was appointed a lecturer in physiology and biochemistry.

Within two years, Ochoa accepted a new position. One of the heads of the Department of Medicine was planning to start an Institute for Medical Research with sections on biochemistry, physiology, microbiology, and experimental medicine. The institute would be partially supported by the University of Madrid, which offered it space in one its new medical school buildings, and partially supported by wealthy patrons, who planned to provide a substantial budget for equipment, salaries, and supplies. The director of the new institute offered the young Ochoa the directorship of the section on physiology, which he accepted, and provided him with a staff of three. However, a few months after Ochoa began work, civil war broke out in Spain. In order to continue his work, Ochoa decided to leave the country in September, 1936. He and his wife immigrated to Germany, hardly a stable country itself in late 1936.

When Ochoa arrived, he found that his mentor Meyerhof, who was Jewish, was under considerable political and personal pressure. The German scientist had not allowed this to interfere with his work, though Ochoa did find to his surprise that the type of research Meyerhof conducted had changed dramatically in the six years since he had seen him last. As he wrote of the laboratory in a retrospective piece for the Annual Review of Biochemistry: "When I left it in 1930 it was basically a physiology laboratory; one could see muscles twitching everywhere. In 1936 it was a biochemistry laboratory. Glycolysis and fermentation in muscle or yeast extracts or partial reactions of these processes catalyzed by purified enzymes, were the main subjects of study." Meyerhof's change in research emphasis influenced Ochoa's own work, even though he studied in the laboratory for less than a year before Meyerhof fled to France.

Before Meyerhof left, however, he ensured that his protege was not stranded, arranging for Ochoa to receive a six-month fellowship at the Marine Biological Laboratory in Plymouth, England. Although this fellowship lasted only half a year, Ochoa enjoyed his time there, not the least because his wife Carmen started working with him in the laboratory. Their collaboration later led to the publication of a joint paper in Nature. At the end of six months, though, Ochoa had to move on, and friends at the lab found him a post as a research assistant at Oxford University. Two years later, when England entered the war, Oxford's Biochemistry Department shifted all its efforts to war research in which Ochoa, an alien, could not take part. So in 1940 the Ochoas picked up stakes again, this time to cross the Atlantic to work in the laboratory of Carl Ferdinand Cori and Gerty T. Cori in St. Louis. Part of the Washington University School of Medicine, the Cori lab was renowned for its cutting edge research on enzymes and work with intermediary metabolism of carbohydrates. This work involved studying the biochemical reactions in which carbohydrates produce energy for cellular operations. Ochoa worked there for a year before New York University persuaded him to move east to take a job as a research associate in medicine at the Bellevue Psychiatric Hospital, where he would for the first time have graduate and postdoctoral students working beneath him.

In 1945, Ochoa was promoted to assistant professor of biochemistry at the medical school. Two years later when the pharmacology chair retired, Ochoa was offered the opportunity to succeed him and, lured by the promise of new laboratory space, he accepted. He remained chairperson for nine years, taking a sabbatical in 1949 to serve as a visiting professor at the University of California. His administrative work did not deter him from pursuing his research interests in biochemistry, however. In the early 1950s, he isolated one of the chemical compounds necessary for photosynthesis to occur, triphosphopyridine nucleotide, known as TPN. Ochoa continued his interest in intermediary metabolism, expanding the work of Hans Adolf Krebs, who posited the idea of a cycle through which food is metabolized into adenosine triphosphate, or ATP, the molecule that provides energy to the cell. The Spanish scientist discovered that one molecule of glucose when burned with oxygen produced 36 ATP molecules. When the chairman of the biochemistry department resigned in 1954, Ochoa accepted this opportunity to return to the department full-time as chair and full professor.

Once more ensconced in biochemistry research, Ochoa turned his attentions to a new field: the rapidly growing area of deoxyribonucleic acid (DNA) research. Earlier in his career, enzymes had been the hot new molecules for biochemists to study; now, after the critical work of James Watson and Francis Crick in 1953, nucleic acids were fascinating scientists in the field. Ochoa was no exception. Drawing on his earlier work with enzymes, Ochoa began investigating which enzymes played roles in the creation of nucleic acids in the body. Although most enzymes assist in breaking down materials, Ochoa knew that he was looking for an enzyme that helped combine nucleotides into the long chains that were nucleic acids. Once he isolated these molecules, he hoped, he would be able to synthesize RNA and DNA in the lab. In 1955, he found a bacterial enzyme in sewage that appeared to play just such a role. When he added this enzyme to a solution of nucleotides, he discovered that the solution became viscous, like jelly, indicating that RNA had indeed formed in the dish. The following year, Arthur Kornberg, who had studied with Ochoa in 1946, applied these methods to synthesize DNA.

In 1959, five years after he assumed the directorship of the biochemistry department, Ochoa shared the Nobel Prize for Physiology or Medicine with Kornberg, for their work in discovering the enzymes that help produce nucleic acids. While Ochoa was particularly delighted to share the prize with his old colleague, by this time he was no stranger to academic plaudits. The holder of several honorary degrees from both American and foreign universities, including Oxford, Ochoa had also been the recipient of the Carl Neuberg Medal in biochemistry in 1951 and the Charles Leopold Mayer Prize in 1955. Ochoa served as chairperson of NYU's biochemistry department for 20 years, until the summer of 1974, just before his seventieth birthday. When he retired from this post, he rejected the department's offer to make him an emeritus professor, preferring to remain on staff as a full professor. But even that could not keep Ochoa sufficiently occupied. In 1974, he joined the Roche Institute of Molecular Biology in New Jersey.

In 1985 he returned to his native Spain as a professor of biology at the University Autonoma in Madrid to continue his lifelong fascination with biochemical research. At the age of 75 Ochoa wrote a retrospective of his life, which he titled "Pursuit of a Hobby." In the introduction to this piece, he explained his choice of title: at a party given in the forties in honor of two Nobel laureate chemists Ochoa listed his hobby in the guest register as biochemistry, although he was professor of pharmacology at New York University. Sir Henry Dale, one of the party's honorees, joked, "now that he is a pharmacologist, he has biochemistry as a hobby." Ochoa concluded this tale with the statement, "In my life biochemistry has been my only and real hobby."

Severo Ochoa died in Madrid on November 1, 1993.

Further Reading

Nobel Prize Internet Archive, "http://www.almaz.com/nobel/medicine/1959a.html," Almaz Enterprises, July 22, 1997.

Nobel Prize Winners, H. W. Wilson, 1987. □

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Ochoa, Severo

Severo Ochoa (sāvā´rō ōchō´ä), 1905–93, American biochemist and educator, b. Spain, M.D. Univ. of Madrid, 1929. After teaching at the universities of Madrid, Heidelberg, and Oxford, he came to the United States in 1940. In 1954 he was appointed chairman of the department of biochemistry at New York Univ. He became an American citizen in 1956. With Arthur Kornberg he received the 1959 Nobel Prize in Physiology or Medicine for the synthesis of ribonucleic acid (RNA), an organic compound that carries hereditary qualities in all reproduction.

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