International Union of Biochemistry and Molecular Biology

The Severo Ochoa Lecture

(inaugurated: 1979 in Toronto)

Toronto1979A. Kornberg, USA
Perth1982C. Weissmann, Switzerland
Amsterdam1985P. Borst, The Netherlands
Pargue1988H. M. Temin, USA
Jerusalem1991R. Tjian, USA
New Delhi1994I. M. Verma, USA
San Francisco1997J. Nyborg, Denmark
Birmingham2000J. C. Venter, USA
Montreal2003J. M. Egly, France
Kyoto2006D. C. Baulcombe; UK
Shanghai2009Sidney Altman, USA

Severo Ochoa

An appreciation by Santiago Grisolia

In 1978, Hoffmann La Roche Inc. provided the International Union of Biochemistry with $12,000 to endow a fund to support a plenary lecture at successive International Congresses of Biochemistry to commemorate the name of Severo Ochoa, who had been the President of the Union from 1961-1967. The first Ochoa Lecture was given by Arthur Kornberg, Ochoa’s fellow Nobel Laureate, at the 10th Congress, in Toronto, in 1979.

I thank the International Union of Biochemistry and Molecular Biology for giving me the opportunity, and this is indeed a great honour, to write some lines in memory of Severo Ochoa, who was a President of this distinguished International Union  and my teacher and friend.
I have written these notes conscious however that I cannot possibly condense into a few words the brilliant scientific career of Severo Ochoa or his many human attributes, which I had the fortune to observe and learn from in almost 50 years of close relationship. Thus I have written this outline with admiration, nostalgia and deep sorrow.
Admiration, because his scientific personality was great. He admired greatly Ramón y Cajal, the only other Nobel Prize winner of Spanish origin thus far in Physiology or Medicine , a scientist who is still quoted very frequently in spite of the fact that he died in 1932, and who influenced Professor Ochoa, as well as many other young Spanish scientists. Nostalgia because I cannot now listen to his advice and warm friendship. Sadness, great sadness, because he is no longer with us and because I saw him suffer a great deal, particularly since the death of Carmen, his beloved wife for over half a century, who was his constant companion and adviser, and particularly to see him in the last few months in a lengthy and debilitated condition. However, then as always, he never complained and politely inquired about others when they asked about him.

I heard the name of Ochoa  half a century ago, from my first teacher Prof. José García Blanco, as in his opinion the best young biochemist from Spain. This was after the Spanish Civil War. Dr. Ochoa, who had been born in Luarca in Northern Spain, in the Province of Asturias in 1905, had even as a young boy been interested in science. He told me how as a youngster he had planned a scheme to obtain continuous energy, the often dreamed of the perpetual motion machine of many curious youngsters. He learned French mostly by himself and he spent his youth between Asturias and Andalucía, Málaga, principally because of health problems of his widowed mother.  Ochoa had lost his father when he was about 7 years old. He wanted since he was a young boy to succeed and to make his mother happy and proud, as he wrote in a letter to her, which I saw, when he was still a very young medical student in Madrid. He was a very good student in physiology and this was noted by the Professor of physiology and biochemistry, Juan Negrín, who later became Premier of the Republican Government, Dr. Negrín had been well trained in Germany. He used to select brilliant students as laboratory assistants. This was the beginning of the scientific training of Severo Ochoa. He lived for many years in Madrid in the so-called Residence for Students, an exciting and intellectual center, still very much alive, where many gifted individuals, including the painter Salvador Dalí, the movie director Buñuel and the poet Federico García Lorca lived. There were a few laboratories in one of which worked another great and respected scientist pupil of Cajal, Pío del Río Ortega. Dr. Negrin had a laboratory there. Also there were then, as now, many lectures by distinguished visitors such as Marie Curie or Albert Einstein. During the summer of 1927, when he was a 4th year medical student, on the advice of Negrin, Dr. Ochoa went to Glasgow to work with Prof. Paton on the action of guanidine on frog melanophores. Even in this short time and being a beginner he was able to publish a note, his first scientific paper, in the Proceedings of the Royal Society. Shortly thereafter in Madrid he sent to the J.B.C. a paper concerning a micromethod to measure creatine, which after only minor corrections was immediately published. Dr. Ochoa often talked about this. He was very pleased that his English was already good enough. Dr. Ochoa finished his medical training in 1928 and immediately applied for and was successful in obtaining a fellowship to work with Otto Meyerhof in Berlin. The reason for the selection of Meyerhof’s laboratory was because of his interest in muscle contraction and in the possible role of creatine. He renounced the economic portion of his fellowship on behalf of his friend Dr. Valdecasas since he felt Dr. Valdesacas was economically more in need. His stay at Meyerhof’s lab was a happy one for him, where among others he made close friends with Profs. Nachmanson and Fritz Lipmann.

In 1929 Severo Ochoa attended the International Congress of Physiology in Boston and visited several places in America, where at the time one of his brothers lived. I have the impression that he fell in love with America during that visit. On his return to Madrid he completed some of the requirements for his Doctor’s degree. In December of that year he returned to Germany and to Dr. Meyerhof’s laboratory. He returned to Spain in 1930 and continued working on muscle contraction at the Residencia de Estudiantes. He married Carmen in 1931 and shortly thereafter went to England to the laboratory of Sir Henry Dale where in collaboration with Dr. Dudley he worked for the first time on an enzyme, glyoxylase. From that time on he found his true biochemical love, enzymology. He remained in England for some 2 years when he returned to Spain to read his Doctoral dissertation in 1934. The President of the committee for this event was Prof. Jiménez Díaz, who was to influence later on much of Ochoa’s life. Indeed Dr. Ochoa died in his clinic.

In 1935 he attended the XVII International Congress of Physiology in Leningrad. It seems that by that time Professor Negrin had cooled somewhat his interest in helping Severo Ochoa. According to Dr. Ochoa this was because Prof. Jiménez Díaz offered him a position as head of the section of Physiology in his newly created Institute for Clinical Research. However, in the same year, and seemingly on the insistence of Negrin, and against his own wishes, he competed for a chair in Physiology. He hardly spoke of this, and only many years later, but the chair was denied to him, he thought, in spite of a brilliant exercise, as a revenge by Negrin. Certainly, he was very upset, particularly because of the negative attitude of his life-long friend  Valdecasas. Some of his friends took him for a lengthy excursion to the Monastery of Silos in North Spain.

In 1936 the Spanish Civil War started and Ochoa could not stand the terrible atmosphere; he used to tell me how on his way to the laboratory, where he was the only person left and where he kept working to keep his sanity, he often would encounter cadavers of assassinated persons on the streets near the Medical School. He decided to leave Spain and obtained the help of Negrín for a visa to go to France. From there he went again to Germany and to Meyerhof’s laboratory, now in Heidelberg, where he stayed a short time, from November ’36 to June ’37. This was because Meyerhof had to leave Germany, as did many other Jews. Given the situation in Germany, Dr. Ochoa went to England and worked first at Plymouth and then at Oxford with Sir Rudolph Peters. It is important to mention that before Meyerhof left Germany, he wrote a letter which facilitated Dr. Ochoa’s relocation and in obtaining a fellowship at Plymouth. Dr. Ochoa’s affection for his teachers was deep and sincere, especially for Meyerhof. Thus, in the archives of the Museum “Príncipe Felipe” at Valencia, there are also letters of Meyerhof from  America, dated much later, thanking Dr. Ochoa for his help in obtaining research funds. For many years Dr. Ochoa  carried a letter in his wallet from Meyerhof and another from his mother. His stay at Oxford was very productive and indeed resulted in his discovery of oxidative phosphorylation and in the calculation of the P:O ratios, values which have not changed since he proved them experimentally. At Oxford he again encountered Rio Ortega and made many other friends, especially Ernst Chain. Since the laboratory at Oxford, as well as many others in England, shifted towards the war effort, and since he was an alien, he decided to go to America. He left England in 1940 and after a short stay in Mexico, contacted Carl Cori and went to work with him in 1941. However, and mostly on the advice of Carmen and with the help of a fellowship, he transferred to New York in 1942, where I later met him and where he worked until his first retirement when he was 69 years old. From that time until he was 80, he worked at the Roche Research Institute. It should be pointed out, as an example of his character, determination and optimism, that in 1944 he was virtually fired from the department of Psychiatry where he had a laboratory and where he found on arrival one day his desk and equipment in the corridor because he new Department Head needed the space!. He never lost faith in spite of being an alien.

Fortunately, Prof. I. Greenwald immediately offered him his laboratory in the chemistry department which is where I first met Dr. Ochoa. Fortunately also, the Head of that department, Prof. Cannan, to whom Greenwald had spoken of this serious, hard-working young man, provided him with an Assistant Professorship. Dr. Ochoa was 39 years old and that was essentially his first permanent job.

On my arrival in the USA at the end of 1945. I went to visit Ochoa and asked him to take me for training. As already indicated, Dr. Ochoa had no laboratory of his own and told me that he had to request permission from Dr. Cannan. Once this was done, I started working with him on January 2, 1946. Dr. Ochoa’s group consisted of Alan Mehler, a graduate student, the first, and one of the very few graduate students that Prof. Ochoa ever had, since mostly he worked with post-doctorals and Dr. Arthur Kornberg who had arrived a few days earlier than I and a part-time worker Dr. Weiz Tabori. Since that time I maintained a very close relationship with Ochoa and  asked him for scientific advice very often throughout my life. Dr. Ochoa generously accepted me, my wife and later on my children, as very close friends. He and Mrs. Ochoa  shared our modest home in the USA and later on in Spain on a number of occasions.

The scientific career of Dr. Ochoa is very well known. However I would like to point out that he himself thought as one of the most exciting moments of his life, his discovery in 1944 of CO2 fixation in animal tissues. He often spoke of it in his later years. As  mentioned before, his scientific interest was now directed to classical enzymology and he was properly considered one of the best in the world. In 1955 he decided to return to his initial interest in oxidative phosphorylation, which led him to the momentous discovery of the polynucleotide phosphorylase and the synthesis of RNA for the first time in a test tube. This discovery resulted in the award of the Nobel Prize in Physiology or Medicine, which he shared with Arthur Kornberg in 1959.

His work on the genetic code, in a passionate competition with Marshall Niremberg, starting in 1961, led to the complete clarification of the code in some 3½ years. It should be noted that polynucleotide phosphorylase played a crucial role in this work and that Dr. Ochoa was fond of considering it akin to the Rosetta stone. In his later years, and for a period of about 10 at the Roche Institute, his main interest switched to protein synthesis, where he made important advances.

The complete edition of his papers was undertaken on the occasion of his 70th anniversary, a most festive occasion, which was held in Barcelona and Madrid and at which, among other distinguished guests whose work had been related to that of Dr. Ochoa, participated the following Nobel Prize winners: Hans Krebs, Hugo Theorell, Ernst Chain, Carl Ferdinand Cori, Fred Sanger, and Fritz Lipmann. His collected papers up to that time, occupied 3 volumes and some 3,600 pages. His papers from this time until  his last scientific paper, published when he was 82, occupy another volume.

Fortunately, his mind remained perfectly clear until the day of his death. Dr. Ochoa received many distinctions, including 36 Doctorates Honoris Causa, and 120 medals and decorations. These, together with 219 diplomas, nearly 2.000 books and his extensive files containing documents of the main figures of the golden age of metabolic biochemistry, including lab notebooks of Meyerhof, photographs, newspaper clippings and memoranda of the many honours he received, were organized by my wife, Dr. Frances Grisolía, in a small Museum which was started in 1980 with his generous donations. He donated all his non- scientific library, which included incunables, to the Valencian Foundation for Advance Studies, to be used mainly by residents there. Among the very interesting documents contained in the files is his hand-written speech for the ceremonies on receiving the Nobel Award, as well as numerous notebooks and early notes of his work, showing his careful and organized approach to science. His interest in the international scope of science and education led him to accept many offices which occupied much of his time. However, he was never in a hurry and always answered all scientific inquires with a great deal of courtesy.

The main components of the Museum were listed and photographed and made into a book. Dr. Ochoa was not only a great scientist but also a great teacher, both at the undergraduate and at the postdoctoral levels. At this level he left a very large family, his true sons, since he left no children of his own. Students came from every corner of the planet to train with him. Moreover, his influence permeated much of biochemistry, especially in Spain, which largely through his influence changed from practically non-existent, in terms of its ranking in Biochemistry, to occupy the 7th place in the world. He spent many hours preparing his lectures for medical students. They were so well prepared that the rest of the staff attended them regularly, a custom which then extended to the other members of the staff. He told me several times that his worst dream was to go to a class without having prepared his lecture.

His elegant head, face and figure were often compared to those of El Greco figures.

Perhaps the best resume of his love and commitment to science was written by him in Annu.Rev.Biochem. in 1980:

"One evening in the late nineteen forties my wife and I were at a party given in honor of Otto Loewe and Sir Henry Dale, co-recipients of the 1936 Nobel Prize in Medicine for their discovery of the chemical transmission of the nerve impulse. We were all asked to sign the guest book and state our hobby and I did this as Sir Henry looked over my shoulder. As I put down my hobby as Biochemistry he roared with laughter. At that time I was Professor of Pharmacology and Chairman of the Department at the New York University School of Medicine and Sir Henry said, 'now that he is a pharmacologist, he has biochemistry as a hobby'. I tell this story to justify the title of this essay, because in my life biochemistry has been my only real hobby".

However, he was very knowledgeable and fond of photography, painting and music.

He left most of his fortune for the creation of a foundation for the development of biochemistry in Spain. The Foundation, in which I serve as a board member, provides also for an annual Scientific Prize and a Memorial Lecture.

I remember that someone once asked him how he wanted to be remembered and he said, “as a good person”, and that he was.

 

Santiago Grisolia is the Distinguished Emeritus Professor ‘Sam E. Roberts’ in Biochemistry and Molecular Biology, University of Kansas Medical Center, now at the Fundacion Valenciana de Estudios Avanza-dos. c/o Pinot Lopez  7-1,46003, Valencia, Spain.