Search and Discovery: A Tribute to Albert Szent-Györgyi

Search and Discovery: Tribute to Albert Szent-Györgyi is dedicated to Albert Szent-Györgyi and stems from a Symposium, ""Search and Discovery,"" held in his honor at Boston University School of Medicine. Szent-Györgyi, born in Budapest on September 16, 1893, established the Institute for Muscle Research at the Marine Biological Laboratory in 1947. His influence and impact extend beyond the confines of the laboratory. Throughout his life he was intensely concerned with the serious problems of mankind. He opposed Hitler and Stalin, and was outspoken against the involvement of the U.S. Government in the Vietnam War. Starting with recollections of Albert Szent-Györgyi by John T. Edsall of Harvard University, the remainder of the text is organized into six parts that cover the fields of Szent-Györgyi’s major contributions and interests: metabolism, vitamin C, molecular mechanisms of muscle contraction, submolecular biology and cell growth, and cancer; the social interrelations of science were also not neglected. These milestones form the basis of this volume.

• Language: English
• Publisher: Academic Press
• Release date: Jun 28, 2014
• ISBN: 9781483274553

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Massachusetts.

METABOLISM

Outline

Chapter 1: Errors, False Trails, and Failures in Research

Chapter 2: On Some Unusual Nucleotide Polyphosphates

Chapter 3: Ektobiology, Transport of Nutrients, and Chemotaxis

1

Errors, False Trails, and Failures in Research

HANS KREBS

Publisher Summary

This chapter discusses errors, false trails, and failures in research. A field where errors abound is clinical medicine. This does not imply that physicians are less wise and less competent than other people. Errors are forced upon the physician because a sick patient demands treatment, irrespective of whether the science of medicine can supply information on the nature of the disease and irrespective of whether accurate diagnosis is possible. The physician cannot turn away the patient. The physician should act and prescribe a therapy. Therefore, he should have a working hypothesis that guides his action. He is, therefore, forced to work in an area that is no longer simple science but in a situation where a tentative and even wrong hypothesis is better than none at all. But not all errors and misconceptions in medicine stem from this particular situation. An area of many misconceptions was a belief in the curative effects of many plant preparations and of certain spring waters that contain salts or gases or are radioactive.

I must begin by referring to one of the reasons for my special affectionate attachment to Albert Szent-Györgyi. At a very critical time of my career, at the beginning of the Hitler era in the spring of 1933, when I was in difficulty, he proved to be a true friend.

I had met Albert Szent-Györgyi first in 1929 at the International Physiological Congress held at Boston. Early in 1933 I wrote to him from Freiburg im Breisgau at Szeged in Hungary where he was Professor of Biochemistry, begging for a sample of ascorbic acid for research purposes. This was at that time a very scarce chemical, made only in research laboratories. It took some weeks before I received a reply because Szent-Györgyi was traveling, visiting research centers in England and Holland where he had worked earlier. During this interval the political scene in Germany had gravely blackened. His reply in German is reproduced in Fig. 1. The translation is as follows:

Fig. 1 Copy of Szent-Györgyi’s original letter.

The Hague, 12 April 1933

Dear Colleague:

I am glad to know that you are interested in ascorbic acid. Unfortunately, your letter reached me while traveling and it will be three weeks before I shall be back home again. I will then send you ascorbic acid immediately. Should you no longer require it, please let me know as our supplies are at present limited. If I do not hear from you I will send the substance promptly after my return.

I am very sorry to hear that you have personal difficulties in Germany. During the last few days I was in Cambridge where people have in mind helping you somehow. Of course, I have encouraged them as much as possible and I hope that my words will have contributed a little toward the realization of the plans.

With kind regards,

A. Szent-Györgyi

P.S. If you really would like to come to Cambridge it would be best if you wrote to Hopkins and told him that you would be content with very modest opportunities. Senior posts are not available and perhaps he might be diffident to offer you a junior position.

Therefore, ask Hopkins (if you would like to come to Cambridge) to give you an opportunity there. If it does not embarrass you, do refer to my encouragement.

On the very same day I took up the suggestion and wrote to Hopkins, and 10 weeks later I was installed at Cambridge. So it was Albert Szent-Györgyi’s kindness and considerateness, over 42 years ago, which decisively influenced my life at the most awkward, almost catastrophic, stage and I lived happily in England ever after, needless to say, with everlasting memories of deep-felt gratitude to Albi. When a few years ago I had an occasion of showing Albi his 1933 letter, he was amazed that I had preserved this scrap of paper. To me of course his was not a scrap of paper but a very important treasured document, testifying to some of Albi’s endearing qualities.

Another reason for my special affection for Albert Szent-Györgyi, which I am sure I share with many, is my close affinity to his outlook on life and my admiration for his courage and eloquence in expressing his philosophy. In the Bulletin of the Atomic Scientists (April 1975), he published what he called A Little Catechism setting out in 21 succinct paragraphs his passionate concern for real peace and the welfare of fellow man, his moral courage which gives him strength to speak out in support of unpopular truths, and his profound wisdom in discerning the essentials of life. It is reproduced here with the permission of the Editor and Publishers of the Bulletin of the Atomic Scientists.

A LITTLE CATECHISM

ALBERT SZENT-GYÖRGYI

Inflation is mostly but a form of governmental grand larceny, the government’s spending the citizen’s savings.

There can be no healthy economy when one-third of the revenue is spent on instruments and organizations of destruction, when armaments are the biggest and best business, when millions of young men are kept in uniform and when workmen continue to produce means of devastation.

Armies are not instruments of peace, but of war. Every army is a threat to peace; the greater the army, the greater the threat.

Armies mean power and power corrupts. Armies corrupt governments, making them wish for more power and a bigger army.

If you want your country to be strongest, ask first: strongest in what? Do you want to have the strongest capability to kill, destroy, terrorize, overkill? Or, the strongest country in economy, fairness, goodwill, helpfulness, knowledge, health and happiness?

Peace is mostly but disguised domination, be it Pax Romana, Pax Germanica or Pax Americana.

It is untrue that there have always been wars because man is bloodthirsty. Wars have always occurred because there always have been individuals or small groups of people willing to sacrifice others’ lives for their own profit or ambition.

Anything that can happen will happen and anything that can go wrong will go wrong (Murphy’s Law).

We either have to stop proliferating or else move to a better and bigger globe.

There can be no balance with death control (modern medicine) without birth control.

A world transformed by science can be run only by the spirit which created science: the search for truth and putting two and two together with a cool head, without fear, greed and lust for domination.

The basic rule of coexistence is: don’t do to others what you don’t want to be done to yourself.

If you want to be called a democracy, don’t support corrupt dictators or military juntas.

Killing a fellowman is murder regardless of uniform, language, creed, color or slogans.

There will be peace when we will look upon instruments of murder and destruction with revulsion, instead of national pride.

The present crisis will get increasingly worse until dog eats dog, instead of man helps man.

Mankind with atomic forces in his hand and greed, fear, and lust for domination in his heart is destined to eliminate itself.

Rich is he who has more money than desire, and poor is he who has more desire than money. Today’s unskilled laborer has more money than the princes of a few hundred years ago. What makes us poor is the desire for more. The key to happiness is not to get more, but to enjoy what we have and to fill the empty frame of our lives instead of enlarging it.

Life is a late by-product of the forces which created the universe. Life can be wiped out without causing a major disturbance to the universe. Human life can be made lasting by construction, not by destruction. It can be made enjoyable by health, happiness, beauty and knowledge.

Wealth comes from excellence, and not excellence from wealth (Plato). The present crisis is moral and intellectual; economics are secondary.

The present world crisis is not the sum of single national recessions. It is a global phenomenon which cannot be corrected by any local action. It can be corrected only by a global revolution: a revolution by man against outdated ideas and government attitudes, a revolution which will liberate man from the reign of present terror and allow him to use his wonderful abilities for his advantage–improving his life instead of destroying it. Such a revolution would make armies superfluous, liberating man from a terrific burden. It could inaugurate a second, golden age of man.

The development of science and technology are incompatible with the present outdated political ideas and human relations. It is this disharmony which led to two world wars and—if not corrected will lead to a third world war, to a collapse of civilization and, possibly, to the disappearance of man before the end of this century.

I believe it is instructive and healthy to look back at one’s research efforts after intervals of, say, 10, 20 or 30 years, and in the light of subsequent developments to take stock of one’s published–and unpublished–material. Doing this I find that some pieces of my own research have stood the test of time inasmuch as they have proved relevant to the progress of the subject. They turned out to be essential links in the development of the subject. Other pieces proved unimportant to the progress, and still others were downright erroneous-erroneous not in terms of the accuracy of experimental measurements but in respect to conceptual matters, i.e., design and interpretation of experiments. Quite a few of my research efforts never reached the stage of publication and in a sense were therefore failures. Let me add at once that such failures, up to a point, are of course a regular accompaniment of research; they are unavoidable if one explores new territories.

ERRORS AND MISCONCEPTIONS IN THE WORK LEADING TO THE CONCEPT OF THE TRICARBOXYLIC ACID CYCLE

My first papers on the tricarboxylic acid cycle, published in Enzymologia (Krebs and Johnson, 1937) and The Lancet (Krebs, 1937), referred to the intermediary stages of the oxidation of carbohydrate, because I believed at the time, as it turned out incorrectly, that I was studying the oxidation of carbohydrate. I used as experimental material pigeon breast muscle, which had been introduced into biochemistry by Albert Szent-Györgyi. It is a material which shows an exceptionally high rate of oxygen consumption after it is minced and suspended in a saline medium. The material thus presented the phenomenon I wanted to study–the intermediary stages of oxidations–in a relatively stable and easily accessible form. It was a mistake, however, to assume that it was carbohydrate that underwent oxidation.

The basis of the belief that carbohydrate was the chief substrate of oxidation in muscle was the conviction that, in general, carbohydrate is the fuel of muscular contraction. Another reason for believing that muscle oxidizes mainly carbohydrate was Meyerhof’s (1930) concept of the Pasteur effect in muscle: that the primary source of energy is lactic acid formation and that oxidations are mainly concerned with supplying the energy for the resynthesis of carbohydrate from lactate, a view generally accepted although subsequently proved incorrect. At rest and during moderate exercise the oxidation of fat is the main source of energy in muscle. Only during severe exercise do glycolysis and lactate oxidation contribute in a major way to the supply of energy.

In my own experiments I was already puzzled that addition of lactate did not increase the oxygen consumption of minced muscle and that the lactate present (which arose during the process of mincing and was very substantial) did not disappear. In fact all my critical experiments were carried out with unphysiologically high concentrations of pyruvate as substrate, and of course we now know that pyruvate is an effective precursor of acetyl coenzyme A. Acetyl-CoA was discovered some 8 years after the formulation of the tricarboxylic cycle concept.

Another error in the area of the tricarboxylic cycle field of which I was guilty concerns the occurrence of the cycle in microorganisms. Like many other investigators I was sceptical about the occurrence of the cycle in Escherichia coli and in yeast because these two organisms failed to metabolize added citrate, in contrast to some animal tissues where the ready oxidizability of citrate had been an essential piece of evidence. Until the middle 1950’s it was not appreciated that microorganisms, and for that matter some cells of higher organisms, may have permeability barriers for small molecules which prevent the entry of citrate into the cell. The concept of special transport mechanisms–the permeases–was introduced by Monod in the 1950’s (Cohen and Monod, 1957). It was eventually Swim and Krampitz (1954) who, with the help of isotopic carbon, demonstrated conclusively that the cycle can occur at rapid rates within the E. coli cell.

Another interesting misconception in the area of the tricarboxylic acid cycle concerns the interpretation by Szent-Györgyi of his work between 1934 and 1936 (Gözsy and Szent-Györgyi, 1934; Szent-Györgyi, 1935, 1936), a conceptual error which was responsible, at least in part, for the fact that people today talk of the Krebs cycle and not of the Szent-Györgyi cycle. It was Szent-Györgyi who discovered the catalytic role of C4-dicarboxylic acids in the oxidations of pigeon breast muscle. Szent-Györgyi was at that time interested in hydrogen transport from organic molecules to molecular oxygen and his interpretation of the catalytic role of fumarate was based on the correct observation that oxaloacetate is very readily reduced to malate in pigeon breast muscle, even aerobically. He suggested that the malate/oxaloacetate system might act as one of the hydrogen carriers between the fuels of respiration and molecular oxygen. At that time, it must be remembered, information on electron transport was very rudimentary because the roles of the pyridine nucleotides, flavoproteins and cytochromes had not yet been clearly