Albert Claude (1975) - The Coming Age of the Cell

I hope, I'm always warning people that they probably are not going to understand me because I have a low voice. As you know, it has been mentioned that I am going to give this lecture in English. You will recognise that I have a very good accent reminding of Europe but that won’t disturb you. First, at the last minute I made the mistake of writing a last, or a little introduction. And that, I'm afraid, is going to be in my way, because you know, when you think about the script, I wanted to give you some principle, however. I will begin in mentioning the man that many of you know and have heard of, it is Blaise Pascal. The man who claimed or said that man was sitting in the middle between two infinites. However, the infinites of Pascal were very much unbalanced. In one side he had all the space, the billion of light years of the stars shining on one hand. And on the other hand he had a tiny little space which occupied the distance between himself and a little insect which he could barely see with a hand lens. So that was very unfortunate. But we have to accept it as a fact and I can mention in this relation that if he had had a microscope, a very good microscope at his disposal, instead of a hand lens, it would have not mattered very much either. Because at that time the power of the microscope was not very great. And this, I have to say something not very nice about Newton, because you remember, in the 17th century Leeuwenhoek was making microscopes and a very slight improvement would have made a gain of 125 years. If we had been able at that time to compensate the operations of the lens, which was very small, we might even have seen bacteria. As a matter of fact, Leeuwenhoek saw bacteria but there were, the resolving power was insufficient. Now, Newton tried to compensate, and he made an error, he chose the medium to work with in order to determine the ratio between refraction and reflection. He used what they called sugar of lead, actually it’s simply a lead acetate. And with this medium it was zero. So with the prestige of Newton nobody thought of going back and look whether Newton was right or not. And that has been a very great price for biology, because imagine the theory of cell would have been written by Leeuwenhoek or somebody of that period. Pasteur would not have been able to discover the disease and bacteria, because somebody else had written 25 years and have done it. What enormous gain for cell biology. Of course, maybe just as well as it was, you know. Maybe we would have no job anymore ourselves if things had been done so soon. So this introduction, as I told you, I was meant to be disturbed, the text I’ve written, this is true. I hope you forgive me. I'd like, before I start on my formal lecture, to mention a few principles. My introduction is not foreign to that; it has some relation, you will see later. The first principle based on experimentation is that the discovery that we make always was at the measure of our tools. And if we have better tools, supposing that today we increased - and that’s possible, technically possible – the resolving power of a telescope of today by two. That would be, the infinite would be twice as great. The infinite is elastic, it depends on our tools. That is very important to remember when you do experimental work, because if we have some difficulty, you know that the technique always precedes the discovery. So you don’t have to try to repeat indefinitely your experiments, you have to try to invent a new technique. Or else you stop working and do something else. The second one, this refers to Newton, is that when we work in science we should never trust anybody, even Newton and even yourself, especially. When I was at the Rockefeller Institute - I mentioned I had been working at the Rockefeller institute for 15 years – I did everything myself. I was there in the department with Dr. Murphy, he was a very kind man, and I never used my lab boy. At that time you had no technicians, just laboratory boys. And I was giving him detective stories to leave me alone. So one day the boss came - and I don’t know why I had not been thrown out, I was a little embarrassed - and said “Why aren’t you using your helper?”. And I said “Well, I’ve not come here to keep the lab boy busy.” And it was really necessary because I was working at that time with the chicken tumors and I didn’t know how labile it was and I wanted to get to an extremely high titer. Because the technique I wanted to do was to isolate the virus and analyse it chemically. In the course of my talk I will use the word ‘magic’, don’t believe that I'm a magician. What I have said is if there’s a man, 50 years ago or even 100 years ago, if we would bring it here, now, everything is magic. But I don’t believe in magic, I don’t believe that. I also will speak of myself, because I think it’s nice, we are all human beings and we like to watch people around us, not to spy on them but to see, I have been watching human beings all my life. Not spying on them but try to learn something and also sometimes I discovered that there are some that would inspire me to be a little better. I don’t believe I have ever changed, so that has been a failure but it’s my own fault. So now I'm beginning to read and I think that will make a little more sense to you, I may have mislead you and I apologise, but if you think about it, you will find out that it’s not really silly. Now, I’ve chosen for my lecture not to recite simply what I’ve done, because that I hope that you know it by now. And I imagine that’s why I got the Nobel Prize. So I would like to use that in order to draw some conclusion on the impact of the discoveries of the past 30 or 35 years on ourself and on the world around us. Until 1930 or about, biologists were in a situation of astronomers and astrophysicists, as they had been in the time of Leeuwenhoek. We were permitted to see the object of our interest but not to touch them. The cell was as distant from us as they were from their stars in the galaxies. More dramatic, however, and frustrating was that we knew that the instruments were at our disposal. The only instrument of investigation at that time, the microscope, that had been so efficient in the 19th century, but ceased to be of any use having reached immeasurably the theoretical limits of its resolving power. I remember vividly my student days, spending hours at the light microscope, turning endlessly the micrometric screw of the microscope, and gazing at the blurred boundary which concealed the mysterious ground substance where the secret mechanisms of life might be found. Until I remembered an old saying, inherited from the Greeks - that the same causes, always produce the same effects. And I realized that I should stop that futile game, and should try something else. In the meantime, I had fallen in love with the shape and the color of the eosinophilic granules of leucocytes and attempted to isolate them. I failed - and consoled myself later on in thinking that this attempt was technically premature, especially for a premedical student, and that the eosinophilic granules were not pink, anyway. It was only postponed. That Friday, the 13th of September 1929, when I sailed from Antwerp on the fast liner "Arabic" for an eleven-day voyage to the United States, I knew exactly what I was going to do. I had mailed beforehand to Dr. Simon Flexner, Director of the Rockefeller Institute, my own research program, hand-written, in poor English, and it had been accepted. Later on I would have never dared to do what I did, because Dr. Flexner never accepted those kinds of things, he never accepted somebody to come and work on his own work. But probably he had found some virtue in my proposition, which had been to isolate and determine by chemical and biochemical means the constitution of the Rous virus, the first discovered cancer tumour agent, at that time still controversial in its nature and not yet recognized as a bonafide Virus. This task occupied me for about five years. Two short years later the microsomes, basophilic components of the cell ground substance, that blurred boundary that I was seeing in the microscope, had settled in one of my test tubes, still structureless but captive in our hands. In the following ten years, the general method of cell fractionation by differential centrifugation was tested and improved, and the basic principles codified in two papers in 1946. This attempt to isolate cell constituents might have been a failure if they had been destroyed by the relative brutality of the technique employed. But this did not happen. The subcellular fragments obtained by rubbing cells in a mortar, and further subjected to the multiple cycles of sedimentations, washings and resuspensions, in an appropriate medium of course, continued to function in our test tube, as they would have in their original cellular environment. That was great, is it not? The strict application of the balance sheet-quantitative analysis method permitted to trace their respective distribution among the various cellular compartments and thus, determine the specific role they performed in the life of the cell. We had that, I mentioned the balancing, it is like an accountant, we always had to refer to the 100% in determinant, like it is in a respiratory pigment, and finally we found that that fraction that had been dispersing all the cell, localised only in one, and we knew we had it. Small bodies, about half a micron in diameter, and referred to later under the name of "mitochondria" were detected under the light microscope as early as 1894 by Altman. Although they continued to be extensively investigated by microscopy in the course of the following 50 years, leaving behind an enormous and controversial literature, no progress was achieved, and the chemical constitution and biochemical functions of mitochondria remained unknown, to the end of that period. In the early 1940s, I began to make plans for an investigation on the distribution of respiratory pigments in cells. Considering the complexity of the problem, I realized that I should no longer do everything myself, because I wanted to keep the mastery of the isolation of the fraction in the distribution in the cell, which I could not do it and still reasonably isolate the pigments. I realised then it should be a collaborative undertaking. A year or so before, I had collaborated with Dean Burk and Winsler in providing them a material of interest to them, Chicken Tumor 10, which they used in their studies of the respiratory function in cancer cells. We started experimenting, although they were but mildly impressed by the scientific value of my project, they didn’t believe it was really good. But they told me that only years later. Their laboratory was conveniently located at the corner of York and 68th, at street level with the Cornell University Department of Vincent du Vignaud. I remember running across the street, handing them through the open window each fraction, as they were isolated, my share was to return, as I said, in order to analyse the distribution in the constitution of the fraction. One day, Rollin D. Hotchkiss appeared, returning from a one-year fellowship spent in Cambridge, England, who was delighted to find on arrival, quote, “the golden fruit on his doorstep”. We were soon rejoined by Hogeboom, and later by W. C. Schneider as regards the distribution of cytochrome c in the Cell, and its participation in respiratory processes. Together, the observations provided conclusive evidence to support the view that most, if not all, of cytochrome oxidase, succinoxidase and cytochrome c, three important members of the respiratory system responsible for most of the oxygen uptake, were segregated in mitochondria. In parallel with these biochemical studies, evidence was also obtained, by tests carried out with characteristic dyes, both under the microscope and in vitro, showing that the respiratory organelles and the mitochondria seen under the microscope were one and the same, a morphological information which would have remained meaningless, however, if we had not secured beforehand, the knowledge that the power of respiration exists in a discrete state in the cytoplasma. A fact which led me to suggest in my Harvey lecture, that the mitochondria may be considered “as the real power plant of the cell”. At about the same time, with the help of a microscope, this time the microsomes became the endoplasmic reticulum. Looking back 25 years later, what I may say is that the facts have been far better than the dreams. In the long course of cell life on this earth it remained, for our age for our generation, to receive the full ownership of our inheritance. We have entered the cell, the Mansion of our birth, and started the inventory of our acquired wealth. For over two billion years, through the apparent fancy of her endless differentiations and metamorphosis the Cell, as regards its basic physiological mechanisms, has remained one and the same. It is life itself, and our true and distant ancestor. It is hardly more than a century since we first learned of the existence of the cell: this autonomous and all-contained unit of living matter, which has acquired the knowledge and the power to reproduce; the capacity to store, transform and utilize energy, and the capacity to accomplish physical works and to manufacture practically unlimited kinds of products. We know that the cell has possessed these attributes and biological devices and has continued to use them for billions of cell generations and years. In the course of the past 30 or 40 years, we have learned to appreciate the complexity and perfection of the cellular mechanisms, miniaturized to the utmost at the molecular level, which reveal within the cell an unparalleled knowledge of the laws of physics and chemistry. If we examine the accomplishments of man in his most advanced endeavors, in theory and in practice, we find that the cell has done all this long before him, with greater resourcefulness and much greater efficiency. In addition, we also know that the cell has a memory of its past, certainly in the case of the egg cell, and foresight of the future, together with precise and detailed patterns for differentiations and growth, a knowledge which is materialized in the process of reproduction and the development of all beings from bacteria to plants, beasts, or men. It is this cell which plans and composes all organisms, and which transmits to them its defects and potentialities. Man, like other organisms, is so perfectly coordinated that he may easily forget, whether awake or asleep, that he is a colony of cells in action, and that it is the cells which achieve, through him, what he has the illusion of accomplishing himself. It is the cells which create and maintain in us, during the span of our lives, our will to live and survive, to search and experiment, and to struggle. That has some relation with the experiments of Dr. Weller the other day, we want to live for them. The cell, is as I described it, over the billions of years of her life, has covered the earth many times with her substance, found ways to control herself and her environment - you know that the cells are responsible for the atmosphere as it exists now. Man has now become an adjunct to perfect and carry forward these conquests. Is it absurd to imagine that our social behavior, from amoeba to man, is also planned and dictated, from stored information, by the cells? And that the time has come for men to be entrusted with the task, through heroic efforts, of bringing life to other worlds? I am afraid that in this description of the cell, based strictly on experimental facts, I may be accused of reintroducing a vitalistic and teleological concept which the rationalism and the scientific materialism of the 19th and early 20th centuries had banished from our literature and from our scientific thinking. Of course, we know the laws of trial and error, of large numbers and probabilities. We know that these laws are part of the mathematical and mechanical fabric of the universe, and that they are also at play in biological processes. But, in the name of the experimental method and out of our poor knowledge as it is really narrow in the universe, spread out, it’s really observed to be claimed that we take definite conclusions. To the exclusion and claim that everything happens by chance to the exclusion of all probabilities. About a year ago, I was invited to an official party by the Governor of a State. As the guests were beginning to leave, the Governor took me aside in a room nearby. He looked concerned and somewhat embarrassed. The question was unexpected, but I was not unprepared. I told him that for a modern scientist, practicing experimental research, the least that we could say, is that we do not know. But I felt that such a negative answer was only part of the truth. I told him that in this universe in which we live, unbounded in space, infinite in stored energy and, who knows, unlimited in time, the adequate and positive answer, according to my belief, is that this universe may, also, possess infinite potentialities. By that time the wife had joined us. Hearing this, she seized her husband by the arm and said, "You see, I always told you so." I was mentioning that to the credit of the feminine naivety of inconsequence. But actually I believe that she is the one to be right. Life, this anti-entropy, ceaselessly reloaded with energy, is a climbing force, towards order amidst chaos, towards light, among the darkness of the indefinite, towards the mystic dream of Love, between the fire which eats itself and the silence of the Cold. Such in nature does not accept a dictation nor scepticism. No doubt man will continue to weigh and to measure, watch himself grow, and his Universe around him and with him, according to the ever growing powers of his tools. For the resolving powers of our scientific instruments decide, at a given moment, of the size and the vision of our Universe, and of the image we then make of ourselves. Once Ptolemy and Plato, yesterday Newton, today Einstein and Maxwell, and tomorrow new faiths, new beliefs, and new dimensions. As a result of the scientific revolution of the present century we are finding ourselves living in a magic world, unbelievable about hundred years ago-magic our telephone, radio, television by multichannel satellites, magic our conversations with the moon, with Mars and Venus, with Jupiter - magic these means which transform our former solitude into a permanent simultaneity of presence, among the members of the Solar System. And here, at home, thanks to these new media, and the ever increasing speed of transports, we are witnessing a vast mutation of mankind taking place. no longer local, but at the dimensions of the Globe: the birth of a new biological organism, in which all Continents, and all the human races participate and recognise themselves as borders. For this equilibrium now in sight, let us trust that mankind, as it has occurred in the greatest periods of its past, will find for itself a new code of ethics, common to all, made of tolerance, of courage, and of faith in the Spirit of men. I may add some other things, but maybe it is not necessary. Thank you very much.

Albert Claude (1975)

The Coming Age of the Cell

Albert Claude (1975)

The Coming Age of the Cell

Comment

Albert Claude lectured only once at the Lindau Meetings, already the
year after receiving his Nobel Prize. As some other Nobel Laureates in a similar position, after an introduction, he choose to read the text of the Nobel lecture that he had delivered in Stockholm the year before. This is a very unusual and personal Nobel lecture and from a formal point of view constitutes a kind of breach with the Statutes of the Nobel Foundation. These state “It shall be incumbent on a prizewinner…to give a lecture on a subject relevant to the work for which the prize has been awarded”. The idea is partly that the members of the Prize-Awarding Institutions should hear “from the horse’s mouth” how the prize-awarded work came about. But already from the very first Nobel Prize, this rule has been broken. The 1901 Nobel Laureate Wilhelm Conrad Röntgen, e.g., never delivered his lecture. Since he also burned all his papers before he died, no one really knows what happened in his laboratory when he discovered X-rays! In 1923, Albert Einstein choose to speak about the gerenal theory of relativity and not about the cited photo-electric effect. In 1974, Albert Claude read a short poetic text which discusses the impact of discoveries in cell biology during the preceding fifty years and at the same time brings in some personal memories from his life as scientist. Today, this text would probably fit better as part of the autobiography that the Nobel Foundation asks the Laureates to write. In Lindau, the contents of the lecture probably came as a surprise to the students and young researchers in the audience, but for many of them probably as a pleasant surprise!

Anders Bárány

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