How new understandings about the biological function of ascorbic acid may profoundly affect our lives!

• cxeeutivc , ~ - health the report that briefs you on what to watch ©WORLD COPYRIGHT RESERVED 1978 BY EXECUTIVE PUBLICATIONS Volume XIV, Number 8 ® May, 1978 . Pickfair Bldg., Rancho Santa Fe, Calif. 92067 ® Area 714:756-2600 Albert Szent Gyorgyi, M.D., Ph.D.: How new understandings about the biological function of ascorbic acid may profoundly affect our lives! One of the world's most honored scientists, winner of the 1937 Nobel Prize for Physiology and Medicine, outlines what has happened and why this is so vital to our good health and chance for a long life! PUBLISHER'S NOTE: It was August 7th, 1973 at Stanford University's Symposium on Ascorbic Acid (Vitamin C) that I first met Albert Szent-Gyorgyi, then the new member of our Editorial Board. I would like to give you part of the intriguing news story about him that appeared the next day: "STANFORD, CALIF. (AP) Forty years ago a Hungarian physician named Albert Szent-Gyorgyi discovered that a mysterious chemical in certain fruits seemed to protect them against infection and discoloration when they were bruised. "He wondered if the chemical had anything to do with human disease, so he crystallized the substance to study it. "First he called it ignose (because he was so ignorant about it), and then he called it God-knows (because neither he nor anyone else could really tell what it was good for). "Finally he had to settle for calling it ascorbic acid — which has since become more and more famous as Vitamin C. "Szent-Gyorgyi tried to extract enough to study from the adrenal glands of slaughtered cattle. He managed to collect barely 15 grams in a year of work in Minnesota. "Then he went home to Hungary, and while he was visiting the University of Szeged, located in the center of Hungary's paprika-growing region, his wife doused a dinner dish with some of the local sweet peppers. "Yesterday, at Stanford University, Szent-Gyorgyi recalled that momentous dinner. "I didn't like the paprika," he related, "so I told my wife, I'll take it to the lab. "By midnight that night I knew I had found a treasure trove." "The paprika peppers, he discovered, were a bountiful source of ascorbic acid, and within a month he had prepared more than three pounds of it to ship to scientific colleagues all over the world. "In 1937 Szent-Gyorgyi won the Nobel Prize for his discovery of Vitamin C. Now nearly 80, he is still SIR HANS KREBS, M.D., F.R.C.P. (England), Nobel Laureate in Physiology and Medicine. Emeritus Professor of Biochemistry, Oxford University, Metabolic Research Laboratory, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford, England. RICHARD L. BOHANNON, M.D., F.A.C.P., Lieutenant-General, United States Air Force (Ret.); Medical Director, The Institute for Aerobics Research, Dallas, Texas. JAMES F. TOOLE, M.D., F.A.C.P., The Walter C. Teagle Professor of Neurology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina. LEONARD HAYFLICK, Ph.D., Senior Research Cell Biologist, Children's Hospital Medical Center, Bruce Lyon Memorial Research Laboratory, Oakland, California. DEMETRIO SODI-PALLARES, M.D., Professor of Medicine, Chief of the Department of ElectroVectorcardiography, Institute Nacional de Cardiologia, Mexico, D.F. EDITORIAL BOARD ALBERT SZENT-GYORGYI, M.D., Ph.D., Nobel Laureate for Physiology and Medicine, Scientific Director, The National Foundation for Cancer Research, Woods Hole, Massachusetts. JOHN K. LATTIMER, M.D., ScD., FACS, Professor and Chairman, Department of Urology, College of Physicians and Surgeons, Columbia University; Director, Squier Urological Clinic and Director, Urological Service, Presbyterian Hospital, New York City. JOHN STIRLING MEYER, M.D., Professor, Department of Neurology, Baylor College of Medicine; Director, Baylor-Methodist Center for Cerebravascular Disease, Texas Medical Center, Houston, Texas. SOLON PALMER, Jr., M.D., Scripps Clinic and Research Foundation, La Jolla, California. HANS SELYE, C.C., M.D., Ph.D., D.Sc., F.R.S. (C), President, International Institute of Stress, University of Montreal, Montreal, Quebec, Canada. LINUS PAULING, Ph.D., Nobel Laureate in Chemistry and in Peace; Emeritus Professor of Chemistry, Stanford University, Stanford, California. Research Professor, Linus Pauling Institute of Science and Medicine, Menlo Park, California. MARK D. ALTSCHULE, M.D., Visiting Professor of Medicine, Harvard Medical School; Lecturer in Medicine, Yale University; Staff Consultant, Boston City Hospital; Attending Physician, Boston Veterans Administration Hospital, Boston, Massachusetts. ALTON OCHSNER, M.D., Senior Consultant in Surgery, Ochsner Clinic and Ochsner Foundation Hospital and Emeritus Professor of Surgery, Tulane University School of Medicine, New Orleans, Louisiana. ROGER J. WILLIAMS, Ph.D., D.Sc., Professor of Chemistry, Co-founder and Consultant, Clayton Foundation Biochemical Institute, The University of Texas; Past President, The American Chemical Society, Austin, Texas. vigorous and hard at work. He heads the Institute for Muscle Research at Woods Hole, Mass. "Yesterday he was a major speaker at a symposium on Vitamin C, organized at Stanford by the vitamin's most zealous promoter, bio-chemist Linus Pauling, himself the winner of two Nobel Prizes." The report that follows by Dr. Szent-Clyorgyi (now the Scientific Director of the National Foundation for Cancer Research) is closely reasoned and requires your concentrated attention . . . but your ultimate reward may well be far greater health, freedom from sickness and a vital, longer life.  _Richard Stanton In a remarkably short time after we discovered ascorbic acid fifty years ago, we knew everything about its structure that was worth knowing .. . but its biological function remained unknown. It was not possible to use it intelligently as long as we did not know how it functioned. "We can control only what we understand." Without such an understanding we could not decide even simple questions. Take, for example, the long controversy over the so-called "Minimum Daily Requirements" (MDR) . . . because no one knew for sure how ascorbic acid functioned in our bodies. Now my associates and I have found out how and this new understanding opens vast new vistas for its use in medicine. But let us begin at the beginning. We divide the surrounding world into animate and inanimate, that is alive and not-alive. The division is sharp, unequivocal. It is very rarely that we are in doubt where something belongs. What characterizes life is its wonderful, subtle reactivity. There has to be some fundamental difference between the living and the lifeless. The definition of this difference in terms of exact sciences is one of the main problems of biology on which the solution to many important medical problems depends. The main bearer of life is protein, so one expects that proteins share with living systems their reactivity. They do not! Apart from enzymic activity, they show no special reactivity at all. Proteins are built of relatively clumsy large molecules (macromolecules) in which the electrons, the small electric particles which surround the atomic nuclei (core) are held firmly in their places and have no mobility. Approaching this problem four decades ago I felt that the wonderful reactivity of the living cell cannot be generated by unreactive, clumsy large molecules and the real actors of life had to be much smaller and more mobile. They could hardly be anything else than electrons.== The proteins consisting of large molecules could not be the actors. They had to be, rather, the stage on which the drama of life was enacted. To be mobile, electrons need a conductor which made me propose (1941) that proteins may be conductors. My proposition was unanimously rejected for the simple reason that none of the great number of proteins which were isolated and thoroughly studied showed any signs of semiconductivity. Biology was and is a molecular science which took litle cognizance of the electronic dimension. The only way in which I could explain this situation * Electrons are elementary particles that are a fundamental constituent of matter, having a negative charge, a mass, a spin and are components of an atom outside the nucleus. to myself was by supposing that the same protein which showed no signs of life in vitro was in a different physico-chemical state in vivo, in the living cell. I called this physicochemical state in which I supposed the proteins to be in the living system "the living state." To avoid misunderstanding and confusion I must interject here that there is no such thing as "the protein." Proteins are exceedingly versatile substances which, in the living organism, perform very different functions, some of which are very simple and demand no special reactivity and conductivity, and so what I will say pertains only to the proteins which partake in the generation of the great signs of life, like motion, secretion, excitability. This difference between the live proteins within the living organism and the same proteins after they have been purified and isolated, presents in a nutshell the difference between the animate and inanimate world, and my problem boiled down to defining this difference. The first question which had to be answered was this: is there a method by which an unreactive protein macromolecule can be transformed into a highly reactive one? There is one way, and this by taking out single electrons from it. In the protein molecule the electrons form pairs, the two electrons of the pair spinning in opposite directions. A spinning electron is a little magnet, and the two electrons of the pair represent opposed charged magnets, compensating each other's magnetic moments which strongly couples them. Taking out single electrons from a molecule requires that electron pairs have to be separated, uncoupled. A molecule containing an uncoupled electron is called a "free radical" and free radicals are known to be highly reactive. They contain not only an uncoupled electron, they contain also half-filled orbitals, the eliminated electron leaving a positively charged "electron hole" behind. All this upsets the balance of the molecule and makes it highly reactive. The protein molecule has only a definite number of places (orbitals) on which it can hold electrons. If all these places are occupied by electrons then there can be no electronic mobility. The situation is similar to a completely filled parking lot. To induce mobility a car has to be taken out. This makes all the rest mobile. So my problem was: how can electrons be taken out of a protein molecule? Electrons can be taken out of a protein molecule by "electron acceptors," that is, other molecules which have an empty orbital on which they can accommodate an additional electron. The transfer of single electrons from a "donor" to an "acceptor" is called "charge transfer" which is one of the most important biological reactions. The electron transferred from the donor to the acceptor will oscillate between the two. What part of its time it will spend on the acceptors depend on energy relations. If it spends only a small part of its time there, then it is customary to say that only "a small part of the electron" has been transferred — the half, one tenth, a hundredth, as the case may be. The situation in most organic molecules, as well as in proteins, is similar to the situation in a completely filled parking lot in which (as I said) no single place is free, in which all cars are immobile. By taking out one car all the cars become mobilized there being one free place now which allows shuffling. So in proteins too, taking out one (or more) electrons make all the electrons mobile. To have the electrons mobile the protein must be desaturated electronically. The more it is desaturated, the more electrons are taken out, the more mobile the other electrons will be. All this, taken together, opens the possibility that the basic difference between "alive" and "not alive" is an electronic desaturation. While in inanimate systems the molecules are "closed shell molecules" in which all allowed places (orbitals) are occupied by electron pairs, in living systems the proteins are desaturated electronically, the living state of protein being the desaturated, free radical state. Desaturation depends on the availability of electron acceptors which can take the electrons out of the proteins.(I) When the number of unpaired electrons formed is small it means that only a small part of the electrons has gone over and the charge transfer is a weak one. Such a weak charge transfer can lead only to a low degree of desaturation of protein. This is very important because when life originated billions of years ago, our globe was covered by dense water vapor, and there was no light and no oxygen at the surface, and the only acceptor available was methylglyoxal (MG) that could produce only a low level of protein desaturation. So, in this first dark and anaerobic (oxygen-free) period of life only the simplest, most primitive living forms were developed. This situation changed when, owing to cooling, the water vapor envelope of our globe condensed and, eventually, light could reach the surface of the globe. Life captured the photons of this light and used their (1) The research of my laboratory showed that the main acceptor used by animal cells is methylglyoxal, (MG). It was discovered more than sixty years ago that all living systems studied contained a most active enzyme, a "glyoxalase," for the inactivation of methylglyoxal (its conversion into D-lactic acid). Actually glyoxalase is two enzymes, glyoxalase I and II which use SH-glutathione as coenzyme. Nature does not indulge in luxuries, and if there is such a highly active ubiquitous enzymic system it must have something very important to do, but nobody could find out what. A role in the desaturation of protein mould fully justify its existence. MG can attack proteins by interacting with its aldehydic group, with the 2 NHz (amino) groups of protein. The reaction between C = O and NHs, being possibly one of the most central reactions of cell life, demands a more thorough study. Proteins being very complex, I started this study with simple models containing methylamine, MA, instead of protein, MA being the simplest aliphatic amine. Mixing a watery solution of MA and MG a dark color develops, indicating that reaction occurred. As shown by Gascoyne, in the ESR spectroscope the solution gave a strop signal, which meant that electrons have gone over from MA to MG. Charge transfer occurred. energy for separating the elements of water (I-I and 0), producing free oxygen, which is a very strong electron acceptor. This opened the way to development and differentiation ... the end result today is us! I have called the first dark, and anaerobic period of life the a period. In this period only the simple organisms could be built which could perform only the simplest reactions, the most important of which was proliferation, which was favored by the simplicity of structure and made life perennial. The subsequent "aerobic and light period I called the R period. In it life developed increasingly complex structures capable of increasingly complex and subtle reactions, while proliferation was subjected to regulation. In this R period proliferation must have been inhibited by the solid structures built and strong cohesive forces developed to hold these structures together. The cohesive forces, as shown by Laki and Ladik, were greatly enforced by the electronic desaturation of protein. What lends an acute interest to these reactions is the fact that they are not limited to the far distant past. Structures and cohesion interfere with cell division, so a dividing cell has to disassemble its structures and relax its cohesive forces; it has to return to an extent to the a state. The a F—* f3 transformation had thus to be reversible and occur in every cell division. All dividing cells have to be in the Ce state which explains why all dividing cells (embryonic and cancer cells alike) have very similar properties. After cell division is completed the cell has to build up its 8 state again. Should this state become unstable, then the cell has to persist in the proliferative Oe state, and tumor results! The next question we had to answer was: how did oxygen desaturate the protein? If free oxygen would attack protein we would burn up! Here is where ascorbic acid assumes a basic role in the mechanisms of life. It is present in tissues as a salt, ascorbate. As Gascoyne has found, when ascorbate meets oxygen it passes onto it one of its electrons, and becomes itself a very reactive free radical. This radical, having lost an electron, is a very good electron acceptor which can readily take a whole electron from the methylglyoxal, attached to the protein. This means that the protein becomes desaturated, becomes a reactive conductant free radical. Its electron is passed to methylglyoxal, methylglyoxal passes it on to ascorbate (which has made room for it by giving an electron to oxygen). The real final electron acceptor of protein is thus the oxygen. In this process in which the protein is transduced into the living state, ascorbic acid plays a central role. Without it no electrons can be transmitted to oxygen and the protein cannot be desaturated. McLaughlin discovered that these charge transfer reactions lead to the production of free radicals which can be studied in the light spectroscope. In the interaction of methylglyoxal, methylamine and ascorbic acid and oxygen two free radicals are formed, one with a maximum of absorption at 380 and another with a maximum of absorptions around 475 nm. Pethig, Bone, Lewis, and myself have shown that if protein is treated with methylglyoxal it turns brown, assuming the color of liver and becomes an electronic conductor. (This explained why the liver is brown.) Methylglyoxal can actually be isolated from the liver proteins. Does all this help us to decide how to apply ascorbic acid? It does! It also explains the difference between ascorbic acid and other vitamins. Other vitamins have a favorable action on health only as they correct a deficiency, be it small or great! Ascorbic acid, transducing the protein into the living .state, enables it to perform. The more ascorbic acid is available, the better the protein will work. The spectroscopic observations (mentioned above) indicate that methylglyoxal and ascorbic acid are incorporated into the protein, linked to it by covalent bonds. The protein is thus activated by incorporating into it the acceptor. The ascorbic acid ingested by man is excreted only partly with his urine. Its greatest part simply disappears! What happened to it was a mystery. My studies indicate that it is incorporated into the living machinery! This brings out a point which is important in relation to medical application. To have a well functioning cellular machinery the ascorbic acid must be available while the machine is built. (If we build a wall, the mortar must be applied to every brick. One does not raise a wall putting bricks together and then pouring cement over them.) So one should not wait for the application of this vitamin until one gets ill, trying to put the situation right by taking big doses. We should take it all the time. To have plenty of ascorbic acid is especially important in our young years when we build our body. But ascorbic acid should be available at all ages. The older we become the less we are able to store and use it, thus the more we need of it. (No doubt, we can stay alive on very small doses, as a car can run also without servicing. The difference will only be that without good servicing the car will become useless after 50,000 miles, while with good service it may last several times as long.) The electronic desaturation of protein greatly increases the cohesive force holding the living structures together. This explains why in scurvy old scars open up. In absence of ascorbic acid the cohesive forces weaken. Ascorbic acid is needed to keep these cohesive forces at a maximum which prevents the body falling apart. The action of ascorbic acid on cohesion leads also to another important conclusion about the ascorbic acid medication. We need ascorbic acid not only for holding our body together, but also for putting it together. Without sufficient ascorbic acid the body cells cannot be built precisely. This is very important because if a body has been left without a satisfactory ascorbic acid supply for a long period, the damage cannot be put right by a big dose of ascorbic acid. As you know, a full grown human of 60 kg needs about 60 grams of protein daily in his food to stay in nutrition balance. This means that 60 grams of protein have to be remade daily. Without sufficient ascorbic acid the cells cannot be put together correctly, and if they were put together in an unsatisfactory manner it has to take a long time to put the damage straight. In my calculations it takes six months to put such damage right, six months-during which the body has been supplied with ample ascorbic acid, at least 2-8 grams daily. Last year I collected a rather unfortunate personal experience on this. I broke down with pneumonia which I could not shake off for months, until I discovered that the quantities of ascorbic acid which I took (one gram daily) had become insufficient at my age (84). When I went up from 1 gram to eight, my troubles were over. I strongly believe that a proper use of ascorbic acid can profoundly change our vital statistics, including those for cancer. For this, ascorbic acid would have to cease to be looked upon as a medicine, sold in milligram pills by the druggist. It would have to become a household article, like sugar and salt and flour, sold in the supermarket in powder form by the pound. Ascorbic acid is a vitamin which has to be taken as food because mankind grew up in the tropical jungle where there was plenty of it and there was no need to make it. I suspect that the lost paradise of the old biblical story was actually the tropical jungle with its ample supply of ascorbic acid. During my long research career I have become deeply impressed by the perfection of the human body. All those diseases, about which I had to learn as a medical student, are to a great extent due to our abuse, our mishandling of our body, in which a lack of ascorbate plays an important role. Present medicine is lopsided. As a medical student I had to listen no end to lectures on disease, but cannot remember one on health, full health! 4 1 A. Szent-Gyorgyi EXECUTIVE HEALTH is published monthly by Executive Health Publications, Pickfair Bldg., Rancho Santa Fe, California 92067. SUBSCRIPTIONS $24 A YEAR IN U.S.A. and its possessions, Canada and Mexico. Individual reports (back issues) $2.00 per copy. All other countries $26 by surface mail, $30 by air mail. (Only International Money Order or check cashable on U.S. bank will be acceptable.) Second Class postage paid at Rancho Santa Fe, California and at additional mailing offices. 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