스크랩 암세포는 알카리와 산소가 풍부한 곳에 살수 없다. / Otto Warburg (오토 바르부르크)

[通知が]

Otto Heinrich Warburg   바르부르크(Otto Heinrich Warburg) 박사 - 독일 생화학자, 세계적 암 연구학자, 노벨상   오토 바르부르크는 1931년에 '세포호흡의 산소전이 효소 발견' 으로 의학부분에서 노벨상을 받았고 1944년에 '수소전이 효소의 활용그룹 발견'으로 두 번째 노벨상을 수상했다. O. Warburg won the Nobel Prize in Medicine in 1931 for his discovery of the oxygen-transferring enzyme of cell respiration, and was voted a second Nobel Prize in 1944 for his discovery of the active groups of the hydrogen transferring enzymes.  “암세포의 발생은 산소부족에 있다고 확실히 단정하고 있다. 인체의 세포는 공기 중에 산소가 있어야 하는 유산소(aerobic) 생활을 하고 있기 때문에, 산소가 부족하면 생명을 이어 가려고 하는 생체 내의 세포는 변화를 일으키고 당분해작용(glycolysis)을 비롯하여무 산소(anaerobic)생활로 바뀐다. 이렇게 바뀐 세포의 핵은 암세포의 핵과 일치한다는 이론을 발표하였다.”
오토 바르부르크 박사는 1883년 10월 8일 바덴의 프라이버그에서 태어났다. 그의 아버지 물리학자 에밀 바르부르크는 “Physikalische Reichsanstalt, Wirklicher Geheimer Oberregierungsrat” 의 총장이었다. 오토는 대 에밀 피셔 밑에서 화학을 공부하고 1906년에 베를린 대학에서 박사 학위를 받았다. 그리고는 하이델버그 대학에서 von Krehl 밑에서 공부하여 1911년에 의학박사 학위를 받는다.  1차대전중 그는 프로이센 근위기병으로써 근무하였고 1918년에 카이저 빌헬름 생물대학의 교수로 임명되었다.    <산화의 과정에 대해 연구> 1931년부터 그는 그곳의 세포생리학 담당자로 있었으며 바르부르크의 피셔와의 초기연구는 폴리펩티드 영역에 있었고, 하이델버그에서는 산화의 과정에 대해 연구하였다. 그의 물리적 화학적 방법의 의한 중요한 과정의 발견은 비슷한 무기적 현상으로 연관시키는 노력으로 이어졌다.  그의 방법은 식물의 이산화탄소 흡수, 종양의 변이, 그리고 산소를 운반하는 호흡 효소의 화학적 구성물에 대한 심도있는 연구들을 포함한다. 바르부르크는 선생이 아니었지만, 그는 일생에 모든 시간을 과학연구에 바칠수 있는 걸 감사하게 생각했다. 카이저 빌헬름 대학에서의 후기연구는 플라빈과 니코틴아미드가 수소를 운반하는 활동적인 그룹이라는 것을 발견하는것으로 이어졌다.  이것은 이전에 발견된 철 옥시나아제와 함께 이 세상에 모든 산화 환원 과정의 설명을 가능케 하였다. 그는 1931년에 호흡효소의 활동에 대한 발견으로 노벨상을 수상하였다. 이러한 발견은 세포 호흡과 세포 변이에 대한 새로운 장을 열었고, 그는 암세포가 산소가 부재한 상태에서 발전된다는것을 제시하였다.     Otto Heinrich Warburg 의 암치료 원리 < 무산소 당분해작용(無酸素解糖 anaerobic glycolysis : 학술적으로는 嫌氣的)이란? > 말 그대로 산소 없이 당을 분해한다는 뜻이다. 산소 없이 화학작용을 한다는 뜻.  무산소해당과정은 1930년대 독일의 생화학자들인 엠덴(G. Embden), 마이어호프(O. Meyerhof) 바르부르크(O. Warburg ) 박사에 의하여연구되어 졌는데 이것을 바탕으로 1931년에  바르부르크와 마이어호프는 노벨상을 수상하였다. 연구내용은 다음과 같다. 포도당 1분자 : 10단계를 거치며 각 단계마다 관련된 효소의 도움으로 분해 되어 피부르산 2분자를 만들고 포도당이 만드는 총 ATP의 약 5% 인 2ATP만 나온다. ① C6 H12 O6 ⇒ 2C3H4O3 +2(2H) +2ATP    (포도당)      (피루브산) ※ ATP : 에너지를 저장하고 있는 화합물 포도당 1분자량이 완전히 산화, 분해하면 38개의 ATP가 만들어지고 ATP 1개에 약 7.3㎉의 에너지가 저장되어 있으므로 포도당 1분자에서 실제로 이용할 수 있는 에너지는 277.4㎉가 된다. 7.3㎉ × 38ATP = 277.4㎉ 위 ①에서 만들어진 피루브산 2분자는 산소를 소비하면서 다음 단계로 들어가야 하지만 산소가 부족하거나 없는 경우 수소와 결합하여 락트산(Lactic acid) 2분자로 되어버린다. ② 2C3H4O3 +2(2H) = 2C3H6O3     (피루브산)          (락트산) 여기서 일어나는 화학반응은 효소의 도움으로 일어나므로 락트산발효라 한다. 체내 산소가 부족하면 락트산은 더 이상 분해 되지 않고 몸 안에 축적되게 된다. 근육에 락트산이 쌓이면 피로 후 통증이 오게 된다. 그래서 락트산을 피로물질, 혹은 통증물질이라고 한다. 이때 만약 산소만 풍부하게 공급되면 락트산은 수소를 떼어내며 즉시 피루브산이 된다. 이 반응에서 락트산 탈수소 효소(LDH : lactate dehydrogenase))가 중요한 작용을 한다. ※ 락트산 탈수소효소와 암과의 상관관계가 있을까? 암세포와 종양은 무 산소 해당과정에서 나오는 소량의 에너지만을 이용하여 쉬지 않고 자란다. 에너지 발생량은 적으나 여기에만 의존해야 하니 정상세포에 비하여 포도당을 훨씬 더 많이 소비하며 종양 주위에는 그만큼 락트산이 더 많이 쌓인다. 이에 따라 수소이온이 많아지니 pH도 떨어진다. 포도당 이외의 당인 프룩토오스, 만노오스, 갈락토오스, 펜토오스들도 이 과정에 들어와 이용된다.  <유산소 TCA회로 란?> 유산소(학술적으로는 好氣的)라는 말은 산소를 많이 이용하여 반응이 일어난다는 뜻,  TCA회로는 생명을 유지하는 데 필요한 거의 모든 에너지를 만드는 가장 귀중한 신진대사 과정 ※ TCA회로 : 영국에서 활동한 독일 생화학자 크레브스 경과 리프만 박사에 의하여 발견, 1953년 노벨상 수상이론, 크레브스 회로 또는 시트르산 회로라고도 한다. 앞의 ① 분자식에서 포도당 1분자가 피루브산 2분자로 분해 된 다름 피루브산이 세포핵 안에 있는 미토콘드리아 속으로 들어가서, 다시 효소의 도움을 받으며 산소를 소비하여 다음단계의 중요한 신진대사 과정으로 들어온다. 여기에서는 포도당이 만드는 총 ATP의 약 95%인 36개의 ATP가 나온다. ③ 2C3H4O3 + 6O2 + 2(2H) ⇒  6CO2 + 6H2O + 36ATP    (피루브산)  (산소)            (이산화탄소)(물)  ③의 반응결과를 보면 산소를 이용하여 물과 이산화탄소로 완전 분해하므로 포도당은 신진대사의 중간 생성물인 노폐물이나 찌꺼기를 몸 안에 남기지 않게 된다. 물은 땀, 소변, 대변으로, 이산화탄소는 폐를 통해서 완전히 배출된다. 인체가 병과 싸우는 저항력이나 면역력도 이 에너지에서 나오므로 이 대사가 원만하게 이루어지지 않으면 건강과 생명을 유지하기 어렵다. 병원에서 포기한 말기 암 환자의 경우 TCA 회로의 대사가 원활하게 이루어지지 않아 몸 안에 락트산이 많이 쌓이고 에너지가 충분히 만들어지지 않고 면역반응도 충분히 일어나지 않는다. 이러한 사실은 일반적인 혈액검사로는 잘 발견되지 않는다. <참고서적> 기적의 암치료법 - 황봉실
Otto Heinrich Warburg 의 히스토리 Otto Heinrich Warburg was born on October 8, 1883, in Freiburg, Baden. His father, the physicist Emil Warburg, was President of the Physikalische Reichsanstalt, Wirklicher Geheimer Oberregierungsrat. Otto studied chemistry under the great Emil Fischer, and gained the degree, Doctor of Chemistry (Berlin), in 1906. He then studied under von Krehl and obtained the degree, Doctor of Medicine (Heidelberg), in 1911. He served in the Prussian Horse Guards during World War I. In 1918 he was appointed Professor at the Kaiser Wilhelm Institute for Biology, Berlin-Dahlem. Since 1931 he is Director of the Kaiser Wilhelm Institute for Cell Physiology, there, a donation of the Rockefeller Foundation to the Kaiser Wilhelm Gesellschaft, founded the previous year. Warburg's early researches with Fischer were in the polypeptide field. At Heidelberg he worked on the process of oxidation. His special interest in the investigation of vital processes by physical and chemical methods led to attempts to relate these processes to phenomena of the inorganic world. His methods involved detailed studies on the assimilation of carbon dioxide in plants, the metabolism of tumors, and the chemical constituent of the oxygen transferring respiratory ferment. Warburg was never a teacher, and he has always been grateful for his opportunities to devote his whole time to scientific research. His later researches at the Kaiser Wilhelm Institute have led to the discovery that the flavins and the nicotinamide were the active groups of the hydrogen-transferring enzymes. This, together with the iron-oxygenase discovered earlier, has given a complete account of the oxidations and reductions in the living world. For his discovery of the nature and mode of action of the respiratory enzyme, the Nobel Prize has been awarded to him in 1931. This discovery has opened up newways in the fields of cellular metabolism and cellular respiration. He has shown, among other things, that cancerous cells can live and develop, even in the absence of oxygen. In addition to many publications of a minor nature, Warburg is the author ofStoffwechsel der Tumoren (1926), Katalytische Wirkungen der lebendigen Substanz (1928), Schwermetalle als Wirkungsgruppen von Fermenten (1946),Wasserstoffübertragende Fermente (1948), Mechanism of Photosynthesis (1951),Entstehung der Krebszellen (1955), and Weiterentwicklung der zellphysiologischen Methoden (1962). In the last years he added to the problems of his Institute: chemotherapeutics of cancer, and the mechanism of X-ray's action. In photosynthesis he discovered with Dean Burk the I-quantum reaction that splits the CO2, activated by the respiration. Otto Warburg is a Foreign Member of the Royal Society, London (1934) and a member of the Academies of Berlin, Halle, Copenhagen, Rome, and India. He has gained l'Ordre pour le Mérite, the Great Cross, and the Star and Shoulder Ribbon of the Bundesrepublik. In 1965 he was made doctor honoris causa at Oxford University. He is unmarried and has always been interested in equine sport as a pastime. From Nobel Lectures, Physiology or Medicine 1922-1941, Elsevier Publishing Company, Amsterdam, 1965 This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/Nobel Lectures. The information is sometimes updated with an addendum submitted by the Laureate. To cite this document, always state the source as shown above.    Otto Heinrich Warburg 은 암이론으로 두 번째 노벨상을 받음  His father was a doctor and he studied under a Nobel Prize Winner, who helped him advance in his understanding and knowledge in science. He won a Nobel Prize and was award a second. He was unable to except his second Nobel Prize because because he was a Jew during the Hitler regime. Basically Otto Warburg won 2 Nobel Prizes in cancer.  When your doctor gets nominate for a Nobel Prize or listens to the facts about cancer then he could say he knows what he is talking about.  Until then his is just mixing poisons such as Hitler did. Mustard gas. Ask them to mix you enough mustard gas to make your time short.    Otto Warburg (biochemist) about 30 years after being awarded the first Nobel Prize, he begin working with Dr. Carl Reich on a part time bases. This was between of 1962 and until his death in 1970. They were doing the final experiments regarding cancer and we’re almost ready to produce the book that would have changed the treatment for cancer totally.  Seems after his death Dr. Reich was not allowed to even pickup their privately owned equipment or the life saving research.  Some 30 years later the privately owned research has not been released to the public.   오토 바르부르크(생화학자)가 노벨상을 수상한  후 30년동안 칼 라이히박사와 함께 일하기 시작했다.  그들은 암에 관한 마지막 실험를 하였고 암을 위한 전체적인 처방을 바구는 책을 발간할 준비가 거의 되었다. 그런데 칼 라이히 박사의 죽음으로 생명을 구하는 연구와 그들의 사적으로 소유된 장비를 고르는 것 조차 허락되지 않았다.  But Dr. Carl Reich never gave up and some 20 years later he and Robert Barefoot (biochemist) produce “The Calcium Factor”.  To simplify the research Robert Barefoot wrote “Death by Diet”. Robert Barefoot being a biochemist such as Otto Warburg has enough knowledge to put the remaining pieces together.            As you read this lecture I want you to realize that Otto Warburg is talking about an enzyme deficiency with cook foods. What basically happens when cooked foods which are enzyme destroyed are eaten, is that it causes the red blood cells to cluster together.            A smaller view is 4 microns in diameter. A red blood cell is 7 microns in diameter. When you feed your family enzyme deficient foods the red blood cells are weaken and stick together in a groups and cannot travel through the smaller veins. This causes the body to have many anaerobic (low or no oxygen areas within the body) that allows cancer to develop. But than, if the your body is towards an alkaline state then the cancer cannot continue to survive because your body is basically more oxygenated.          Cancer basically needs and low oxygen environment to survive. Over the years I have heard about a lot of vegetarians getting cancer. And I'm guessing here, but if the saliva pH test is done I'm sure they will be extremely alkaline. Meaning that acidic or alkaline extremes unnatural to the body are causing a steady low oxygen environment which cancer needs to survive.  It can get started and has the environment it needs to continue. Basically 99% of the time a terminal cancer victim body is a thousand time more acidic, then normal. But both these environments are causing a low or no oxygen environment which cancer loves you for. This is causing a low oxygen environment. Which means you are normally calcium deficient. And your cells are oxygen starved. 암이 좋아하는 환경은 산소가 적거나 없는 환경이다. 산성이 된다는 것은 산소가 적은 환경을 야기하고 이것은 정상적인 칼슘(알칼리)의 부족을 의미한다. 그래서 당신의 세포들은 산소가 결핍이 되어진 것이다.  Otto Heinrich Warburg 의 1966년 6월 30일 노벨상을 받은 논문 개정한 강의 내용 (암의 예방) with two prefaces on prevention Revised lecture at the meeting of the Nobel-Laureates on June 30, 1966 at Lindau, Lake Constance, Germany by Otto Warburg Director, Max Planck-Institute for Cell Physiology, Berlin-Dahlem English Edition by Dean Burk National Cancer Institute, Bethesda, Maryland, USA The Second Revised Edition Published by Konrad Triltsch, Würzburg, Germany 1969 Preface to the Second Revised German Edition  of the Lindau Lecture (The way to prevention of cancer)         Since the Lindau lecture of June 1966 many physicians have examined - not unsuccessfully - the practical consequences of the anaerobiosis of cancer cells. The more who participate in these examinations, the sooner will we know what can be achieved. It is a unique aspect of these examinations that they can be carried out on human patients, on the largest scale, without risk; whereas experiments on animals have been misleading many times. The cure of human cancer will be the resultant of biochemistry of cancer and of biochemistry of man.         A list of selected active groups of respiratory enzymes will soon be published, to which we recently added cytohemin and d-amino-Levulinic acid, the precursor of oxygen-transferring hemins. In the meantime commercial vitamin preparations may be used that contain, besides other substances, many active groups of the respiratory enzymes. Most of these may be added to the food. Cytohemin and vitamin B 12 may be given subcutaneously. (A synonym of "active group" is prosthetic" group of an enzyme.)         There exists no alternative today to the prevention of cancer as proposed at Lindau. It is the way that attacks the prime cause of cancer most directly and that is experimentally most developed. Indeed millions of experiments in man, through the effectiveness of some vitamins, have shown, that cell respiration is impaired if the active groups of the respiratory enzymes are removed from the food; and that cell respiration is repaired at once, if these groups are added again to the food. No way can be imagined that is scientifically better founded to prevent and cure a disease, the prime cause of which is an impaired respiration. Neither genetic codes of anaerobiosis nor cancer viruses are alternatives today, because no such codes and no such viruses in man have been discovered so far; but anaerobiosis has been discovered.) The Prime Cause and Prevention of Cancer with two prefaces on prevention Revised lecture at the meeting of the Nobel-Laureates on June 30, 1966 at Lindau, Lake Constance, Germany by Otto Warburg Director, Max Planck-Institute for Cell Physiology, Berlin-Dahlem Part II         As emphasized, it is the first precondition of the proposed treatment that all growing body cells be saturated with oxygen. It is a second precondition that exogenous carcinogens be kept away, at least during the treatment. All carcinogens impair respiration directly or indirectly by deranging capillary circulation, a statement that is proved by the fact that no cancer cell exists, the respiration of which is not impaired. Of course, respiration cannot be repaired if it is impaired at the same time by carcinogens. It has been asked after the Lindau lecture why the repair of respiration by the active groups of the enzymes was proposed as late as 1966, although the fermentation of the cancer cell was discovered as early as 1923. Why was so much time lost? He who asked this questions ignored that in 1923 the chemical mechanism of enzyme action was still a secret of living nature alone1). The first active group of an enzyme, "Iron, the Oxygen-Transferring Part of the Respiratory Enzyme" was discovered in 1924). There followed in two decades the discoveries of the O2-transferring metalloproteins, the flavoproteins and the pyridinproteins, a period that was concluded by the "Heavy Metals as Prosthetic Groups of Enzymes") and by the "Hydrogen Transferring Enzymes") in 1947 to 1949. Moreover, during the first decades after 1923 glycolysis and anaerobiosis were constantly confused, so that nobody knew what was specific for tumors. The three famous and decisive discoveries of DEAN BURK and colleagues) of the National Cancer Institute at Bethesda were of the years 1941, 1956 and 1964: first, that the metabolism of the regenerating liver, which grows more rapidly than most tumors, is not cancer metabolism, but perfect aerobic embryonic metabolism; second, that cancer cells, descended in vitro from one single normal cell, were in vivo the more malignant, the higher the fermentation rate; third, that in vivo growing hepatomas, produced in vivo by different carcinogens, were in vivo the more malignant, the higher the fermentation rate. - Furthermore, the very unexpected and fundamental fact, that tissue culture is carcinogenic and that a too low oxygen pressure is the intrinsic cause were discovered) in the years 1927 to 1966. - Anaerobiosis of cancer cells was an established fact only since 1960 when methods were developed) to measure the oxygen pressure inside of tumors in the living body. This abridged history shows that even the greatest genius would not have been able to propose in 1923, what was proposed at Lindau in 1966. As unknown as the prime cause of cancer was in 1923 was the possibility to prevent it. Life without oxygen in a living world that has been created by oxygen ) was so unexpected that it would have been too much to ask that anaerobiosis of cancer cells should be accepted at once by all scientists. But most of the resistance disappeared when at Lindau it was explained that on the basis of anaerobiosis there is now a real chance to get rid of this terrible disease, if man is willing to submit to experiments and facts. It is true that more than 40 years were necessary to learn how to do it. But 40 years is a short time in the history of science). Wiesenhof über Idar-Oberstein, August 1967 OTTO WARBURG Two years after the Lindau lecture LINUS PAULING (Science Vol. 160, Page 265, 1968) proposed to control mental diseases by adding to the food the active groups of respiratory enzymes. But here the experimental basis was lacking. No mental disease is known so far, the prime cause of which is an impairment of the respiration of brain cells. Preface to the First edition (Prevention of endogenous cancer)   Most experts agree that nearly 80% of cancers could be prevented, if all contact with the known exogenous carcinogens could be avoided. But how can the remaining 20%, the endogenous or so-called spontaneous cancers, be prevented? Because no cancer cell exists, the respiration of which is intact1, it cannot be disputed that cancer could be prevented if the respiration of the body cells would be kept intact.  Today we know two methods to influence cell respiration1. The first is to decrease the oxygen pressure in growing cells. If it is so much decreased that the oxygen transferring enzymes are no longer saturated with oxygen, respiration can decrease irreversibly and normal cells can be transformed into facultative anaerobes.   The second method to influence cell respiration in vivo is to add the active groups of the respiratory enzymes to the food of man. Lack of these groups impairs cell respiration and abundance of these groups repairs impaired cell respiration - a statement that is proved by the fact that these groups are necessary vitamins for man2.  To prevent cancer it is therefore proposed first to keep the speed of the blood stream so high that the venous blood still contains sufficient oxygen; second, to keep high the concentration of hemoglobin in the blood; third to add always to the food, even of healthy people, the active groups of the respiratory enzymes; and to increase the doses of these groups, if a precancerous state3 has already developed. If at the same time exogenous carcinogens are excluded rigorously, then most cancers may be prevented today. These proposals are in no way utopian. On the contrary, they may be realized by everybody, everywhere, at any hour. Unlike the prevention of many other diseases the prevention of cancer requires no government help, and no extra money. Wiesenhof, August 1966 OTTO WARBURG 오토 바르부르크의 " 암의 주요원인과 예방" 논문 The Prime Cause and Prevention of Cancer (Revised Lindau Lecture) By OTTO WARBURG         (Director, Max Planck Institute for Cell Physiology, Berlin-Dahlem, Germany) English Edition by DEAN BURK*),  National Cancer Institute, Bethesda, Maryland*)  Note by DEAN BURK: Adapted from a lecture originally delivered by O. Warburg at the 1966 annual meeting of Nobelists at Lindau, Germany. O. Warburg won the Nobel Prize in Medicine in 1931 for his discovery of the oxygen-transferring enzyme of cell respiration, and was voted a second Nobel Prize in 1944 for his discovery of the active groups of the hydrogen transferring enzymes. Many universities, like Harvard, Oxford, Heidelberg has offered him honorary degrees. He is a Foreign member of the Royal Society if London, a Knight of the Order of Merit founded by Frederick the Great, and was awarded the Great Cross with Star and Shoulder ribbon of the Bundesrepublik. His main interests are Chemistry and Physics of Life. In both fields no scientists has been more successful. There are prime and secondary causes of diseases. For example, the prime cause of the plaque is the plaque bacillus, but secondary causes of the plaque are filth, rats, and the fleas that transfer the plaque bacillus from rats to man. By a prime cause of a disease I mean one that is found in every case of the disease.   Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar. All normal body cells meet their energy needs by respiration of oxygen, whereas cancer cells meet their energy needs in great part by fermentation. All normal body cells are thus obligate aerobes, whereas all cancer cells are partial anaerobes. From the standpoint of the physics and chemistry of life this difference between normal and cancer cells is so great that one can scarcely picture a greater difference. Oxygen gas, the donor of energy in plants and animals is dethroned in the cancer cells and replaced by an energy yielding reaction of the lowest living forms, namely, a fermentation of glucose. The key to the cancer problem is accordingly the energetics of life, which has been the field of work of the Dahlem institute since its initiation by the Rockefeller Foundation about 1930. In Dahlem the oxygen transferring and hydrogen transferring enzymes were discovered and chemically isolated. In Dahlem the fermentation of cancer cells was discovered decades ago; but only in recent years has is been demonstrated that cancer cells can actually grow in the body almost with only the energy of fermentation. Only today can one submit, with respect to cancer, all the experiments demanded by PASTEUR and KOCH as proof of the prime causes of a disease. If it is true that the replacement of oxygen-respiration by fermentation is the prime cause of cancer, then all cancer cells without exception must ferment, and no normal growing cell ought to exist that ferments in the body. An especially simple and convincing experiment performed by the Americans MALMGREN and FLANEGAN confirm‎s the view. If one injects tetanus spores, which can germinate only at very low oxygen pressures, into the blood of healthy mice, the mice do not sicken with tetanus, because the spores find no place in the normal body where the oxygen pressure is sufficiently low. Likewise, pregnant mice do not sicken when injected with the tetanus spores, because also in the growing embryo no region exists where the oxygen pressure is sufficiently low to permit spore germination. However, if one injects tetanus spores into the blood of tumor-bearing mice, the mice sicken with tetanus, because the oxygen pressure in the tumors can be so low that the spores can germinate. These experiments demonstrate in a unique way the anaerobiosis of cancer cells and the non-anaerobiosis of normal cells, in particular the non-anaerobiosis of growing embryos. The Fermentation of Morris Hepatomas A second type of experimentation demonstrates a quantitative connection between fermentation of tumors and growth rate of tumors. If one injects rats with cancer-inducing substances of different activities, one can create, as HAROLD MORRIS of the National Cancer Institute in Bethesda has found, liver cancers (hepatomas) of very different degrees of malignancy. Thus, one strain of tumor may double its mass in three days, another strain may require 30 days. Recently DEAN BURK and MARK WOODS 3), also of the National Cancer Institute, measured the in vitro rates of anaerobic fermentation in different lines of these hepatomas, and obtained a curve (Fig. 1) that shows a quantitative relationship between fermentation and growth rate, and therefore between fermentation and malignancy, in these various tumor strains. The fermentation increases with the malignancy, and indeed the fermentation increases even faster than the malignancy. Special interest attaches to the fermentation of the most slowly growing hepatomas, because several investigators in the United States believed that they had found *) that such tumors had no fermentation; that is that anaerobiosis cannot be the prime cause of cancer. For example see C. H. BÖHRINGER SON, Ingelheim am Rhein, the factory Work-Journal "Das Medizinische Prisma" , Vol. 13, 1963. Here a lecture of VAN POTTER (Madison, Wisconsin) is reprinted where owing to the slow-growing Morris-tumors anaerobiosis as prime cause of cancer is rejected and the lack of "intracellular feeding back" is claimed to be the real cause of cancer. Fig. 1. Velocity of growth and fermentation of the Morris-Hepatomas, according to DEAN BURK and MARK WOODS DEAN BURK and MARK WOODS saw immediately from their curves that in the region of the zero point the rate of fermentation was so small that it could no longer be measured by the usual gross methodology employed by the aforementioned workers, whereas in the same region the smallest growth rate was always easily measurable. BURK and WOODS saw, in other words, that in the region of the zero pint of their curves the growth test was more sensitive than the usual fermentation test. With refined and adequate methods for measuring fermentation of sugar (glucose) they found, what any physical chemist after a glance at the curve would realize, that even the most slow-growing Morris hepatomas fermented sugar. The results of DEAN BURK and MARK WOODS were confirmed and extended by other workers with independent methods. PIETRO GULLINO, also in Bethesda, developed a perfusion method whereby a Morris hepatoma growing in the living animal could be perfused for long periods of time, even weeks, by means of a single artery and single vein, and the blood entering and leaving any given tumor could be analyzed. GULLINO found with this method that the slow-growing Morris hepatomas always produced fermentation lactic acid during their growth. This was in contrast to liver, where, as known since the days of CLAUDE BERNARD, lactic acid is not produced but consumed by liver; the difference between liver and Morris tumors in vivo is thus infinite (+ vs. -). GULLINO further found that tumors grow in vivo with diminished oxygen consumption. In summary, GULLINO’s findings indicate that the slow-growing Morris hepatomas are partial anaerobes. SILVIO FIALA, a biochemist at the University of Southern California, found that not only did the slow-growing hepatomas produce lactic acid, but also that the number of their oxygen-respiring grana was reduced. The slow-growing Morris hepatomas are therefore far removed from having refuted the anaerobiosis of tumors. On the contrary, they are the best proof of this distinctive characteristic. For forty years cancer investigators have searched for a cancer that did not ferment. When finally a non-fermenting tumor appeared to have been found in the slow-growing Morris tumors, it was shown to be a methodological error. Transformation of Embryonic Metabolism into Cancer Metabolism A third type of experiment, from the institute in Dahlem with coworkers GAWEHN, GEISSLER and LORENZ, is likewise highly pertinent. Having established that anaerobiosis is that property of cancer cells that distinguishes them from all normal body cells, we attacked the question, namely, how normal body cells may become transformed into anaerobes 6)7)8). If one puts embryonic mouse cells into a suitable culture medium saturated with physiological oxygen pressures, they will grow outside the mouse body, in vitro, and indeed as pure aerobes, with a pure oxygen respiration, without a trace of fermentation. However, if during the growth one provides and oxygen pressure so reduced that the oxygen respiration is partially inhibited, the purely aerobic metabolism of the mouse embryonic cells is quantitatively altered within 48 hours, in the course of two cell divisions, into the metabolism characteristic of fermenting cancer cells. Fig. 2 illustrates the very simple experimental procedure involved. If one then brings such cells, in which during their growth under reduced oxygen pressure a cancer cell metabolism has been produced, back under the original high oxygen pressure, and allows the cell to grow further, the cancer metabolism remains. The transformation of embryonic cell metabolism into cancer cell metabolism can thus be irreversible, and important result, since the origin of cancer cells from normal body cells is an irreversible process. It is equally important that these body cells whose metabolism has thus been transformed into cancer metabolism now continue to grow in vitro as facultative anaerobes. The duration of our experiments is still too limited to have yielded results of tests of inoculation of such cells back into mice, but according to all previous indications such cells will later grow as anaerobes upon transplantation into animals. In any case, these experiments belong to the most important experiments in the field of cancer investigation since the discovery of the fermentation of tumors. For cancer metabolism, heretofore, measured so many thousand of times, has now been induced artificially in body cells by the simplest conceivable experimental procedure, and with this artificially induced cancer metabolism the body cells divide and grow as anaerobes in vitro*). The experiments were at once repeated, when they were published, of course without acknowledgment. See for example Th. Goodfriend, D. M. Sokol and N. O. Kaplan, J. molecular Biol. 15, 18, 1966. In recent months we have further developed our experimental arrangements so that we can measure manometrically the oxygen respiration and fermentation of the growing mouse embryonic cells during the metabolic transformation. Fig. 3 shows the experimental arrangement. We find by such experiments that 35 percent inhibition of oxygen respiration already suffices to bring about such a transformation during cell growth**). Oxygen pressures that inhibit respiration 35 percent can occur at the end of blood capillaries in living animals, so that the possibility arises that cancer may result when too low oxygen pressures occur during cell growth in animal bodies. These experiments show, like the curve of Dean Burk and Mark Woods in Fig. 1, that it is more correct to designate tumor cells as "partial anaerobes" rather than "facultative anaerobes". A body cell is transformed into a tumor cell if only a part of the respiration is replaced by fermentation. Fig. 2. Method to transform embryonic metabolism into cancer metabolism by decreasing the oxygen pressure The induction of cancers by solid materials injected into animals is a further experimental indication of this possibility. If one implants discs of solid substances under the skin of rats, the discs will soon be surrounded by capsules of living tissue that will be nourished with blood vessels from the hypodermis. Sarcomas very frequently develop in these capsules. It is immaterial whether the solid discs are chemically plastics, gold, or ivory, etc. What produces the cancer is not the chemical nature of the solid discs, but the special king of blood nourishment supplied to the tissue encapsulating the discs. This blood provision varies with the site and in adequacy within a given animal, and induces cancer from the low oxygen pressure in the encapsulating disc. Fig. 3. Method to measure manometrically respiration and fermentation during the transformation of embryonic into cancer metabolism*) The vessels are not shaken, because shaking inhibits growth. Therefore, the oxygen pressure in the liquid phase at the bottom of the vessels is much lower than in the gasphase. For example, when the oxygen pressure in the gas phase was 2000 mm H2O it was at the bottom of the vessels 130 mm H2O. (O. Warburg, A. Geissler and S. Lorenz, Zeitschr. Für Naturforschung 20b, 1070, 1965.) Thermodynamics If a lowered oxygen pressure during cell growth may cause cancer, or, more generally, if any inhibition of respiration during growth may cause cancer, then a next problem is to show why reduced respiration induces cancer. Since we already know that with a lowering of respiration fermentation results, we can re-express our question: Why does cancer result if oxygen-respiration is replaced by fermentation? The early history of life on our planet indicates that life existed on earth before the earth’s atmosphere contained free oxygen gas. The living cells must therefore have been fermenting cells then, and, as fossils show, they were undifferentiated single cells. Only when free oxygen appeared in the atmosphere - some billion years ago - did the higher development of life set in, to produce the plant and animal kingdoms from the fermenting, undifferentiated single cells. What the philosophers of life have called "Evolution créatrice" has been and is therefore the work of oxygen. The reverse process, the dedifferentiation of life, takes place today in greatest amount before our eyes in cancer development, which is another expression‎ for dedifferentiation. To be sure, cancer development takes place even in the presence of free oxygen gas in the atmosphere, but this oxygen may not penetrate in sufficient quantity into the growing body cells, or the respiratory apo-enzymes of the growing body cells may not be saturated with the active groups. In any case, during the cancer development the oxygen-respiration always falls, fermentation appears, and the highly differentiated cells are transformed to fermenting anaerobes, which have lost all their body functions and retain only the now useless property of growth. Thus, when respiration disappears, life does not disappear, but the meaning of life disappears, and what remains are growing machines that destroy the body in which they grow. But why oxygen differentiates and why lack of oxygen dedifferentiates? Nobody would dispute that the development of plants and animals and man from unicellular anaerobes is the most improbable process of all processes in the world. Thus there is no doubt, that EINSTEIN descended from a unicellular fermenting organism - to illustrate the miracle, molecular O2 achieved. But according to the thermodynamics of Boltzmann, improbable processes require work to take place.  It requires work to produce temperature differences in a uniformly temperatured gas; whereas the equalization of such temperature differences is a spontaneous process that does not require work. It is the oxygen-respiration that provides in life this work, and dedifferentiation begins at once when respiration is inhibited in any way. In the language of thermodynamics, differentiation represents a forced steady state, whereas dedifferentiation - that is, cancer - is the true equilibrium state. Or, illustrated by a picture: the differentiated body cell is like a ball on an inclined plane, which, would roll down except for the work of oxygen-respiration always preventing this. If oxygen respiration is inhibited, the ball rolls down the plane to the level of dedifferentiation. But why respiratory energy and not fermentation energy can differentiate, whereas in general, for example in growth, respiratory energy and fermentation energy are equivalent? Obviously, there would be no cancer if there were not this discrimination of fermentation energy, that is, if fermentation like respiration could differentiate. Then, when respiration is replaced by fermentation, fermentation would take over differentiation, and a high state of differentiation would be maintained even in the fermenting body cells. Chemistry Physics cannot explain why the two kinds of energy are not equivalent in differentiation; but chemistry may explain it. Biochemists know that both respiration energy and fermentation energy do their work as phosphate energy, but the ways of phosphorylation are different. If one applies this knowledge to carcinogenesis, it seems that only oxidative phosphorylation but not fermentative phosphorylation can differentiate, a result, that may in future explain the mechanism of differentiation. Yet Biochemistry can explain already today why fermentation arises, when respiration decreases. Figure 4 shows that the pathways of respiration and fermentation are common as far as pyruvic acid. Then the pathways diverge. The endproducts of fermentation is reached by one single reaction, the reduction of pyruvic acid by dihydro-nicotinamide to lactic acid. On the other hand, the endproducts of the oxidation of pyruvic acid, H2O and CO2, are only reached after many additional reactions. Therefore, when cells are harmed, it is probable that first respiration is harmed. In this way the frequency of cancer is explained by reasons of probability. Figure 4 To sum up:   Impairment of respiration is frequent than impairment of fermentation because respiration is more complicated than fermentation.   The impaired respiration can be easily replaced by fermentation, because both processes have a common catalyst, the nicotinamide.   The consequence of the replacement of respiration by fermentation is mostly glycolysis, with death of the cells by lack of energy. Only if the energy of fermentation is equivalent to the lost energy of respiration, is the consequence anaerobiosis. Glycolysis means death by fermentation, anaerobiosis means life by fermentation.   Cancer arises, because respiration, but not fermentation, can maintain and create the high differentiation of body cells. To conclude the discussion on the prime cause of cancer, the virus-theory of cancer may be mentioned. It is the most cherished topic of the philosophers of cancer. If it were true, it would be possible to prevent and cure cancer by the methods of virology; and all carcinogens could be eaten or smoked freely without any danger, if only contact with the cancer virus would be avoided. It is true that some virus-caused cancer b) occur in animals, but no one sure human virus-cancer has been observed so far, whereas innumerable substances cause cancer without viruses in animals and man. Thus viruses do not meet the demands of Pasteur, that is must be possible to trace the prime cause in every case of the disease. Therefore science classifies viruses as remote causes of cancer, leading to anaerobiosis, the prime cause that meets the demands of Pasteur. b) The chicken Rous sarcoma, which is labeled today as a virus tumor, ferments glucose and lives as a partial anaerobe like all tumors. O. WARBURG, Bioch. Zeitschrift 160, 307, 1925; F. WIND, Klinische Wochenschrift, Nr. 30, 1926. Many may remember how anaerobiosis as prime cause of cancer was recently disputed emphatically, when one single cancer - the slow Morris hepatomas - was believed (wrongly) to lack in fermentation. In contrast the virus theory is adhered to although all cancers of man are lacking in virus-origin. This means the surrender of the principles of Pasteur and the relapse into bygone times of medicine. Applications Of what use is it to know the prime cause of cancer? Here is an example. In Scandinavian countries there occurs a cancer of throat and esophagus whose precursor is the so-called Plummer-Vinson syndrome. This syndrome can be healed when one adds to the diet the active groups of respiratory enzymes, for example: iron salts, riboflavin, nicotinamide, and pantothenic acid. When one can heal the precursor of a cancer, one can prevent this cancer. According to ERNEST WYNDER 3) of the Sloan-Kettering Institute for Cancer Research in New York, the time has come when one can exterminate this kind of cancer with the help of the active groups of the respiratory enzymes. It is of interest in this connection that with the help of one of these active groups of the respiratory enzymes, namely nicotinamide, tuberculosis can be healed quite as well as with streptomycin, but without the side effects of the latter         c). Since the sulfonamides and antibiotics, this discovery made in 1945 is the most important event in the field of chemotherapy generally, and encourages, in association with the experiences in Scandinavia, efforts to prevent cancer by dietary addition of large amounts of the active groups of the respiratory enzymes. Since there can scarcely be overdosage, such experiments can do no harm. c) V. CHORINE: C. R. sci. Paris, 220, 150 (1945). – H. FUST and A. STUDER, Schweizerische Z. für allgemeine Pathologie, Band 14; Fasc 5 (1951).         I would like to go further and propose always making dietary additions of large amounts of the active groups of the respiratory enzymes after successful operations when there is danger from metastatic growths. One could indeed never succeed in redifferentiating the dedifferentiated cancer cells, since during the short duration of human life the probability of such a back-differentiation is zero. But one might increase the respiration of growing metastases, and thereby inhibit their fermentation, and - on the basis of the curve of DEAN BURK and MARK WOODS obtained with the Morris hepatomas - thereby inhibit the growth of metastases to such an extent that they might become as harmless as the so-called "sleeping" cancer cells in the prostates of elderly men. A Second Example of Application The physicist MANFRED VON ARDENNE has recently attacked the problem of the therapy of cancer. ARDENNE discovered that cancer cells owing to their fermentation, are more acid – inside and on their surface – than normal cells and hence are more sensitive to high temperatures. On this basis, he and his medical colleagues have treated cancer patients, after surgical removal of the primary tumors, by raising the body temperature of the patients to about 109º Fahrenheit for an hour, in the hope that the metastases will then be killed or their growth so slowed up as to become harmless. It is not yet decided whether this idea can be described as a practical success. But the provisional work of ARDENNE is already of great significance in a field where hopes of conventional chemotherapy have been dimmed but might be brightened by combination with extreme or moderate hyperthermy. A third application. According to an estimate by K. H. Bauer of the Cancer Institute in Heidelberg, at least one million of the now living twenty five million male inhabitants of West Germany will die of cancer of the respiratory tract; still more will die from other cancer. When one considers that cancer is a permanent menace, one realizes that cancer has become one of the most dangerous menaces in the history of medicine. Many experts agree that one could prevent about 80% of all cancers in man, if one could keep away the known carcinogens from the normal body cells. This prevention of cancer might involve no expenses, and especially would require little further research to bring about cancer prevention in up to 80 percent . Since this estimate was published, some though 80% even to low. Yet prevention remained taboo and early diagnosis was the only consolation that was offered. Why then does it happen that in spite of all this so little is done towards the prevention of cancer? The answer has always been that one does not know what cancer or the prime cause of cancer be, and that one cannot prevent something that is not known.  But nobody today can say that one does not know what cancer and its prime cause be. On the contrary, there is no disease whose prime cause is better known, so that today ignorance is no longer an excuse that one cannot do more about prevention. That prevention of cancer will come there is no doubt, for man wishes to survive. But how long prevention will be avoided depends on how long the prophets of agnosticism will succeed in inhibiting the application of scientific knowledge in the cancer field. In the meantime, millions of men must die of cancer unnecessarily. Literature to Preface of Second Edition: WILLSTAETTER, WIELAND and EULER, Lectures on enzymes at the centenary of the Gesellschaft Deutscher Naturforscher. Berichte der Deutschen Chemischen Gesellschaft, 55, 3583, 1922. The 3 lectures of the 3 chemists show that in the year 1922 the action of all enzymes was still a mystery. No active group of any enzyme was known. OTTO WARBURG, Biochem. Zeitschrift, 152, 479, 1924. OTTO WARBURG, Heavy Metals as prosthetic groups of enzymes, Clarendon Press, Oxford, 1949. OTTO WARBURG, Wasserstoffübertragende Fermente, Verlag Werner Sänger, Berlin, 1948. DEAN BURK, 1941. On the specificity of glycolysis in malignant liver tumors as compared with homologous adult or growing liver tissues. In Symposium of Respiratory Enzymes, Univ. of Wisconsin Press. pp. 235-245,1942. DEAN BURK, Science 123,314,1956. Woods, M. W., Sandford, K. K., Burk, D., and Earle, W. R. J. National Cancer Institute 23, 1079-1088, 1959. DEAN BURK, Burk, D., Woods, M. and Hunter, J. On the Significance of Glucolysis for Cancer Growth, with Special Reference to Morris Rat Hepatomas. Journ. National Cancer Institute 38, 839-863, 1967. O. WARBURG und F. KUBOWITZ, Bioch. Z. 189, 242, 1927; H. GOLDBLATT und G. CAMERON, J. Exper. Med. 97, 525, 1953. O. WARBURG, 17. Mosbacher Kolloquium, April 1966. Verlag Springer, Heidelberg, 1966. O. WARBURG, K. GAWEHN, A. W. GEISSLER, D. KAYSER and S. LORENZ, Klinische Wochenschrift 43, 289, 1965. O. WARBURG, Oxygen, The Creator of Differentiation, Biochemical Energetics, Academic Press, New York, 1966. O. WARBURG, New Methods of Cell Physiology, Georg Thieme, Stuttgart, and Interscience Publishers, New York, 1962. Literature to Preface of First Edition: OTTO WARBURG, A. W. GEISSLER, and S. LORENZ: Über die letzte Ursache und die entfernten Ursachen des Krebses. 17. Mosbacher Kolloquium, April 1966. Verlag Springer, Heidelberg 1966. Any book on vitamins, such as Th. Bersin. Biochemie der Vitamine. Akad. Verlags.-Ges. Frankfurt 1966. ERNEST L. WYNDER, SVEN HULTBERG, FOLKE JACOBSSON, and IRWIN J. BROSS, Environmental Factors in Cancer. Cancer, Vol. 10, 470, 2057. Find this article on: Ozone Serviceshttp://www.ozoneservices.com/ozoneser/c&n/contact.htm         <What can be achieved by the active groups, when tumors have already developed?> The answer is doubtful, because tumors live in the body almost anaerobically, that is under conditions that the active groups cannot act. On the other hand, because young metastases live in the body almost aerobically, inhibition by the active groups should be possible. Therefore we propose first to remove all compact tumors, which are the anaerobic foci of the metastasis. Then the active group should be added to the food, in the greatest possible amount, for many years, even forever. This is a promising task. If it succeeds, then cancer will be a harmless disease. Moreover, we discovered recently a) in experiments with growing cancer cells in vitro that very low concentrations of some selected active groups inhibit fermentation and the growth of cancer cells completely, in the course of a few days. From these experiments it may be concluded that de-differentiated cells die if one tries to normalize their metabolism. It is a result that is unexpected and that encourages the task of inhibiting the growth of metastases with active enzyme groups.          In press in Hoppe-Seylers Zeitschrift für Physiologische Chemie 1967. 10 g riboflavin per ccm or 10 g d-Aminolevulinic acid inhibit in vitro growth and fermentation completely but inhibit respiration less. As expected, ascites cancer in vivo is not cured. === 몸의 산성화 와 활성산소 감소는 암세포가 활동하기에 좋은 환경...