Emanuel Revici MD (1896-1998) : Revici Method for Cancer - Clinical Findings of a Pioneer in Lipid-Based Cancer Therapy (Selenium, Sulfur, Calcium, Zinc) and Omega 3

Emanuel Revici, MD: Efforts to Publish the Clinical Findings of a Pioneer in Lipid-Based Cancer Therapy by Marcus A. Cohen Dr. Emanuel Revici died during his 101st year on January 9, 1998, after a career that bridged seven decades in the history of modern medicine. Since the 1980s, mainstream research has independently confirmed a number of his therapeutic breakthroughs. Dr. Revici was the first physician to develop selenium compounds low enough in toxicity to give cancer patients doses far in excess of safety limits for ordinary forms of selenium. 1 He was among the first research clinicians to treat cancer with naturally derived Omega 3 fatty acids.2 He also appears to have been a pioneer in utilizing lipids to transport cytotoxic agents through the bloodstream to sites of abnormal tissue.3 Still awaiting mainstream corroboration are numerous reports of patients with advanced cancer who obtained long-term remission under his treatment after failing to benefit from any other therapy. New York's Office of Professional Medical Conduct (OPMC) revoked Revici's license to practice in 1993. The formal charges against him amounted to a sharp divergence in approach from conventional oncology practice. The state education department returned the license in late 1997. (In New York, the health department – OPMC – revokes the licenses of physicians, the education department processes applications to restore them.) Governor George Pataki wrote a letter in support. New York Assemblyman Sheldon Silver, Speaker of the Assembly, issued a legislative resolution posthumously lauding Revici’s accomplishments and devotion to patients. The behind-the-scenes campaign to reinstate Revici’s license has droll and infuriating moments worth telling, but it is too long to relate here. This article, in three parts, concentrates on Revici's efforts to publish his findings and on evaluations of his therapy. The history of Revici's publications and evaluations, extending back to World War II, exemplifies the problems that most originators of non-standard approaches to cancer experience in seeking mainstream understanding and trials of their therapy. Capsule Biography Emanuel Revici, born September 6, 1896 in Romania, received his doctorate in medicine and surgery from the University of Bucharest in 1920.4 Teaching himself advanced chemistry in the mid-1920s, he became absorbed in exploring the relationship between lipids and cellular metabolism. Eager to further his investigations, he sampled the facilities available at the foremost European research centers, opting for Paris in 1936, where he pursued his studies at hospital clinics and laboratories directed by academic physicians. Revici's Parisian years ended in March 1941. The head of the Paris police department, a fast friend, warned him that he could no longer protect him from the German occupation forces rounding up the city's Jews. (Revici was Jewish.) Shortly after the warning, Revici fled to Nice and spent the next six months in southern France as a leader of the Resistance. Revici had discovered a lipid substance that staunched bleeding within minutes, enabling wounded Underground fighters to avoid notice by the Gestapo, but the Gestapo soon tumbled onto his clandestine activities. Comrades in the Resistance spirited him overland into Portugal and from there by sea to Casablanca, Morocco, where he boarded a ship carrying members of the Spanish Republican government – in exile after Generalissimo Franco's fascist regime controlled Spain. On the prowl in the North Atlantic, U-boats in the German "wolf pack" were raising their periscopes to sight the vessel, bent on torpedoing it. The ship inched down the west coast of Africa, sailing at night without lights, then steamed across the southern Atlantic to the Bahamas, a voyage lasting two months. The Underground had entrusted to Revici a microfilm with information for the Allies. At the Portuguese border, guards had detained and searched him and would have executed him on the spot had they discovered the film. Patting his body from heels to head, poking their fingers into every possible hiding place in his clothing, they never thought to pry apart the fingers of his upraised hands. When the ship anchored in the Bahamas, Revici was the first passenger British intelligence officers debriefed. He delivered the microfilm and also, unexpectedly, a roll of film showing the German submarine installations at Casablanca, which he had snapped on his own (another impromptu act of daring, punishable upon discovery by summary execution). Revici then settled in Mexico City for the duration of the war. In 1942, Dr. Revici converted a modern hotel in the Mexican capital into a medical institute. With over 100 rooms, it specialized in cancer, treating patients free. The idea and money came from a friend, Gaston Merry, formerly European representative of E.I. Du Pont de Nemours & Co, the chemical and pharmaceutical giant, headquartered in Wilmington, Delaware. Merry had tracked Revici's research in Paris, where their professional relationship had warmed into a deep friendship. After the fall of France, Merry requested reassignment by Du Pont to Central America, sharing a house with Revici and his family in Mexico City. 4 "Our Institute," recalled Revici in 1954, when the memory was vivid, "consisted of a clinic for outpatients, a hospital with all modern equipment, a Clinical Laboratory, a Research Department with eight laboratories, and a section for experimental research on animals. The staff...numbered 15 physicians and chemists, in addition to a personnel of 60 which included nurses, helpers, and orderlies. The records were kept in Spanish."4 Completing the picture, Revici noted: "Besides obtaining the services of competent Mexican physicians and scientists, we were fortunate in interesting several eminent physicians, surgeons, and scientists who were also refugees in Mexico City...who, after investigating my background and research, joined the Institute staff. The object of the Institute was to concentrate on following my line of research." While still in Romania, Revici had patented a process for refining crude oil into a lubricant for airplane engines. "Revoil," as the product was known, yielded him royalties that had financed his travels and research in Europe. The war had interrupted the flow of these payments (Romania fought against the Allies), but they resumed just before the war’s end. Revici repaid Merry, then the flow ceased permanently with the postwar Communist take-over of Romania. (The Communists nationalized the oil industry, expropriating the "Revoil" refineries.) Dr. George Dick, dean of the University of Chicago medical school, brought Revici to the US in 1946, promising him research facilities. Dick resigned suddenly the next year, and Revici promptly accepted an invitation from physicians, businessmen, and civic leaders to found an experimental cancer clinic in New York City. 4 The clinic, named the Institute of Applied Biology (IAB), opened later in 1947. He earned his medical license in NY by examination in 1947 and maintained his dual career as a scientist and physician in New York City until his death. Scientific Findings & Medical Applications Revici's medical findings derived from a number of different lines of investigation, each simple enough by itself. Interwoven, they make a complex body of knowledge.5 The starting point was an observation Revici made in the 1920s, while he was still in his 20s. Cancer patients in pain showed a cycling in their levels of discomfort. In some patients, the pain worsened in the morning; in others it intensified at night. Eating eased the pain in some, but sharpened it so much in others, they dreaded eating. Hypothesizing that this cycling might relate to an underlying cycling of the patients' physiology, Revici looked at various aspects of blood and urine (using the relatively simple technology available to him at the time). His investigations showed that healthy persons typically had daily rhythmic fluctuations in such basic physical parameters as urinary pH and levels of free potassium in the blood. In contrast, cancer patients had abnormal fluctuations, showing either patterns of acidic imbalance or alkaline imbalance. Further investigation found that patients in acidic imbalance could relieve their pain temporarily by ingesting a small amount of sodium bicarbonate. But patients in alkaline imbalance who ingested sodium bicarbonate suffered worse pain. Repeating the experiment with dilute phosphoric acid gave roughly converse results. Realizing that these small amounts of dilute acid or base wouldn't change bodily pH, Revici next placed platinum electrodes in painful loci of patients with superficial tumors, as well as in nonpainful parts of the tumor mass and in normal tissue. All these experiments led Revici to conclude that the pH of painful local lesions was not only different from the rest of the body, but that ingestion of small amounts of base or acid could specifically and quickly alter these painful lesions. As a result of these studies, Revici proposed that a crucial distinction be made between pathological pain and what he termed "physiological pain" (a distinction supported by many subsequent years of research). To ease pain in his cancer patients, he then turned to developing lipidic means to change pH, recognizing that interventions based on amino acids, ions, or proteins would not last long enough for meaningful relief. Before proceeding, he felt it necessary to redefine lipids (fatty acids and sterols), which were generally regarded in the early 20th century as greasy, water-insoluble substances extractable in ether, a definition that still appears in many biochemistry books. Decades ahead of anyone else in the field, Revici described lipids at a molecular level, correctly noting the importance of their polar and non-polar regions. As his career progressed, Revici's definition guided his clinical use of lipids by supplying an accurate structural guide for analysis of therapeutic compounds he wished to create. During his European years, Revici also launched into a systematic study of the effects of different elements on bodily function, a research path ending in his categorization of elements as either inducing anabolic or catabolic states of metabolism. Later, he discovered that within a vertical series of the Periodic Table, elements acted similarly – their valency shell partly determined their bioactivity, and the concentration of an element in different organizational levels of the body was both precisely regulated and a key determinant of normal and pathological states. By the time he had emigrated to the US, Revici's investigations into the molecular structure of carcinogens and other bioactive molecules had revealed that many bioactive molecules exhibited a charge structure in which adjacent carbon atoms would be predicted to carry identical charges. The concepts Revici evolved from study of these "twin formations" (as he termed them), or energetic centers, also played a crucial role in his design of therapeutic agents. As with so much of his work, examination of molecular structures makes one wonder why Revici's American peers resisted this discovery: Flip the pages of the Merck Index, and example after example of bioactive molecules with such an energetic configuration march by. Repeatedly, Revici's studies on lipid function pointed the way to findings that predate ideas widely accepted today. Decades before Bengt Samuelsson reported on leukotrienes, earning a Nobel Prize, Revici essentially described them, indicating their crucial role in inflammation.6,7 It was characteristic of him, though, to view these compounds as part of a much larger picture. Instead of choosing to concentrate on this one topic for years, he swiftly moved on to elucidate the role of bioactive lipids in the early stages of cellular and systemic host defense processes. Intervention by lipids at this level of the body's defenses, he reasoned, might affect outcome and even the extent of mobilization at other levels. As he developed his theories and applications, Revici incorporated another basic insight: The damage caused by disease frequently isn't done by the pathogenic focus alone, but by the body's defense mechanisms as well. He may not have been the first to codify this key insight as a therapeutic principle, but once more, he seems to have preceded the mainstream in incorporating the principle to treat patients. Because Revici believed that these defense mechanisms might do more harm than the pathogenic focus itself (once activated into disequilibrium), he devoted himself to devising therapeutic agents that could restore normal bodily function. Based on his European research, he utilized the properties of elements to alter different levels of function and the ability of lipids to induce longer-lasting alterations to create a large series of therapeutic compounds in which elements were conjugated into lipids. He thereby anticipated, again by decades, interest in lipids as carriers of pharmaceutically useful compounds. In sum, the different paths of research Revici followed throughout his career enabled him to pioneer, intentionally and with foresight, a great number of therapeutic compounds designed to produce specific effects on the function of normal and diseased tissues. Without exaggeration, then, one may say that he developed a theory of rational drug design long before the concept entered the imagination of the larger scientific community. Notes 1. Revici E. Research in Physiopathology as Basis of Guided Chemotherapy: With Special Application to Cancer. Princeton: D. Van Nostrand, 1961; also: Schrauzer GN. Selenium and cancer: Historical developments and perspectives. In Spallholz JE, et al. (eds). Selenium in Biology and Medicine. Westport: AVI Press, 1981:98-102. 2. Revici E, 1961, op cit.; Also: Simopoulos AP, Robinson J. The Omega Plan. New York, NY: Harper Collins, 1998:61-74. 3. Revici E, 1961, op cit.; Also: Mizushima Y, et al. Use of lipid microspheres as a drug carrier for anti-tumor drugs. J Pharm, Pharmacol. 1986;38:132-134. 4. Revici E, Affidavit, sworn and notarized 2/3/55. This document serves as the basis for all biographical information included here. 5. Prof. Mark D. Noble originally prepared the section here on Revici's scientific findings and medical applications for an appraisal of Revici published in The Journal of Alternative and Complementary Medicine. 1998; 4 (2). 6. Samuelsson B, Leukotrienes. Science. 1987;237:1171-1176. 7. Revici E, The influence of irradiation upon unsaturated fatty acids. Paper read by Robert Ravich, MD, before the Sixth International Congress of Radiology, London, 7/26/50. Section 2 Emanuel Revici's difficult publishing history began in Paris on the eve of World War II and continued through the end of the war in Mexico City, where US physicians visiting the medical facility he had opened witnessed the results of his lipidic treatment for cancer. Most of Revici's publishing history took place in New York City, after he moved to the US in 1946, and where, a year later, he founded the Institute of Applied Biology (IAB), which specialized in clinical cancer research. Revici's 50-year struggle to publish exemplifies the problems most originators of non-standard approaches to cancer experience in seeking mainstream understanding and acceptance of their therapies. Publications, 1930s & 1940s Emanuel Revici's medical research commanded attention during his years in France (1936-41). Between 1937 and 1938, the sub-director of the Pasteur Institute deposited five papers by the Romanian-born physician in the National Academy of Sciences, a prestigious way of registering scientific innovations.8 These papers summarized observations Revici had made about the influence of lipids in pathological pain and cancer. In 1943, a year after establishing his Institute in Mexico City, Revici sought to acquaint visiting US physicians with his findings, hoping they would assist in publishing them in peer-reviewed English-language journals. His associate and friend Gaston Merry, in a personal letter dated September 5, 1945, aired his suspicion that the US doctors had intended to publish Revici's findings as their own. Perhaps with that aim in mind, these physicians took a glancing swipe at Revici. The Journal of the American Medical Association (JAMA), August 18, 1945, printed a letter signed by these physicians under the heading, "A Mexican Treatment For Cancer—A Warning." The letter, not referring to Revici by name, disparaged both his theories and results. "What seems to be behind the paper," Merry wrote, "is the desire to work along the ideas of Revici and to claim the paternity of some of his ideas. A hint is given by an article published in Cancer Research on page 480 of the August number and called 'The Effects of 3–4 Benzpyrene on the Auto Oxidation of Unsaturated Fatty Acids.' It is signed by G.C. Meuller and H.P. Rusch, the latter being the doctor from Wisconsin who came at the end of 1943 to spend about 5 weeks here and who came again at the end of 1944." "His article," continued Merry, "is the reproduction of an experiment made in Paris, the conclusions of which having been published at two or three occasions. When Dr. Rusch was here in December 1943, I was present at the conversations as an interpreter, and Revici candidly discussed his findings at length, mentioning specifically the linoleic and linolenic acids which are also the ones used by Dr. Rusch who took plenty of notes during the conversations…As you know, according to Revici's classification, 3–4 Benzpyrene is one of the first bodies to be considered as Lipobase. Dr. Rusch does not go so far as to talk about Lipobases and Lipoacids but his method is a close reproduction of the technique mentioned by our friend. I am afraid that all the notes taken 18 months ago and later will serve as subjects for publications which so far could not be made from here." Merry ended: "I guess the best thing would be to liquidate what we have here and have Revici working in a laboratory in the States with the proper help to repeat all his experiments in support of his theory and especially the suitable collaboration for writing up the publications. It is a great handicap for him that his English is too poor for writing the necessary articles. This is what we asked for when the Texas and Wisconsin gang came here but they acted deaf."9 From the moment Revici co-established the IAB in Brooklyn, New York, in 1947, the Institute reported on its investigational programs. Summaries of Revici's findings prior to the opening of the IAB appeared in booklet form, printed and bound in blue paper covers, with each booklet devoted to a single subject. Itemizations of new or ongoing studies periodically circulated as mimeographed typescripts. For example, "Report on the Research Conducted at the Institute of Applied Biology," issued 10/15/48 by the Cancer Research and Hospital Foundation (the IAB's funding arm), listed over 20 different experiments. "The fixation of oxygen, sulfur, and selenium in unsaturated fatty acids" was the second experiment in this itemization. The 21st experiment was "The influence of lipids in healing of tissue injured by radium emanation."10 Revici's research on radiation injury had blipped onto the US Navy's radar screen 18 months earlier. A letter from a Colonel Thomas G. Cassady, dated just four days before the IAB report, confirmed the Navy's interest: (Military scientists were testing nuclear weapons on isolated atolls in the Pacific Ocean in the late 1940s, seeking to protect servicemen on the battlefront from lethal radioactive fallout.) "I have had several conversations," Cassady wrote, "at the Naval Medical Research Center at Bethesda, MD, regarding Dr. Revici…About a year-and-a-half ago …they had conversations with the Doctor. They were interested in his research work and offered him certain facilities…As well as I could, in my layman's language, I told them of his further research in the matter in question. They will see him again as it is their policy to leave no stone unturned in seeking relief or a possible cure for the type of injury in which the Doctor has made some progress."11 Twice in the late 1940s, the Office of Naval Intelligence cleared Revici to work on this top-secret project. Twice he declined, preferring to work on radiation primarily in relation to the broad problem of cancer. Publications and Presentations, 1950s Between July 1950 and June 1951, three papers about Revici's findings on lipids and radiation came to the attention of the clinical research community. Robert Ravich, a colleague at the IAB (fresh out of the College of Physicians & Surgeons, Columbia University), read a paper by Revici at the Sixth Annual Congress of Radiology in London on July 26, 1950. Titled "The Influence of Irradiation Upon Unsaturated Fatty Acids," this paper dwelt on abnormally conjugated lipids, which clearly fit Samuelsson's description of leukotrienes published in 1987.6 Revici didn't use the terms "leukotrienes" or "prostaglandins" here, but in later publications, he indicated the role these substances play in inflammation, and he attributed the high bioactivity of prostaglandins to a "twin formation…which appears through the cyclization of arachidonic acid." Dr. Ravich presented another paper by Revici (co-authored by Ravich) before the American Association for the Advancement of Science in Cincinnati in December 1950. The paper bore the title, "The Effect of n-Butanol in Sodium Salt Solutions Upon Shock and the Survival of Mice Exposed to Severe Thermal Burns."12 Waldemar Kaempffert, a senior science writer for The New York Times, devoted a column to Ravich's presentation in the March 4, 1951 issue of the Times, stressing the potential value of Revici's findings on radiation injury should American cities be hit by A-bombs.13 "Fall-out" from a paper delivered by Leonard Goldman, MD, at a meeting of the AMA in Atlantic City, NJ, in June 1951 marked the first documented instance of mainstream opposition to independent clinicians trying to follow Revici's line of research. Notice of Goldman's study, titled the "Use of Lipids to Enhance the Effect of Roentgen Therapy in the Treatment of Pain from Advanced Cancer,"14 made its way into a dossier that the American Cancer Society (ACS) maintained on Revici. The dossier was labeled, "Summary of information contained in the American Cancer Society, Inc.'s files concerning the Institute of Applied Biology and Dr. Emanuel Revici, as well as other persons concerned in the matter."15 Here's an entry about a memorandum from Dr. B. Aubrey Schneider of the ACS, who had heard Goldman's paper, to Dr. Charles Cameron, scientific director of the national ACS: "In his memorandum to Dr. Cameron, Dr. Schneider adds that in a private conversation with Dr. George Cooper, Director of the Virginia Division of the Society, he indicated that he was going to try out the Lipid therapy on some cases now under his care at the University of Virginia Hospital. A copy of Dr. Goldman's paper is in the files." Goldman had reported on the palliative effects of Revici's therapy. He next proposed a trial of its therapeutic effects, requesting approval from the Institutional Review Board (IRB) at Queens General Hospital, where he served as a resident. Another entry from the ACS dossier on Revici picked up the story: "Early in January, Dr. Cameron received a phone call from Dr. Alfred Angrist, Pathologist at Queens General Hospital. Dr. Cameron prepared a memorandum which is in the files. Dr. Angrist felt that Dr. Revici exerted strong psychotherapeutic influences on patients and discussed his personal feelings, as Chairman of the Hospital Committee on Research and Publications, with regard to hospital approval of a paper on the Revici treatment by Dr. Goldman. Because of Dr. Angrist's strong 'anti' feelings, an ad hoc committee had been appointed to consider the particular paper, and Dr. Angrist felt that the committee's membership had been stacked. At his request, Dr. Cameron suggested Drs. Gellhorn, Bodansky, and Schoenbach as additional committee members."16 Minutes from meetings of the IAB's board of directors in 1952 relate that the "restacked" IRB at Queens General denied Goldman approval. In 1986, Dr. Goldman addressed the Regents of the State of NY, in a written plea supporting Revici's struggle with the OPMC to remain in practice. He noted his early interest in Revici's treatment, and—for the first time publicly – he disclosed that his studies on lipid therapy had cost him his residency privileges. While the ACS and associated elements in mainstream medicine were helping to clip Dr. Goldman's wings behind the scenes, The New York Times printed a feature on the IAB in its December 2, 1952 issue.17 The writer, William L. Laurence, was probably the most distinguished science reporter at that time; the US had broken the news of the A-bombing of Hiroshima and Nagasaki under his byline. The first three paragraphs of Laurence's report on the IAB ran as follows: Animal experiments and tests on patients in advanced stages of cancer were described last night by leaders in medicine as lending "strong support" to a new concept of malignant disease that may lead to a radically new approach to its ultimate control. The progress reports on the new methods, developed at the Institute of Applied Biology, Brooklyn, were presented at the fifth annual dinner of the Cancer Research and Hospital Foundation at the Waldorf-Astoria Hotel. More than 400 leaders in medicine and other professions, as well as leaders in industry and civic affairs, were present. One of the reports was prepared by Dr. John Masterson of Brooklyn, former president of the Medical Society of the State of New York and a member of the House of Delegates of the American Medical Association. He is now attending the AMA meeting at Denver and the report was read in his absence. Other reports were presented by Dr. John M. Galbraith, past president of the Nassau County Medical Society; Dr. Emanuel Revici, scientific director of the Institute; and Dr. Robert Ravich, assistant director. Laurence's last paragraph, notes: "Prof. Jacques Maritain of the Institute of Advanced Study at Princeton, NJ, one of the world's leading philosophers, is a director of the Cancer Research and Hospital Foundation, a non-profit organization to raise funds for the cancer research program of the Brooklyn Institution."17 By the mid-1950s, at least one of Revici's associates believed a distinct pattern had become discernible in the reception of papers submitted to peer-reviewed journals by the IAB. In a letter to one of the Institute's chief funders, dated 11/12/55, Robert Ravich recounted the publication history of an article he had co-authored with Revici, titled, "Antihemorrhagic Action of n-Butanol in Advanced Cancer" (Angiology, December 6, 1953).18 Bear in mind that butanol – the higher sterol Revici gave to control bleeding in Resistance fighters in southern France – worked so well, it set the Nazis on its developer's trail; in effect, it amounted to his "ticket" out of Europe. (See Part 1 for details.) In the US after the war, Revici had developed butanol for cancer patients too ill to stem internal hemorrhages surgically. Injected intravenously, it sped through the blood system to the site of a severed artery or vein, permanently constricting the muscle tissue circling the vessel at the rupture point. The Revici-Ravich paper reported on two small series of patients, one group injected with butanol and the other, control arm, not given Revici's antihemorrhagic agent. (Revici discovered the mechanism of action after publication.) Ravich's letter started with an assertion: "I told you that the Institute of Applied Biology had encountered a mysterious form of censorship whenever it attempted to have an article concerning cancer published in the regular channels. The following is a case history which…bears out my statement."19 In short, Ravich's case history of the butanol paper goes like this: rejection in 1951 by Cancer (after a recommendation to accept by the reviewer); rejection in 1951 by the Journal of Laboratory and Clinical Medicine and the Journal of the National Cancer Institute; and rejections in 1953 in the original submission and resubmission to the New York State Journal of Medicine. The editors cited various reasons. Consultants didn't think the paper represented a controlled clinical experiment (Cancer). The subject was not of sufficient interest to readers (Journal of Laboratory and Clinical Medicine). Not suitable for publication here: try a journal of a more general nature (Journal of the American Cancer Institute). It was doubtful that n-Butanol had any relation to the cessation of hemorrhage in the patients studied (New York State Journal of Medicine). Dr. Ravich closed his letter with these paragraphs: On August 12, 1953, the article was submitted to Angiology. It was accepted without comment and was published on December 6, 1953. Angiology is a journal with very limited circulation, and not one that is likely to be read by doctors interested in cancer or by general practitioners who might find the article of value. We have received requests for reprints from all over the country and the world and some interesting comments and observations. The experience with this paper indicates beyond any question that the problem of publishing our work on cancer is not a simple one. Why this invisible form of censorship is permitted to exist in scientific and medical publications and how it operates are questions that I am not able to answer. But I do believe we are justified in saying, on the basis of such experiences, that the normal channe