Overcoming the Conceptual Barriers Boveri’s Aneuploidy theory of cancer The aneuploidy theory was introduced by David von Hansemann in 1890 [19] and first formally stated by Theodor Boveri in 1914 [20]. Almost the first thing that researchers noticed when they looked at cancer cells under the microscope was that they had excess chromosomes. Anueploidy provides a simple and coherent explanation for all the properties of cancer [9-13, 15-17]. But precisely because the aneuploidy theory was proposed so long ago, scientists today are inclined to think (if they know about Boveri at all) that some fundamental flaw in the theory must have been discovered. They also assume that the gene mutation theory of cancer must be superior because it is newer and uses the latest sexy technologies. Some American researchers, eager to dismiss the aneuploidy theory, ask, "What is the mechanism?" They remind Athel Cornish-Bowden [21]of the obstinate rejection of Alfred Wigener’s theory of Continental drift by American geologists [22] on the grounds that he could offer no mechanism for how the continents moved. In 1914, Boveri offered the first coherent explanation (including a mechanism) of how chromosomal imbalance leads to cancer [20]. The developmental consequences of chromosomal imbalance in sea-urchin eggs suggested to him that malignant tumors could be due to an abnormal chromosome constitution originating during cell division. The only other author with similar ideas was von Hansemann [19]. He captured the essence of cancer as, "a process carrying the cell to some entirely new direction–a direction, moreover, which is not the same in all tumors, nor even constant in the same tumor…. The [cancer] cell then is one in which, through some unknown agency, a progressive disorganization…occurs, which in turn results in…a new biologic entity, differing from any cell present at any time in normal [development]." (Translated by Whitman [23]). Hansemann’s "unknown agency" is the relentless randomization of the genome caused by aneuploidy. Boveri extended Hansemann’s insight. The essence of Boveri’s hypothesis is that cancer results from "a certain abnormal [chromosome] constitution, the way in which it originates having no significance. Each process which brings about this constitution would result in the origin of a malignant tumor" [20]. His theory predicts that cancer results from a single cell that has acquired an abnormal chromosome constitution. In other words, he predicted the clonal origin of cancer. It is well known that a tumor cell has an abnormal metabolism. According to Boveri, "if the individual chromosomes have different qualities, chromosome aberrations will result in deviant metabolic functions. If, therefore, certain chromosomes are missing and others are present in abundance, certain substances will be produced also in abundance, and there will be a deficiency in others." [24] In Boveri’s time X-rays and certain chemicals were known to cause chromosomal imbalance. Boveri said the time interval between the time of the insult and the origin of a tumor may be explained by the assumption that the cancer-causing agent first interferes with the process of cell division, producing an aneuploid cell. In the second step, the aneuploid cell must be stimulated to divide further, producing daughter aneuploid cells. In heavily proliferating tissues, the risk of a tumor is increased. Boveri points out that a natural consequence of his aneuploidy theory is that the risk of tumors would increase with age since in aging cells the process of cell division is more frequently disturbed [24]. (In addition, enough time has elapsed in an older organism for many cell divisions to have occurred.) Boveri even predicted tumors that had the correct number of chromosomes but with an abnormal complement–the so-called pseudodiploid cancers. Boveri’s aneuploidy theory of cancer is as valid today as it was in 1914. Metabolic control analysis supports the aneuploidy theory of cancer In November, 1996, Peter Duesberg left for the first of many trips to Mannheim to work on aneuploidy as a possible cause of cancer. I stayed at Berkeley and studied the literature on aneuploidy and the consequences of changes in gene dose. One day I came across Charles Epstein’s book The consequences of chromosome imbalance: principles, mechanisms, and models [25]. When I happened upon a figure extracted from a paper by Henrik Kacser and James Burns, it changed my life. I immediately realized that the reigning gene mutation hypothesis of cancer was almost certainly wrong and that the aneuploidy theory of cancer was almost certainly right. In 1973 Kacser and Burns [26], and independently Heinrich and Rapoport [27], invented the field of metabolic control analysis. It is a quantifiable means of analyzing changes in a cell, tissue, or organ by taking into consideration the combined activities of all the metabolic elements (all the gene products) that contribute to the phenotype (stable characteristics) of the whole. For systems as complex as a cell, changes in the activities of a few or even scores of specific genes would be buffered by the many thousands of other genes contributing to the overall properties of a cell. There was simply no way for a handful of "oncogenes" or "tumor suppressor" genes to perturb a normal cell sufficiently to turn it into a massively abnormal cell. At UC Berkeley we have shown that transforming the robust normal cell into a cancer cell requires massive changes in the number and composition of chromosomes [15]. Aneuploidy provides the necessary boost in genetic material leading to cancer. It is entirely independent of gene mutation. The effect of aneuploidy on cells can be visualized by analogy with an automobile factory, in which each assembly line corresponds to a chromosome. An "aneuploid" assembly line would randomize the output of an automobile factory and produce cars with five wheels, three brakes, two engines, no transmission, etc., and every car would be different from the one before. Most such cars wouldn’t function, and would go directly to the junkyard. By chance, however, the aneuploid factory would also produce the rare, bizarre car that worked well enough to appear on the highways and keep right on running when you slammed on the brakes! It would be a menace to the society of normal cars. In this analogy, the genes correspond to individual workers on the assembly lines. The effect of "mutating" individual workers is much more limited than randomly altering the number and composition of the assembly lines. Workers typically work at a fraction of their capacity. If the output of a few individual workers in an assembly line was "mutated" by sickness, death or vacation, the effects would be buffered by the remaining un-mutated workers upstream and downstream and by the redundant capacity built in to the workforce. The overall output and quality of cars would not noticeably change. By the same token, alterations in a handful of specific genes [35, 36] are insufficient and probably irrelevant to the generation of cancer because their numbers are too few to alter the normal cell. The attraction of the gene mutation theory of cancer was its promise of simplicity: cancer resulted from a manageable number of specific mutations. A manageable number was the hoped-for key to unlocking the mysteries of cancer and to the taming of an ever growing modern scourge [37]. Instead, we find that the seven mutations proposed to cause colon cancer [38] are drowned in an aneuploid sea of nearly 5,000 additional genes in the aneuploid cells of a cancerous colon [39]. Far from providing insights into the nature of cancer, and hence into prevention and more effective treatments, the gene mutation theory is now so burdened with the complexity of its details that it has lost all explanatory power. Analyzing close to 49,000 genes of normal and cancer cells (colon and pancreas), Zhang et al. acknowledged that, "most of the genes could not have been predicted to be differentially expressed in cancers" [39]. Results such as these will eventually kill what Stephen Friend, CEO of Rosetta Inpharmatics in Seattle, calls the "my-favorite-gene approach." He adds: "God, were we stupid!" [40]. Political & Sociological Barriers The conceptual barriers to accepting aneuploidy as the cause of cancer are not trivial but they shrink in comparison with the political and sociological obstacles. US taxpayers have forked over tens of billions of dollars in the war on cancer only to find that after 20 years of battling viruses, "oncogenes", and "tumor suppressor" genes we are losing the war [37]. But it is a one-front war with almost no resources devoted to alternative approaches. In spite of a century of evidence implicating aneuploidy as the cause of cancer, a leading researcher guesses that "If you were to poll researchers … 95 percent would say that the accumulation of mutations [to key genes] causes cancer" [1]. I think it is a safe bet that if 50 percent of cancer-research funds went towards investigating the role aneuploidy plays in cancer, a poll of researchers would soon show that close to half would say that chromosomal imbalance causes cancer. Scientists, these days, tend to accept or reject a theory depending on whether or not there is funding for it. Our lab at the University of California at Berkeley has been unable to get a penny from the National Institutes of Health or the National Cancer Institute to investigate aneuploidy and cancer. Our work is supported entirely by private benefactors and volunteer help. Peter Duesberg is forced to spend part of each year in Germany because there is some funding in Mannheim for work on aneuploidy. With so many careers and reputations dependent on the failed gene mutation theory, researchers cannot afford to question something that has supported them for decades. The highly publicized sequencing of the human genome, the commercialization of diagnostic tests for cancer genes [41-43], and the recent hype about Gleevec being "at the forefront of a new wave of cancer treatments [that] differs from other existing chemotherapies because it affects a protein that directly causes cancer" [44] make it even more difficult for researchers to consider the possibility that mutant genes may not cause cancer after all. It would not help the images of the cancer research establishment and the multi-billion dollar biotech industry if it became widely known that an unfunded lab just may have come up with a preferable explanation of the cause and progress of cancer. If a small group with virtually no money has rediscovered the cause, why should taxpayers continue to dole out billions of dollars for work on mutant genes that has never panned out? And what would happen to the biotech industry that has bet so heavily on cancer diagnostics and therapeutics based entirely on the gene mutation theory? Max Planck said that, "A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it" [45]. We will soon see if he is right, for the old guard of mutant gene researchers is indeed getting old. It is encouraging to see that a new generation of cancer researchers are more inclined to consider aneuploidy as an alternative to gene mutation. Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. 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