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The Most Comprehensive, Productive, and Satisfying Explanation of Cancer: The Chromosomal Imbalance Theory of Cancer: The Autocatalyzed Progression of Aneuploidy is Carcinogenesis.

Science Publishers; [c]2012; $119.95; 330 pp.

This book was written for cancer researchers, but the basic principles and unifying simplicity of the theory of chromosomal imbalance are understandable to anyone. I present here a plain-language summary.

Cancer is defined as the uncontrolled growth of abnormal cells that invade surrounding tissues. Metastasis is when cancer cells spread to other parts of the body.

The ancient Egyptians and Greeks knew about cancer. However, the present epidemic of cancer started with the Industrial Revolution around 250 years ago. In plants, parasites can cause apparently benign tumors, but there is little evidence of bona fide cancer. Cancer is rare in wild animals but quite common in domestic dogs, cats, and birds. This is strong evidence that sharing the environment of humans puts these animals at risk of cancer. The products and conditions of modern life are most likely responsible for cancer.

The broadly held conviction among researchers today is that cancer ultimately results from an abnormality of the genome. The two principal competing theories on the nature of that abnormality (chromosomal imbalance versus gene mutation) is the subject of The Chromosomal Imbalance Theory of Cancer.

Molecular medicine's search for the "material" cause of cancer in the form of gene mutations dominates cancer research and commands virtually all sources of funding. According to this theory, certain genes, when they are mutated, turn a normal cell into a cancer cell. Many researchers believe that the mutation of just one, or perhaps several genes, is sufficient to transform a normal cell into a cancer cell. The attraction of the gene mutation theory of cancer is its promise of simplicity: cancer is supposed to be caused by a manageable number of specific mutations. This was the hoped-for key to unlocking the mysteries of cancer leading to the taming of an ever-growing modern scourge. This theory has endured since the 1970s, and more than one Nobel Prize has been awarded to researchers who have made these claims. One prize-winner is Harold Varmus, the former director of the National Institutes of Health and current director of the National Cancer Institute.

But there are problems with the mutation theory that will not go away. For example, there is a growing list of carcinogens that do not mutate genes. In addition, there are no cancer-specific gene mutations. Even cells of the same tumor rarely have the same mutations in common. Since the effects of mutation are immediate, why are the latent periods between exposure to a carcinogen and the appearance of cancer exceedingly long, ranging from many months in laboratory animals to decades in humans? Most problematic of all, no genes have yet been isolated from cancers that can transform normal human or animal cells into cancer cells.

Despite the well-documented problems with gene research, oncologists still test for mutations and, when found, target them with highly toxic and carcinogenetic drugs. This is what we regularly see in the mainstream media. Most disturbing of all, 1 in 6 new cancers is caused by the chemotherapy used to treat cancer. This we don't see in the mainstream media.

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 tens of thousands of genes of normal and cancer cells (colon and pancreas), Bert Vogelstein, an expert on colon cancer, acknowledged that "most of the genes could not have been predicted to be differentially expressed in cancers." In other words, it is impossible to predict which genes are responsible for causing cancer. Acknowledging the failure of the "my-favoritegene approach," Stephen Friend, cofounder of Rosetta Inpharmatics in Seattle, exclaimed: "God, were we stupid!"

Early History of the Aneuploidy Theory of Cancer

The aneuploidy theory of cancer was introduced by David von Hansemann in 1890 and formally stated by Theodor Boveri in 1914. Aneuploidy is an imbalance in the number or composition of chromosomes. Almost the first thing that researchers noticed when they looked at cancer cells under the microscope was the excess number of chromosomes (called chromatin in their time). Because the aneuploidy theory was proposed so long ago, scientists today are inclined to think (if they know about Boveri at all) that there must be some fundamental flaw in the theory. They also assume that the gene mutation theory of cancer must be superior because it is newer and uses the latest sexy technologies that are now able to "see" and manipulate individual genes.

Some American researchers, eager to dismiss the aneuploidy theory, ask, what is the mechanism; meaning, how does aneuploidy cause cancer? But as early as 1914, Boveri offered the first coherent explanation of how chromosomal imbalance leads to cancer. 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 at the time with similar ideas was von Hansemann. 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]." Hansemann's "unknown agency" is the progressive unbalancing of the genome every time that aneuploid cells divide--scrambling chromosomes, much like shuffling a deck of cards.

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." This explains why many different physical and chemical carcinogens can cause the same type of cancer. Boveri's theory predicts that cancer results from a single cell that has acquired an abnormal chromosome constitution. In other words, he predicted the well-established clonal origin of cancer--meaning that cancer originates from a single cell.

Boveri had experimentally determined that the individual chromosomes possess different properties such that only certain combinations permit the cell to function normally or, at least, keep it alive. Boveri used this result to explain the well-known fact that a tumor cell has an abnormal metabolism: "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."

In Boveri's time, X-rays and certain chemicals were known to cause cancer. Boveri said that the 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 pointed out that his aneuploidy theory explains the increasing risk of cancer with age because in aging cells, division is more frequently disturbed. Enough time has elapsed in an older organism for many cell divisions to have occurred. Boveri even predicted tumors that had the correct number but wrong mix of chromosomes.

The aneuploidy theory of cancer is as valid today as it was in 1914. However, the combination of Boveri's sudden death in 1915 and World War I dealt an almost mortal blow to his great idea. In Germany, the ruinous aftermath of the war effectively closed down biological research there for more than a decade, allowing the aneuploidy theory to slumber until it was resurrected by Peter Duesberg's lab at the University of California at Berkeley in 1996. During the intervening 81 years, the US ascended to prominence following the World War II, the double helix of DNA was discovered in 1953, and the genetic code elucidated by the mid-1960s. All three momentous events contributed to the molecularization of biology, which led to the seductive idea dominant today that cancer could be explained and understood as mutations in the smallest genetic units--that is, damage to individual genes.


The aneuploidy (chromosomal imbalance) theory of cancer reemerged as the problems confronting the gene mutation theory reached insurmountable proportions. In contrast with gene mutations, aneuploidy disrupts the normal balance and interactions of many thousands of genes.

The chromosomes are where the genes reside. Normal human cells have a balanced set of exactly 46 chromosomes (23 from each parent) and are called diploid. Diploid cells from normal kidneys, liver, intestine, brain, and so on, are uniform and look the same as other normal cells of their respective organs. Cancer cells, on the other hand, are like snowflakes: you know one when you see it, but no two are alike. Cancer cells never have the normal set of chromosomes. Aneuploidy is the name given to an unbalanced complement of chromosomes. All cancer cells are aneuploid and typically have 60 to 90 chromosomes. In addition, cancer cells almost always have abnormal or Frankenstein-like combinations of chromosomes called markers. Thus, aneuploidy is far more devastating to the life of a cell than a handful of gene mutations.

Down syndrome is a familiar problem caused by aneuploidy. It results when a baby is born with three copies of chromosome 21 instead of the normal two. One extra copy of the smallest chromosome, with 300 or so normal genes, is sufficient to cause the syndrome. Most Down fetuses are spontaneously aborted. Nonetheless, the imbalance is small enough to permit occasional live births. By contrast, there is no case of a live birth with three copies of the largest chromosome 1, with its 4300 genes. While the level of aneuploidy in Down syndrome is far below the threshold of 60 to 90 chromosomes found in invasive cancer, the extra chromosome gives these patients a head start toward developing the same cancers that normal people get. Down syndrome patients have up to a 30-fold increased risk of leukemia, for example, compared with the general population.

There is one important difference between the low-level aneuploidy found in Down syndrome and the more pronounced aneuploidy of cancer cells. With Down syndrome, the defect occurs in the germ line, making the chromosomal error present in every cell in the body, causing the syndrome. But, when the chromosomal imbalance occurs only in some cells of the body (as with cancer), the defect is called somatic. In other words, somatic aneuploidy means that the chromosomal imbalance occurs in a particular cell after the body is formed.

How Chromosomal Imbalance Causes Cancer

In December 1996, I 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. My life changed when I happened upon a figure extracted from a paper by Henrik Kacser and James Burns. 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. I no longer say "almost" in either case.

In 1973, Kacser and Burns, and independently Reinhart Heinrich and Tom Rapoport, invented the field of metabolic control analysis. It is a way of measuring and analyzing changes in a cell, tissue, or organ by taking into consideration the combined activities of all the metabolic elements and gene products (proteins) 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 or diluted by the many thousands of other genes contributing to the overall properties of a cell. There is 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 cancer cell.

Aneuploidy destabilizes a cell in much the same way that a dent disrupts the symmetry of a wheel. Each revolution of the wheel leads to increasing distortions. As aneuploid cells divide, their genomes become increasingly disorganized to the point where most stop dividing and die. But, rarely, an aneuploid cell wins the genetic lottery and keeps right on dividing to become a cancer.

Cells with a normal complement of chromosomes are intrinsically stable and not prone to transformation into cancer. What, therefore, causes normal cells to become aneuploid? That is a hotly contested question among the researchers bogged down in a labyrinth of gene mutations It has been known for more than 100 years, however, that radiation striking the nucleus or cytoplasm of a cell will either kill or damage it. If the damaged cell then divides by mitosis, an error may arise, leading to chromosomal imbalance. In short, radiation can cause aneuploidy. Certain chemicals, such as tars, can also give rise to aneuploid cells. Tars and radiation sources are known carcinogens. Cancer-causing asbestos fibers mechanically disrupt cell division, causing an unbalanced distribution of chromosomes. So far, all carcinogens that have been examined cause aneuploidy. That is why international regulatory bodies specifically classify anything causing chromosomal imbalance as carcinogenic (including chemical and physical substances, radiation, drugs, and environmental factors).

Transforming the robust normal cell into a cancer cell requires massive changes in the number and composition of chromosomes. Aneuploidy provides the necessary boost in genetic material leading to cancer, entirely independent of gene mutation. The effect of aneuploidy on cells can be visualized by analogy with an automobile factory, in which each arm of an assembly line would correspond 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, and so on, and every car would be different from the one before. Most such cars would not function, and go directly to the junkyard. By chance, however, the aneuploid factory may 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 would 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 (chromosomes). Workers typically operate 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 "unmutated" or normal 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 are insufficient and irrelevant to the generation of cancer because their numbers are too few to alter the normal cell.

There is another way of visualizing the fundamental difference between the theories of gene mutation and chromosomal imbalance. The human genome (consisting of about 25,000 genes) is like the Oxford English Dictionary, wherein each gene functions as a biological word. Continuing the analogy, the 23 different chromosomes can be thought of as the volumes of the OED, with each chromosome containing an average of 1000 different genes linked together in sequence, like beads on a necklace. on all the chromosomes If the whole genome is a biological dictionary, divided into volumes called chromosomes, then we can view the life of a cell as a Shakespearean drama. If one were to leave out or misspell a word here and there, in Hamlet for example, such "mutations" would go unnoticed. A human with 100 trillion cells is at least as resistant to "gene mutations" as a Shakespeare play.

On the other hand, without "mutating" a single word, one could transform the script of Hamlet into a legal document, a love letter, a declaration of independence, or more likely gibberish, by simply shifting and shuffling, copying and deleting, numerous individual words, sentences, and whole paragraphs. That is the literary equivalent of what aneuploidy does. Aneuploidy is the most efficient means of rewriting a cell's script by the wholesale shifting and shuffling of the chromosomes (and therefore, genes), which on occasion leads to cancer.

Nonetheless, the presence of mutations in a handful of genes continues to be viewed as causing cancer, even though any given mutated gene is found in only a minority of cancer cells. The same mutated genes can also be found in normal cells, exemplifying the well-known fact that most mutations are innocuous. Mixing metaphors, fishing for mutant genes in a sea of aneuploidy is a classic example of not seeing the forest for the trees.

Political and Sociological Barriers to the Theory of Chromosomal Imbalance

Sufficient (indeed overwhelming) evidence is already in hand to convict aneuploidy of the crime of cancer and release gene mutations from custody. Nevertheless, the gene mutation theorists, when faced with the undeniable evidence that aneuploidy is necessary for cancer, have adopted a fallback position. They argue that gene mutations must initiate the aneuploidy, or, as Scientific American reported, "[Christoph] Lengauer insists aneuploidy must be a consequence of gene mutations."

There would be no need to "insist" if there were proof that gene mutations really do cause cancer. What would gravely weaken the chromosomal imbalance theory would be confirmed cases of diploid cancer (in which the tumor cells have a completely balanced set of chromosomes), and with the culprit genes found lurking in every cell. That would go a long way toward proving the gene mutation theory. But where has that been demonstrated? It would be a front-page story. The fact is, researchers have not yet produced any convincing examples of diploid cancer, and the evidence continues to mount against the mutation theory of cancer.

The conceptual barriers to accepting aneuploidy as the cause of cancer are not trivial, but they shrink in comparison with the political, economic, and sociological obstacles. US taxpayers have forked over hundreds of billions dollars in the War on Cancer only to find that after 40 years of battling viruses, "oncogenes," and "tumor suppressor" genes, we are losing the war. 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, cancer researcher Christoph Lengauer guesses, "If you were to poll researchers, ... 95 percent would say that the accumulation of mutations [to key genes] causes cancer." I think that it is a safe bet that if 50% of cancer-research funds went toward investigating the role that aneuploidy plays in cancer, a poll of researchers would soon show that close to half would say that chromosomal imbalance causes cancer. Unfortunately, too many scientists these days tend to accept or reject a theory depending on the level of funding for it.

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 and the commercialization of diagnostic tests and drugs for cancer genes make it even more difficult for researchers to consider the possibility that mutant genes do not cause cancer after all.

For 15 years, Duesberg's lab at the University of California at Berkeley has led the world in developing the chromosomal imbalance theory of cancer. The work is supported entirely by private benefactors and volunteer help. The National Institutes of Health and the National Cancer Institute have turned down every one of his grant proposals. Duesberg is forced to spend part of each year in Germany because there is some funding for work on aneuploidy.

It would not help the images of the cancer research establishment and the multibillion dollar biotech industry if it became widely known that a meagerly funded lab had come up with a superior explanation of the cause and progression of cancer. If a small group with virtually no money has rediscovered the cause of cancer, 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?

To Sum Up

Thomas Kuhn remarked that the great theoretical advances of Copernicus, Newton, Lavoisier, and Einstein had less to do with definitive experiments than with looking at old data from a new perspective. This applies equally to cancer.

We have before us the facts to explain the entire multistep sequence of carcinogenesis. This sequence begins with the production of aneuploidy, which is caused predominantly by environmental carcinogens and occasionally by natural errors in cell division. Once a cell becomes aneuploid, all its surviving descendants produce completely different aneuploid offspring with each cell division. If a population of aneuploid cells continue to reproduce, some will eventually cross the threshold of chromosomal imbalance leading to cancer. Thus, aneuploidy is necessary and--if it progresses--sufficient for carcinogenesis.

Cancer cells are formed from precursor cells by rearranging genes into new sets of chromosomes. This is exactly how new species are generated. As Hansemann said more than 100 years ago, cancer is "a new biologic entity, differing from any cell present at any time in normal [development]." Thus, cancer cells can be seen as new parasitic species distinct from the host. While invasiveness, drug resistance, and metastasis are never exhibited by normal cells, these characteristic features of cancer are the product of the chromosomal diversity of individual cancer cells.

Aneuploidy provides a simple and coherent explanation for all the properties of cancer. As chromosomal imbalance theory becomes widely studied, and accepted, it will alter the course of cancer research, prevention, diagnosis, and treatment. We will see profound differences in how governments, departments of health, clinicians, and patients think about and deal with cancer. The four-decade-long, fear-based War on Cancer will be replaced by an ecological problem that can be understood and solved.
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Author:Rasnick, David
Publication:Townsend Letter
Article Type:Book review
Date:Aug 1, 2012
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