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The Cancer Journal - Volume 8, Number 3 (May-June 1995)

editorial


Controlled Mutation in Cancer



Many share an uneasy feeling that something is fundamentally wrong in our interpretation of cancer; particularly since the guiding principle of cancer treatment fails to cure most patients. Cancer is viewed as a parasite originating in a chance event, transforming a healthy cell into a fierce crab, proliferating without restraint until it destroys its host. This parasite should obviously be eliminated as soon as possible. Yet tumor removal fails to cure most patients. Treatment failure may result from a wrong interpretation of the disease. Of all diseases only cancer is faced by a helpless organism. In all diseases except cancer, the organism actively resists the disease process, only in cancer is it indolent. This knowledge of the organism about how to survive a disease has been called Wisdom of the Body (1).

Wisdom of the Body is an attribute of living organisms. It is inherited, essential for individual survival, and was molded by natural selection. During evolution, Wisdom of the Body encountered all diseases and knows how to heal itself. It anticipates diseases. According to Guyenot the human organism is "first among physicians" (2). When studying a disease one ought to distinguish between its triggering factors, called noxae, and the Wisdom of the Body (3). In cancer such a distinction has never been made. All its manifestations are noxae and Wisdom of the Body does not play any role. Which may explain treatment failure. Tumor removal fails since the Wisdom of the Body was not considered.

Dramatic achievements of molecular biology drove oncology to seek its help. Molecular biology searches for drugs to destroy the crab. Cancer is a genetic disease driven by random mutations. Since genes are uncontrollable by the organism, or "deaf", they cannot be controlled by the Wisdom of the Body. At best, the organism controls gene products, e.g., mRNA and protein. From the present point of view this means that either control by the Wisdom of the Body is incomplete, or mutations are not "deaf". How well is the "deaf gene" dogma supported by experiments? Are all mutations in the organism random?

Mutation is "A change in the character of a gene that is perpetuated in subsequent divisions of the cell in which it occurs; a change in the sequence of base pairs in the chromosomal molecule" (4).

Enzymes that control genes

Recently molecular biology has revealed several mechanisms by which genes are controlled. Reverse transcriptase (5, p.254) is a protein which modifies DNA (genes) in a non random way, which is forbidden by the dogma of the deaf gene. There many more examples: site-specific recombination enzymes move special DNA sequences in and out of the genome (5, p. 246); retrovirus integration (5, p. 254); transposable elements are mobile DNA sequences that are integrated by special enzymes, transposases (5, p. 255). Elements may replicate when moving, amplifying DNA segments (5, p. 256). Some move within chromosomes directly as DNA, while others via an RNA intermediate (5, p. 605). As transposable elements move, they cause a variety of short additions and deletions in nucleotide sequences (5, p. 606). Recombinant DNA technology exploits natural processes of the cell that defy the "deaf gene" dogma., e.g., plasmids (5, p. 259).

Since these mechanisms modify genes, they are mutations, and since genes are modified by enzymes, they might be controlled by the organism. We ought to distinguish between random and non random mutations. The first induce replication errors, and the other are controlled DNA recombinations as in the B cell.

Antibody is formed by controlled mutations

During B-cell development, antibodies are assembled from separate gene segments (5, p. 1024). For each type of Ig (immunoglobulin) chain there is a separate pool of gene segments from which a single polypeptide is synthesized. In the mouse, the light chain forming gene is split into several hundred V-segments, about 4 J-segments and one C-segment. During B-cell development, one V-segment is chosen and moved to lie precisely next to one of the J-segments. This process, known as site specific recombination (5, p. 246), is done by special enzymes that move and assemble DNA segments. Only after DNA has been properly rearranged, is mRNA formed and Ig synthesized.

Since it moves genes along DNA, site-specific recombination causes mutations: non random mutations. A mutation that is caused by site-specific recombination is controlled by the host, and directed by strict guidelines, e.g., "select a V-segment and a J-segment and align them in a prescribed manner." It is a controlled mutation. Segment selection is known as "combinatorial diversification" of antigen-binding sites (5, p. 1024). Gene segment joining is regulated to ensure that B cells are monospecific (5, p. 1027). Yet, in order to generate monospecific cells, B-cell DNA has to be informed about the specificity of other cells. B-cell genes cannot be deaf. Information has to be conveyed to DNA by a protein (enzyme).

Whenever DNA segments are moved around the genome, e.g., plasmids, transposable elements, transduction, and reverse transcription, they are moved by enzymes that may be controlled in the same way as in site specific recombination.

Neoplastic progression

According to the current dogma neoplastic progression is a Darwinian process driven by random mutations (5, p. 1188), while in reality it might be as controlled as B-cell differentiation. In other words, molecular biology methods cannot distinguish between two views of cancer: 1. Neoplasia evolves by random mutations, in a Darwinian fashion, or 2. Neoplasia is an organ created and controlled by the organism (6, 7). The following arguments are based on the book "Molecular Biology of the Cell " (5).

When confronted with cancer, serious scientists seem to be led astray by emotional utterances like: A healthy body is a peculiar society "where self-sacrifice rather than competition is the rule" (5, p. 1188). Endowing the cell with free will. Why use terms that cannot be examined experimentally? In a complex organism where all processes are controlled, self-sacrifice is meaningless. Yet the author continues: "Most cancers derive from a single abnormal cell" (5, p. 1190). Where is the experimental evidence for abnormality? (8). All that molecular biology can say is that the cell is transformed, or mutated, but not abnormal. The same dubious reasoning assures us that "Any change [in DNA proofreading] constitutes a genetic mistake, called mutation since "wrong" DNA [is generated]" (5, p. 97). How does one examine with molecular biology methods whether a mutation was wrong? Is site specific DNA recombination in a B-cell wrong simply because it is a mutation?

The book views cancer development "as micro evolutionary process dependent on the same principles of mutation and natural selection that govern long-term evolution of all living organisms" (5, p. 1188). A cancer cell proliferates without control and gives rise to a neoplasm: "a relentlessly growing mass of abnormal cells" (5, p. 1188). How can a process that may evolve for thirty years, with prolonged remissions of good health, be regarded as uncontrolled and relentlessly growing? Why not view it as control loosening, like in other chronic diseases, e.g., hypertension where rising blood pressure is controlled throughout the disease, only its set point changes. Even in cancer the organism maintains homeostasis, while the set point of the tumor proliferation rate rises.

What appears as a growing cell mass is an organ with blood and nerve supply which has acquired some bone marrow features, e.g., metastasis. Neoplastic evolution should be regarded as organogenesis that proceeds through well defined stages as in the colon: displaces, adenomatous polyp, carcinoma in situ, well differentiated carcinoma, and finally anaplasia. The neoplasm is a differentiating organ like those of an embryo. It appears to us as senseless and chaotic, simply because our reasoning is blurred (6, 7). Neoplastic differentiation is accompanied by gene recombinations, e.g., gene amplification, deletion, chromosome rearrangements, that may be site-specific and controlled as in the B cell.

Chronic myelogenous leukemia

This neoplasm proceeds through two well defined differentiation states, maturation arrest, and Philadelphia chromosome manifestation. A translocation between the two long arms of chromosomes 22 and 9, that joins the bcr gene on chromosome 22 to the c-abl gene from chromosome 9, results in a fusion protein (5, p. 1209). This is an elaborate process requiring precise realignment of two remote genes, like the V-J recombination that generates a "fusion" antibody. This marvelous manifestation of genetic recombination is regarded as a genetic accident (5, p. 1190). How can a predictable event that occurs in the majority of patients be regarded as an accident? While in reality it may result from a controlled site specific gene rearrangement in a growing neoplastic organ?

Philadelphia chromosome appearance has to be controlled. It appears in all descendants of the bone marrow stem cell, precursors of red blood cells, megakaryocytes, and white blood cells. Yet only one lineage turns into a neoplastic organ, while other cell lines function undisturbed.

It is striking that even the Darwinian theory of neoplastic evolution implies that cancer is controlled by the organism. Accordingly, chronic myelogenous leukemia evolves by generating random mutations. The environment then selects the fittest clones. Yet the environment is non other than the host, who decides to select the "random, mistaken, and unfortunate" Philadelphia translocation. Molecular biology thus believes that the organism breeds its own destructive device, in a Darwinian fashion. . . These examples illustrate the conceptual confusion of molecular biology which is particularly dangerous to cancer patients. This poor reasoning generates dubious drugs that poison unfortunate patients. It spreads iatrogenesis.

Gershom Zajicek
e-mail: Gershom@md2.huji.ac.il

1 Zajicek G. Wisdom of the body. The Cancer J. 7, 212-213, 1994.
2 Guyenot in Canguilhem G. Le Normal et le Pathologique (translated into English by CR Fawcett, RS Cohen); Zone Books, New York, p. 130, 1991 .
3 Zajicek G. What is a disease? The Cancer J. 4, 296, 1991.
4 Stedman's Medical Dictionary Williams & Wilkins Co. 1990. Electronic version 2.0 WordPerfect Corp. 1994.
5 Alberts B, Bray D, Lewis J et al. Molecular Biology of the Cell (second edition); Garland Publishing, New York, 1989.
6 Zajicek G. Hypothesis: cancer is a metabolic deficiency. The Cancer J. 4, 356, 1992.
7 Zajicek G .Cancer is a metabolic deficiency. In New Frontiers in Cancer Causation (Iversen OH Editor); Taylor & Francis, Washington DC, pp. 81-96, 1993.
8 Zajicek, G. The normal and the pathological. Cancer J. 7, 48-49, 1994.



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