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Byetta Attorney News – 4/18/2012: If you were prescribed Byetta and have suffered negative side effects, please contact us today so that we can put you in touch with an attorney to advise you of your legal rights.

Byetta Attorney: The rarity of cancer-causing mutations stemmed from the inefficiency of mutagenesis. The responsible agents—chemical and physical mutagens—attacked a cell’s genome randomly. Since the important target genes such as the protooncogenes represented only a minute fraction of the genome, the mutagens would find these crucial targets only rarely. These jackpot hits would have enormous consequences for the cell, but the likelihood of their happening in any defined period of time was vanishingly small. Importantly, mutations appeared to happen at a low but constant rate even without exposure to mutagenic agents. These mutations were seemingly spontaneous and found to be intrinsic to all life forms. Indeed, the evolution of species has depended on the slow, spontaneous change in the base sequences of their DNA. Such mutations, occurring continually since life first appeared on this planet, have generated genetic variability and varied characteristics within species. Natural selection has then favored the survival of the genetically best-endowed members of each species. Agents such as mutagenic chemicals and radiation only serve to accelerate the rate at which mutations happen.

A heavy smoker of cigarettes, for example, might collapse the time usually needed to mutate a gene from a decade to a year simply by flooding his or her cells with potent mutagens. Consequently, the entire process leading to a lung or bladder cancer, which might take hundreds of years to complete in a nonsmoker, could be compressed to a few dozen years in this smoker. But once the actual agents favoring human cancer were identified, it became apparent that this scheme required more refinement. Some chemical agents accelerated cancer formation but did not seem to attack DNA. They were, in other words, poor mutagens. For example, alcohol, asbestos fibers, and estrogen were all known to increase the risk of certain kinds of cancer, sometimes substantially, yet none of these seemed capable of damaging DNA. How could nonmutagenic agents such as these accelerate cancer formation?

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Byetta Attorney: The answers came from reexamining the ways DNA is copied inside living cells. When the DNA double helix was first revealed by Watson and Crick in 1953, its structure seemed perfect and robust, well-designed to resist most of the disruptive influences that might be present inside living cells. For example, the bases in the double helix are turned inward and thus are not very susceptible to direct attack by chemical mutagens. Moreover, the linkages between adjacent bases were found to be resistant to cleavage by alkaline ions that arise continually in the cell. But while the double helix itself is relatively resistant to chemical attack, the process of maintaining a cell’s genetic integrity has a weak link. The vulnerability derives from the need to replicate the cell’s genome each time the cell goes through the process of growth and division. The resulting duplicate copies of the genome enable the mother cell to endow each of its daughters with a genome precisely equivalent to the one that it carries itself.

This process of DNA replication has flaws. On occasion, a cell will miscopy a sequence of its DNA prior to cell division, and as a consequence, one of its daughters will receive a slightly miscopied genome, in effect a mutated one. Even the best functioning cells will occasionally miscopy one in a million (or ten million) bases during each cycle of DNA replication. Hence, cell growth and division create vulnerability to mutation. This imperfection suggested another way cancer formation might be accelerated. Agents that promote cell growth will indirectly create mutations simply because they force cells to replicate their DNA. More DNA copying means more inadvertent copying mistakes, hence more mutations.

Knowing this, we began to speculate how some kinds of carcinogenic agents could work even without having direct DNA-damaging abilities. An oftcited example was that of alcohol, which itself seemed to lack mutagenic powers. Nonetheless, alcohol was a strong carcinogen when consumed in conjunction with tobacco. Repeated exposures of high concentrations of alcohol were known to kill many of the cells lining the mouth and throat. The surviving cells in the tissues lining these cavities would then receive orders to grow and divide to replace their fallen comrades. These repeated rounds of growth and division would yield mutations in the DNA of these cells. Moreover, it seemed that DNA in the midst of replication was even more susceptible to damage from mutagens than DNA from nonproliferating cells. This explained why cigarette smoke, which contains dozens of different mutagens, and alcohol, which promotes cell proliferation, were a deadly combination. When used together, their^r generated as much as a thirtyfold increase in risk of mouth and throat cancer.

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Byetta Attorney: The 1982 discovery of the ras point mutation held great appeal for molecular biologists, whose goal was invariably to reduce complex biological processes down to simple underlying mechanisms. They liked the notion that the development of cancer depended on nothing more than a single mutation in the genome of a normal cell. But within a year, with the discovery of collaborating oncogenes, the number of mutations that were apparently required to make a tumor crept up to two. Even this number held great appeal for them. Two mutant genes still represented a manageable level of complexity. Then even this number came under attack. By the mid-1980s, it became increasingly apparent that the number of mutations accumulated by most kinds of tumors during their development was far more than two. The evidence from epidemiology, remember, suggested that at least half a dozen steps were required to make a cancer; many scientists speculated that each of these steps involved the creation of a mutant gene in cells evolving toward a fully malignant state.

By the mid-1980s, mutant genes very different from oncogenes were finally found in human tumor DNA. The newcomers came to be called “tumor suppressor genes.” Their discovery filled a major gap in the puzzle of how human tumors arise. This new class of genes was uncovered through experiments that were far removed from the work on viruses, gene cloning, and gene transfer—the kinds of experiments that had created the explosion of interest in oncogenes in the decade since 1975. This other line of work made use of an odd experimental procedure termed “cell hybridization.” Those who practiced this technique, most prominently Henry Harris at Oxford University, would take groups of cells growing on the bottom of a petri dish and force them to fuse together. These fusions—in effect, cell-to-cell matings allowed Harris, and later others, to uncover fundamental truths about the behavior of genes operating inside cancer cells, including the discovery of these new cancer genes.

Long before these cell fusions were begun in the mid- 1970s, geneticists had experimented with matings between whole organisms. As described earlier, the first systematic study of mating genetics was carried out in the 1860s by the Austrian monk Gregor Mendel, who hybridized different strains of pea plants. His work was forgotten for a generation, then rediscovered in 1900. It formed the foundation of modem genetics and led to the notion that biological information is transmitted in the discrete packets that came to be called genes.