Tripping over the Truth by Travis Christofferson

Author:Travis Christofferson
Language: eng
Format: epub
Publisher: Chelsea Green Publishing
Published: 2017-01-13T19:37:00+00:00

A Paradigm Shift

Vogelstein knew that the SMT was in trouble. Enough data had been compiled to determine that his model of a series of sequential mutations as the cause of cancer could be scrapped. He tweaked the original theory, proclaiming that, rather than a defined set of specific mutations being the cause of a given cancer, it was caused by mutations that rendered certain biological systems dysfunctional (those involved in the qualitative aspects of cancer like uncontrolled proliferation, inhibition of programmed cell death, and tissue invasion). Cancer, Vogelstein reasoned, must be a cellular systems disease. A given system might need twenty or so constituent genes for it to operate, or so the theory went. If one constituent gene was rendered dysfunctional by a mutation, the whole system was made nonoperational, thrusting the cell one step closer to malignancy. The clutch in a car needs many parts to make the whole system work, but if one part is broken, the entire clutch system becomes nonoperational.

A minority of cancer biologists claimed that this was an ad hoc modification necessary to make a failed theory fit the data. For sure it was a broadening or a dilution of definition; for sure it would make the data easier to fit. Others argued that calling cancer a “systems disease” made perfect sense. The cell does operate through complex systems, and cancer could be categorized as a disease of systems gone awry, but the data would have to validate it.

Concerning the 2008 pancreatic cancer study, Vogelstein wrote this about the SMT paradigm shift: “From an intellectual viewpoint, the pathway perspective helps bring order and rudimentary understanding to a very complex disease.” Applying the modified theory to the study determined that pancreatic cancer was caused by the dysfunction of twelve distinct biological systems. A critical eye was cast on how diluted this modified theory had become. In this case it appeared to have been pretty watered down. It turned out the authors had to use some imagination to assign some of the mutations to one of the twelve systems implicated in the pathogenesis of pancreatic cancer. It appeared that some of the mutated genes were “friends of a friend of a friend” of a gene that was part of the implicated system. By the authors’ own admission, “we cannot be certain that every identified mutation plays a functional role in the pathway or process in which it is implicated.” Rather than bringing order to a complex disease, it seemed like the authors may, to some degree, have been manufacturing it.

Despite the confusion, TCGA soldiered on. In the fall of 2008, Vogelstein’s lab published the results of sequencing glioblastoma multiforme (GBM), an aggressive form of brain cancer. Teams of researchers sequenced more than twenty thousand genes from twenty-two tumor samples. A novel oncogene was found to be mutated in 12 percent of the samples, and Vogelstein’s team cited the discovery as a “validation of the utility of genome-wide genetic analysis of tumors.” The results demonstrated that GBM was caused by mutations that rendered three core biological systems dysfunctional.

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