An article in the New York Times, "Cancer's Secrets Come into Sharper Focus" examined the growing complexity of cancer research. This article explored the growing realization that human biology is not linear.
Included were references to the groundbreaking work of Pier Paolo Pandolfi. It also described the interaction between the human body and its microbial flora. We have long recognized that human health is, in part, associated with our interaction with microbes in our environment.
The gastrointestinal tract has numerous species that are increasingly believed to contribute to our health. The growing field of probiotics, wherein people consume “healthy organisms,” has gone from quackery to community standard in less than a decade.
Dr. Robert Nagourney put this in context back in May, on his blog. Dr. Pandolfi’s findings suggest that the 2 percent of the human genome that codes for known proteins (the part that everyone currently studies) represents only 1/20 of the whole story. One of the most important cancer related genes (PTEN), is under the regulation of 250 separate, unrelated genes. Thus, PTEN, KRAS and all genes, are under the direct regulation and control of genetic elements that no one has ever studied.
This observation represents one more nail in the coffin of unidimensional thinkers who have attempted to draw straight lines from genes to functions. This further suggests that attempts on the part of gene profilers to characterize patients likelihoods of response based on gene mutations are not only misguided but, may actually be dishonest.
The need for phenotype analyses like the functional profiling performed at Rational Therapeutics has never been greater. As the systems biologists point out, complexity is the hallmark of biological existence. Attempts to oversimplify phenomena that cannot be simplified, have, and will continue to, lead us in the wrong direction.
Cancer biology does not conform to the dictates of molecular biology. Genotype does not equal phenotype. Genes do not operate alone within the cell but in an intricate network of interactions. The particular sequence of DNA that an organism possess (genotype) does not determine what bodily or behaviorial form (phenotype) the organism will finally display. Among other things, environmental influences can cause the suppression of some gene functions and the activation of others. Out knowledge of genomic complexity tells us that genes and parts of genes interact with other genes, as do their protein products, and the whole system is constantly being affected by internal and external environmental factors.
The gene may not be central to the phenotype at all, or at least it shares the spotlight with other influences. Environmental tissue and cytoplasmic factors clearly dominate the phenotypic expression processes, which may in turn, be affected by a variety of unpredictable protein-interaction events. This view is not shared by all molecular biologists, who disagree about the precise roles of genes and other factors, but it signals many scientists discomfort with a strictly deterministic view of the role of genes in an organism's functioning.
Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one targeted drug after another. Our solution to this problem has been to investigate the targeting agents in each individual patient's tissue culture, alone and in combination with other drugs, to gauge the likelihood that the targeting will favorably influence each patient's outcome. Functional profiling results to date in patients with a multitude type of cancers suggest this to be a highly productive direction.
The endpoints (point of termination) of molecular profiling are gene expression, examining a single process (pathway) within the cell or a relatively small number of processes (pathways) to test for "theoretical" candidates for targeted therapy.
The endpoints of functional profiling are expression of cell-death, both tumor cell death and tumor associated endothelial (capillary) cell-death (tumor and vascular death), and examines not only for the presence of the molecular profile but also for their functionality, for their interaction with other genes, proteins and other processes occuring within the cell, and for their "actual" response to anti-cancer drugs (not theoretical susceptibility).
A few labs, like Rational Therapeutics and Weisenthal Cancer Group, utilize functional profiling, because cancer dynamics are not linear.
Literature Citation: Poliseno, L., et al. 2010. A coding-independent function of gene and pseudogene mRNAs regulates tumor biology. Nature. 2010 Jun 24; 465(7301):1016-7.)
http://www.nytimes.com/2011/08/16/he...pagewanted=all