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Molecular Biology vs Cellular Biology
By gdpawel at 2012-09-27 09:45

There is a growing litany of observations that call into question molecular biologist's preternatural fixation on genomic analyses. Human biology is not simple and malignantly transformed cells more complex still. Investigators who insist upon using genomic platforms to force disorderly cells into artificially ordered sub-categories, have once again been forced to admit that these oversimplifications fail to provide the needed insights for the advancement of cancer therapeutics. Those laboratories and corporations that offer "high price" genomic analyses for the selection of chemotherapy drugs should read the literature carefully as reports portend a troubling future for their current business model.

The particular sequence of DNA that an organism possesses (genotype) does not determine what bodily or behavioral 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. The 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 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 predicted upon their own unique biology, we will confront one targeted drug after another. A better solution to this problem is 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. Functionally cytometric profiling these results in patients with a multitude type of cancers suggest this to be a highly productive direction.

Without cell function analysis, gene therapy would be beyond imagination. Tissue culture methods have made gene therapy possible. The ability to transfect cultured cells with DNA gene sequences has allowed scientists to assign functions to different genes and understand the mechanisms that activate or redress their function. The interaction between cell biology and genetics gave birth to molecular biology. The set of all malignant cells that could evolve must apply to "all" pathways of tumor cell evolution and "all" combinations of genetic and epigenetic alterations. It must be independent of any particular pathway of tumor cell evolution. The normal cellular machinery that potentially can carry out malignant behavior is encoded within the normal human genome, essentially the same for all types of cancer.

Functional cytometric profiling has allowed the identification of clinically relevant gene expression patterns which correlate with clinical drug resistance and sensitivity for different drugs in specific diseases. There is no single gene whose expression accurately predicts therapy outcome, emphasizing that cancer is a complex disease and needs to be attacked on many fronts. Functional cytometric profiling assesses the activity of a drug upon combined effect of all cellular processes (cell "population" level rather than at the "single" cell level), using combined metabolic (cell metabolism) and morphologic (structure) endpoints.

Molecular tests, such as those which identify DNA or RNA sequences or expression of individual proteins often examine only one component of a much larger, interactive process. Drug resistance and sensitivity is multifactorial. Functional cytometric profiling can show this at the cell population level, measuring the interaction of the entire genome. It visualizes directly the drug effect upon cancer cells. Photomicrographs of actual tumor cells show the condition of cells as they are received and enriched in the lab, and also the conditions of control cells post-culture. In this visualization, the microscopic slides sometime show that the exact same identical individual culture well, shows some clusters have taken up vast amounts of the molecular drug, while right next door, clusters of the same size, same appearance, same everything haven't taken up any of the drug. Not only is this an important predictive test but it is also a unique tool that can help to identify newer and better drugs, evaluate promising drug combinations, and serve as a "gold standard" correlative model with which to develop new DNA, RNA, and protein-based tests that better predict for drug activity.

The functional cytometric profiling platform has the capacity to measure genetic and epigenetic events as a functional, real-time adjunct to static genomic and proteomic platforms. Literature Citation:  BMJ 2007;334(suppl 1):s18 (6 January), doi:10.1136/bmj.39034.719942.94 Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007 Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)

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