Biomolecular Self-Defense and Futility of High-Specificity Therapeutic Targeting

National Cancer Institute, EPN 3108, 6130 Executive Blvd., Rockville, Maryland 20892, USA.
Gene regulation and systems biology 11/2011; 5:89-104. DOI: 10.4137/GRSB.S8542
Source: PubMed


Robustness has been long recognized to be a distinctive property of living entities. While a reasonably wide consensus has been achieved regarding the conceptual meaning of robustness, the biomolecular mechanisms underlying this systemic property are still open to many unresolved questions. The goal of this paper is to provide an overview of existing approaches to characterization of robustness in mathematically sound terms. The concept of robustness is discussed in various contexts including network vulnerability, nonlinear dynamic stability, and self-organization. The second goal is to discuss the implications of biological robustness for individual-target therapeutics and possible strategies for outsmarting drug resistance arising from it. Special attention is paid to the concept of swarm intelligence, a well studied mechanism of self-organization in natural, societal and artificial systems. It is hypothesized that swarm intelligence is the key to understanding the emergent property of chemoresistance.

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    • "But there is more. The viewpoint being advanced in the previous paper by this author63 is that a community of cells is not simply a collection of units dwelling within certain architectural structures. This is indeed a living community possessing the emergent property of swarm intelligence. "
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    ABSTRACT: Two drastically different approaches to understanding the forces driving carcinogenesis have crystallized through years of research. These are the somatic mutation theory (SMT) and the tissue organization field theory (TOFT). The essence of SMT is that cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations, and that those mutations occur on genes which control cell proliferation and cell cycle. Thus, according to SMT, neoplastic lesions are the results of DNA-level events. Conversely, according to TOFT, carcinogenesis is primarily a problem of tissue organization: carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signaling and compromising genomic integrity. Hence, in TOFT the DNA mutations are the effect, and not the cause, of the tissue-level events. Cardinal importance of successful resolution of the TOFT versus SMT controversy dwells in the fact that, according to SMT, cancer is a unidirectional and mostly irreversible disease; whereas, according to TOFT, it is curable and reversible. In this paper, our goal is to outline a plausible scenario in which TOFT and SMT can be reconciled using the framework and concepts of the self-organized criticality (SOC), the principle proven to be extremely fruitful in a wide range of disciplines pertaining to natural phenomena, to biological communities, to large-scale social developments, to technological networks, and to many other subjects of research.
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    • "QS is found to be a promising target in oncology, and a number of peptide drugs are currently under investigation for their preventive, diagnostic, and therapeutic properties. As discussed in much detail in the work by this author,15 QS and other aspects of swarm intelligence contribute to the phenomena of biological robustness and acquired chemoresistance. "
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    • "While there are a number of studies on biological robustness, the role of redundancy is still a theoretical debate in the phenomenon of biological robustness [55]. Our study provided a unique viewpoint of genetic robustness beyond duplication-based compensation and suggested the candidates of nonhomologous functional compensatory genes based on three features: (1) the existence of synthetic lethal interaction; (2) the ratio of shared common interacting partners; (3) the degree of coregulation. "
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