Article

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 01/2011; 5:89-104. DOI: 10.4137/GRSB.S8542
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
65 Views
  • Source
    [Show abstract] [Hide abstract]
    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.
    Cancer informatics 12/2013; 12:221-229. DOI:10.4137/CIN.S13013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target-the-weakness strategy. Our most detailed example involves the immune system. The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target-the-weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation.Also watch the Video Abstract.
    BioEssays 07/2014; 36(9). DOI:10.1002/bies.201400070 · 4.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Complex biological systems manifest a large variety of emergent phenomena among which prominent roles belong to self-organization and swarm intelligence. Generally, each level in a biological hierarchy possesses its own systemic properties and requires its own way of observation, conceptualization, and modeling. In this work, an attempt is made to outline general guiding principles in exploration of a wide range of seemingly dissimilar phenomena observed in large communities of individuals devoid of any personal intelligence and interacting with each other through simple stimulus-response rules. Mathematically, these guiding principles are well captured by the Global Consensus Theorem (GCT) equally applicable to neural networks and to Lotka-Volterra population dynamics. Universality of the mechanistic principles outlined by GCT allows for a unified approach to such diverse systems as biological networks, communities of social insects, robotic communities, microbial communities, communities of somatic cells, social networks and many other systems. Another cluster of universal laws governing the self-organization in large communities of locally interacting individuals is built around the principle of self-organized criticality (SOC). The GCT and SOC, separately or in combination, provide a conceptual basis for understanding the phenomena of self-organization occurring in large communities without involvement of a supervisory authority, without system-wide informational infrastructure, and without mapping of general plan of action onto cognitive/behavioral faculties of its individual members. Cancer onset and proliferation serves as an important example of application of these conceptual approaches. In this paper, the point of view is put forward that apparently irreconcilable contradictions between two opposing theories of carcinogenesis, that is, the Somatic Mutation Theory and the Tissue Organization Field Theory, may be resolved using the systemic approaches provided by GST and SOC.
    Gene regulation and systems biology 01/2013; 7:23-39. DOI:10.4137/GRSB.S10885

Preview (2 Sources)

Download
1 Download
Available from