Force and genomic change.

An article, "DNA Dreaming" by D. Eldridge, appearing in Frontier Perspectives, (1) describes some significant findings made by Maniotis, et al. regarding impressed forces and genome behavior in response to such forces. More specifically, it describes an experimental situation where mechanical forces impressed upon the external cellular membrane are transmitted via the cytoskeletona complex of inner cellullar microtubules that gives the cell structural integrity--to the nucleus, resulting in near--instantaneous rearrangements within the nucleus. (2,3)

Though actual genomic mutation in this situation was not detected by Maniotis, et al., the article by Eldridge nevertheless appears to imply that this cytoskeleton force-carrying network could be a means for the generation of an environmentally responsive mutation. Relevantly, Maniotis, et al. (2) do state that this "type of 'mechanical signaling' [of force to the nucleus] could serve to switch cells between different genetic programs [in development]." As programmed genetic mutation can also play a role in development, (4,5,6) an adaptive process, such mutation could also be seen as a mutation that is adaptively responsive to the dynamic signals conveyed from the cellular environment to the genome via the cytoskeleton and inner cytoplasmic membranes. A complex membrane system is in place that would enable this. An inner, vesicular membrane network, the endoplasmic reticulum, is continuous with the nuclear membrane and outer-cellular membrane, and is, in fact, connected in many regions to the cytoskeleton. (7) The cytoskeleton itself might be regarded as a type of complex, multi-tubular membrane in continuity with other cellular membranes and organelles, the latter being complex compartments within membrane systems.

Through my own investigations on directed or programmed mutation, I predicted a very similar situation regarding forces, various membrane systems, and adaptively responsive mutation. For several years, I investigated the genetic control of mutability in fungi and bacteria, especially in regard to the responsiveness of such control to environmental stress. (6, 8, 9, 10, 11, 12) It was proposed, and evidence indicated, that genetically controlled mutation as a genetic mutator system would have to be a significant component of any epigenetic system in which mutations were to be generated adaptively in response to an environmental situation. (10,11) The question was how. In 1989, and again further described in 1996 and 1998, it was hypothesized, and hence predicted, that stressful forces from the environment, which would include mechanical forces, are conveyed non-uniformly via the cell's external and internal membrane system to the genome, resulting in unstable, non-uniform configurational changes within the genome. (9,11,12,13) This instability would be through a non-uniform distribution of forces throughout the genome.

The consequences of such instability in genome configuration, it was further conjectured, would be a global hypermutation resulting in the re-establishment of genomic stability, that is, a stable force configuration. This reinstitution of dynamic stability was seen as the basis of the adaptive response to non-uniform force or stress.

Such environmentally responsive, yet inner-directed global hypermutation, was observed by the author. (8,9,10,11) The genome appears to respond mutagentically as a developmental unit, a global dynamic whole, where mutations not apparently adaptive in themselves are necessary for the occurrence of those which are (9,10,11,12). Only by responding as a whole, in a non-linear, connected manner, could the genome generate a comprehensive stability of forces. (14)

Why would such impressed forces via the continuous cellular membranes lead to the eventual restabilization of genomic forces, as manifested by directed adaptive mutation? What does this reinstitution of dynamic stability mean? To what does it point? Is it indicative of a deeper, more universal process or principle? In fact, such a principle was described several years ago (15) and elaborated further by this writer in connection with biological phenomena. (11,12,13,14,16) Such a principle or its features would predict phenomena such as adaptively responsive mutagenesis to environmental stress. A significant feature of the principle is the drive of all phenomena, irrespective of scale and level of organization, for dynamical completion.

More specifically, in a biological system or cells under stress, a non-uniformity of force is imprinted upon the biological organism. By means of the very non-uniformity of force, a uniformity or stability of force is established or even increased. This is done through the instantaneous, non-local generation of complete force configurations. The organism is driven to complete, within itself and within its force connections to the environment, any non-uniformity of force that occurs. From this perspective, looking at the genome's response to a conveyed stress or dynamic non-uniformity via complex membranes, adaptively responsive mutagenesis is a necessary, near instantaneous completing process involving force, giving forth stability and integrity throughout the genome and its environs, and manifested cytologically as near-instantaneous movements and realignments of nuclear structures. This is the deeper significance or meaning of this type of mutagenesis and the conveyance of mechanical force to the nucleus.

The research by Maniotis, et al. gives further experimental support to this theoretical basis or model of adaptively responsive mutation, in which the genome via force is driven to respond mutagenetically, completingly, as a connected whole to a conveyed stress, where absolute gene and chromosomal boundaries necessarily cease to exist and become changing. (16) Studies from classical cytogenetics would also lend support to this continuity and lack of absolute boundaries. On the cytological level, during interphase, the chromosomes in animals, such as flies, are all joined together in a common heterochromatic region, referred to as the chromocenter. (17) In some situations, there is even a physical continuity between chromosomes and membrane. For example, in organisms as diverse as insects and amphibians, chromosomes are known to be attached to the nuclear membrane. (18,19) Through this nuclear membrane, a destabilizing, dynamical imprinting, from more external membranes, could also be conveyed to the attached chromosomes, resulting in a responsive mutation. (11) In fact, it was argued, some years ago, that chromosomes interacting with proposed nuclear membrane attachment-sites might have played a significant role in a programmed genomic change within a fungus. (6) Moreover, Maniotis and his group have shown that the chromosomes in mammalian cells are connected by strings of DNA. (3) These could also act as further avenues of conveyed and completing force, underlying a unitary, adaptive mutagenetic response, independent of boundaries.

Further evidence of the model would be the demonstration that an adaptively responsive mutagenesis is associated with the generation of uniform or complete force configurations within the genomes and the membranes of the cells, where completions in the genome would contribute globally to completions within these membranes and the organelles composed of such. The result could be an increase in the dynamic integrity of the cell, a feature of which would be increased tensional integrity, especially that of the cytoskeleton. Manitois, et al. do speak of the importance of such integrity for the maintenance of cellular shape and properties, presumably necessary for proper function.

In fact, "changes in the balance [uniformity] of force between cells and ECM [extracellular matrix] ... can change cell shape and switch cells between growth and differentiation. ... Cell shape changes influence gene expression" [sup.2] and, possibly related to such expression, responsively directed mutation. Such changes and influences could very well be a manifestation of the adaptive process to maintain or continually re-establish a genomic and cellular stability of force through a repeated generation of completing force configurations. Because of the global, dynamic connections within the cell, a re-established cellular stability might even lead to a still greater stability of force within the genome through further completion. As Manitois, et al. state, "... Regulation of genomic stability may be similarly achieved through maintenance of an internal tensegrity force balance." (3) In effect, developmental, epigenetically directed mutation becomes an extension of a global, non-linear, and adaptive stabilization within cells.

The nature of the forces involved in the generation of completion, upon which adaptive stabilization is based or driven, would not be the issue; they could be electromagnetic as well as mechanical, or include other types, as yet unknown. There may even be the inclusion of nuclear forces, temporarily acting long-range. The phenomenon of Cold Fusion might suggest the feasibility of this. In fact, the completion drive on all scales could very well involve an interrelationship among various forces and may reflect and utilize a deeper connection or unity among all forces. (11,12, 20,14) A truly unified field theory in physics may very well be found through an investigation of the deeper, dynamical basis of adaptively responsive mutagenesis.

References

(1.) Eldridge, D. (1998). DNA dreaming. Frontier Perspectives, 7(2), 42-44.

(2.) Maniotis, A., et al. (1997). Demonstration of mechanical connections between integrins, cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure. Proceedings of the National Academy of Sciences, USA, 4 (3), 849-854.

(3.) Maniotis, A., et al. (1997). Mechanical continuity and reversible chromosome disassembly within intact genomes removed from living cells. Journal of Cellular Biochemistry, 65(1), 114-130.

(4.) McClintock, B. (1965). The control of gene action in maize. Brookhaven Symposium of Biology, 18, 162- 203.

(5.) Lieber, M. (1975). Environmental and genetic factors affecting chromosomal instability at mitosis in aspergillus nidulans and the importance of chromosomal instability in the evolution of developmental systems. Evolutionary Theory, 1, 97-104.

(6.) Lieber, M. (1976). The genetic and mutagenetic interaction of chromosomal duplications present together in haploid strains of aspergillus nidulans. Mutation Research, 37, 33-66.

(7.) Klopfenstein, D. R, et al. (1998). A novel direct interaction of endoplasmic reticulum with microtubules. Embo Journal, 17(21), 6168-6177.

(8.) Lieber, M. and Persidok, T. (1983). Mutability in escherichia coli K12 enhanced by a P1-plasmid and by generalized transduction. Rivista di Biologia/Biology Forum, 76(3), 493-499.

(9.) Lieber, M. (1989). New developments on the generation of mutations in escherichia coli lysogens. Acta Microbiologica Hungarica, 36, 377-413.

(10.) Lieber, M. (1990). Mutagenesis as viewed from another perspective. Rivista di Biologia/Biology Forum, 83-84, 513-522.

(11.) Lieber, M. (1998). Environmentally responsive mutator systems: toward a unifying perspective. Rivista di Biologia/Biology Forum, 91(3), 425-458.

(12.) Lieber, M. (1998). Hypermutation as a means to globally re-stabilize the genome following environmental stress. Mutation Research, Fundamental and Molecular Mechanisms of Mutagenesis, 421(2), 219-220.

(13.) Lieber, M. (1996). Force, development, and neoplasia: development from another perspective as illustrated through a study of in vitro plant development from neoplasm. Rivista di Biologia/Biology Forum, 89(2), 245-274.

(14.) Lieber, M. (2000). Adaptively responsive hypermutation and its configurational-based regulation due to global position effect. Mutation Research, Fundamental and Molecular Mechanisms of Mutagenesis, 449(1&2), 57-60.

(15.) Lieber, P. (1969). Aspects of evolution and a principle of maximum uniformity. In Towards a Theoretical Biology II, C. H. Waddington (ed.), University of Edinburgh Press, Edinburgh, pp. 293- 316.

(16.) Lieber, M. (In press). Temporal control of environmentally responsive hypermutation involving cryptic genes. Mutation Research, Fundamental & Molecular Mechanisms of Mutagenesis.

(17.) Goodenough, U. and Levine, R. P. (1974). Genetics. New York: Holt, Rinehart, and Winston, Inc.

(18.) Murray, A. B. and Davies, H. G. (1979). Three-dimensional reconstruction of the chromatin bodies in the nuclei of mature erythrocytes from the newt triturus cristatus: the number of nuclear envelope-attachment sites. Journal of Cell Science, 35, 59-66.

(19.) Marshall, A. F., et al. (1996). Specific interactions of chromatin with nuclear envelope: positional determination within the nucleus in drosophila melanogaster. Molecular Biology of the Cell, 7, 825-842.

(20.) Lieber, M. (1998). The living spiral: a dimensionless biological

Michael M. Lieber, Ph.D.

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