Moss - What genes cant do - 2003 (522929), страница 29
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The phenotypic differences between Prader-Willi individuals and Angelman individualsand between different subclasses of patients with Turners are correlatedwith the possession of different epialleles. Huntington’s disease, which isroutinely touted as a paradigm example of the utility of classical genetics owing to its high rate of “penetrance,” is in fact notably nonMendelian in a number of ways, including epigenetic based parent oforigin affects.The other pattern of chromosome marking is that which occurs, notduring gametogenesis, but rather during the whole subsequent lifehistory of the organism and results in tissue-specific patterns of geneactivity and inactivity.
Where imprinting discriminates between thematernal and paternal alleles at a single locus, developmental chromosome marking discriminates between different loci. While the contextsensitivity of imprinting only entails distinguishing between that of male(spermatogenesis) and female (oogenesis), the chromosome marking thatA Critique of Pure (Genetic) Information113is part and parcel of nuclear differentiation must be responsive to manyfeatures of a cell’s milieu.The role of chromosome marking as a stable parallel system of biological “information” can be observed in a number of ways. High levelsof methylation are seen both in the regions of chromosomes (heterochromatin) which remain transcriptionally silent during the course ofan organism’s lifetime, and in the case of inactivated X chromosomesmethylation is seen throughout.4 These patterns of inactivation arepassed on somatically through the course of the organism’s lifetime(Jablonka & Lamb 1995).
As inductive interactions during ontogenyresult in cellular differentiation, tissue-specific patterns of methylationare seen to play a role in allowing differentiated cells to give rise to entirelineages which inherit and retain the differentiated pattern of geneexpression. Changes in patterns of methylation have also been implicatedas part of the adaptive response of cells-organisms to environmentalchallenges.
While the mechanisms of heritability of chromatin markingare fairly well characterized, the means by which de novo marking iscontextually induced is not well understood.As a heritable “parallel” system of biological order, chromatinmarking is deemed to be of evolutionary significance. CpG methylationis an ancient structure found in one-celled organisms whereby the abilityof the cell to create epialleles in response to environmental signals provides in effect an environmentally inducible system of variation. Perhapsmore importantly, the ability of cells to induce patterns of chromatinmarking in each other may have been a key to the evolution of multicellularity.
The gambit of multicellularity involves a balancing actbetween the potential benefits of specialization with the danger that specialized parts will compete with one another. The successful multicellular individual has achieved the ability to straddle that line. The complex,highly differentiated, multicellular organism achieves its system-levelintegration through the course of a developmental life history. Wherebymost plants and certain invertebrates can be regenerated from an aggregate of tissue—i.e., the interplay between the cell lineages represented inthe aggregate can lead to the reproduction of the larger developmentalpattern—in those organisms deemed to be most complex, this is not thecase. Where the challenge of balancing differentiation and integration is114Chapter 3greatest, it appears that the replication of the whole developmental lifehistory is required.
The organism must be reproduced from the onecelled stage with a concommitant erasure of the epigenetic memory ofthe previous generation. It may thus be the case that the achievement ofan advanced level of specialization is protected by the inability of anyof the differentiated parts to give rise to a new organism that lacks thecompetence to reproduce the whole repertoire of subspecialities.For the vast majority of extinct and extant organisms (protoctistas,fungi, plants, most invertebrates) that do not sequester their germ linesearly in development, the production of heritable epialleles throughepigentic chromatin marking is likely to have had direct evolutionarysignificance. It may provide a key mechanism for the genetic assimilation of phenotypic adaptations.
To what extent adaptive “marks” influenced by the life histories of parental organisms may also be representedin vertebrate imprinting, is yet to be determined. The further elucidationof the processes of chromosome marking will provide another importantwindow on the plasticity and contextual responsivness of the nuclearconstituents of the cell.From the Hereditary Code-Script to Cycles of ContingencyFifty years ago Schrödinger argued that the kind of specificity of orderwhich underlies the faithful inheritance of a characteristic such as the“Hapsburg lip” must rely upon a new principle of order-from-order.
Hethen based his influential paean to the hereditary code-script on the claimthat only solid-state covalent bonds could be the ultimate source of suchorder. I’ve endeavored to “take Schrödinger seriously” by reconsidering,with the benefit of 50 years of hindsight, the empirical basis for this latterclaim. I have offered evidence and argument on behalf of the view thatbiological order is realized, preserved and propagated on many mutuallydependent levels.
Just as the roots and shoots (foliage) of a tree are circularly the cause and effect of each other (to recall the language of Kant),so too are the multiple aspects of biological order—invested in membrane structure, dynamic regimes, nucleic acid sequence and nucleic acidmodification—the cause and effect of each other. Biological order reposesupon highly regulated, energy dependent membrane flow just as muchA Critique of Pure (Genetic) Information115as it does upon genetic sequence stability. Perhaps even more to the point,the very idea of order from crystalline stability must be reworked intoan idea of order from dynamic steady-state systems within which crystalline structures function as constituent resources that are subject todynamic modifications, rearrangements, expansions, contractions, andreplications.
Fifty years of hindsight reveals that life is indeed an orderfrom-order phenomenon but rejects the claim that the chemistry of thesolid state provides the only, or even a privileged, basis for this order.With the rejection of the warrant for any claims for the primacy of ahereditary code-script, the door opens for a new overarching perspectiveon the nature of the living organism.
And just such a perspective is beginning to emerge.Drawing on a number of disciplines and contributions [including anearlier expression of this work (Moss 1992)], new advocates of a developmental systems theory (DST) are beginning to explore the implicationsof a biology which is neither explicitly nor implicitly encased in themetaphorical space of the code-script.From a DST perspective, ontogeny is best viewed as contingent cycles of interaction amongst a heterogeneous set of developmental resources, no one of which‘controls’ or ‘programs’ the process. These resources range from DNA to cellular and organismic structure and to social and ecological interactions.
Many ofthese resources, both inside and outside the organism, can be reliably reconstructed down evolutionary lineages. Evolution is change in these developmental cycles. The change in gene frequency often used to define evolution are butone aspect of the richer complex of stabilities and changes captured by the developmental systems approach. (Oyama, Griffiths & Gray5 2001)From the DST perspective (Oyama 1985, Griffiths & Gray 1994,Griffiths & Gray 2001) the achievement of any phenotype will rely onthe presence of some set of heterogeneous resources, none of which singlydetermines it and the absence of any of which—be it a vitamin, a gene,or some other developmental cue—may equally result in a characteristicaberration.
The developmental systems perspective is thus permissive ofmany different kinds of biological explanations which may be tailoredto local needs and local contexts. At minimum it provides a perspectivalantidote to that malady by which the richness and vitality of lifeprocesses are lost by slippage into that which is (genetically) known inadvance. If no developmental resource is necessarily accorded causal116Chapter 3primacy then any explanatory account must place all its cards on thetable. When the conflationary temptation to pack contingent developmental outcomes into the one-dimensional sequence arrays of polymersis set aside, then the coding sequences of DNA may be reconceptualizedas one type of resource among many, i.e., as Gene-D (Moss 2001).Beyond just a formal parity of resources, DST provides a new openingwithin which the relationship between different hierarchical orders of theliving world may be reconceptualized.4Dialectics of Disorder: Normalization andPathology as ProcessEpigenetics (Waddington’s term for the analytical study of individual development) can shed light on the process of tumorigensis, and vice versa.—Julian Huxley, 1958Overgrowth or dedifferentiation are effects of .
. . disorganization—repercussions not driving forces. Cancer is no more a disease of cells than a traffic jamis a disease of cars. A lifetime of study of the internal-combustion engine wouldnot help anyone to understand our traffic problems. The causes of congestioncan be many. A traffic jam is due to a failure of the normal relationship betweendriven cars and their environment and can occur whether they themselves arerunning normally or not . . .
Cancer is a disease of organization, not a disease ofcells . . .What we need most at present is to develop an autonomous science of organismal organization, the social science of the human body; a science not so naïveas to suppose that its units, when isolated, will behave exactly as they do in thecontext of the whole of which they form a part, and willing to recognize thatwhole functioning organisms are its proper concern. I will try to explain normalgrowth, differentiation, maintenance, and repair, as well as their disorder. It willtake biological orderliness in action as its field of study.
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