Moss - What genes cant do - 2003 (522929), страница 30
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It lies, in wait for a name,between cytology and sociology. It is much more than oncology, for it is the studyof the organization of whole organisms as well as that of disorganisationaltumour formation.—D. W. Smithers, 1962It is well known from classic genetics that the expression of any multigenic phenomenon is very dependent on the genotypic milieu, so that a given mutationmay be deleterious in one genetic milieu and advantageous in another. Thus,the combination of mutagenic changes in genotypic milieus which are differentin every human, plus the sensitivity of multigenic phenotypes to the surrounding environment, account for the difficulty in predicting the likelihood of nonfamilial or sporadic cancers or their outcome once they appear. .
. . Even wherethere is a dominant germ line mutation that favors development of cancer with118Chapter 4a probability approaching unity, the time of onset cannot be predicted, and onlya very small fraction of the cells, all of which carry the mutation, become transformed; to do so, additional mutations are required, but they can be found innormal tissue as well.
To achieve a better understanding of cancer, it will be necessary to take into account the genome of the transformed cell, the state of thesurrounding tissue, the age of the organism, its diet and the environment in whichit lives.—Harry Rubin, 1999From Black Bile to Misguided Developmental PotentialThe history of the biology of cancer can be divided into three periods.The debate between a genetic versus an epigenetic-developmental emphasis in explaining cancer can only be dated as far back as Boveri’s somaticmutation hypothesis of the first decade of the twentieth century. Thecommencement of the genetic position in cancer thus squares well withthe phylogenetic turn in biology (see chapter 1) and marks the beginning of the third period.
The developmental view first emerged duringthe nineteenth century alongside, and in direct relation to, therise of modern cell theory, histology, and embryology, all of which hadtheir origins in the ferment of the 1790s. We will thus identify thelast decade of the eighteenth century as the beginning of the secondperiod.The first period of cancer biology begins with the Greeks. Classicalmedicine referred to cancer but did not distinguish sharply betweeninflammation, ulcers, benign lesions, and neoplasia—all were taken upin a humoral theory of disease (Rather 1978).
Hippocratic writers associated the properties of the four elements, hot, cold, wet, and dry, withthe four humors, blood, phlegm, black bile, and yellow bile. In somemanner, the historical details of which are not clear, blood became associated with hot and moist, phlegm with cold and moist, yellow bile withhot and dry, and black bile with cold and dry.This scheme, appropriated by Galen, became canonical for medicinewell into the seventeenth century (Rather 1978). Good health in Galenicmedicine involved maintaining the right balance of the humors. Thesource of the humors was understood to be ingested food, which wasbroken down through “concoction” and distributed through the body.Dialectics of Disorder: Normalization and Pathology as Process119The general approach to all inflammations was one of understandingthem in terms of humoral flows.
A tumor was understood to be the resultof the damming up of humoral flow with a localized buildup of humors.A flux of black bile mixed with blood gave rise to a kind of inflammation Galen called “scirrhus,” which in some cases resulted in cancer. Aflux of black bile unmixed with blood gave rise to cancer directly. Whilecancer could arise in any part of the body, the most familiar case, andthe source of the classical identification of the disease with a crablikemorphology (hence the name cancer), was that of the female breast(Rather 1978). With Harvey’s seventeenth-century work came a shiftin understanding toward the recognition of the circular flow of bloodpowered by the pumping of the heart in place of the classical notion ofthe expulsive and retentive forces of organs—yet the humoral model ofcancer was otherwise largely retained.During the nineteenth century, much debate turned in relation to thequestion of whether the orgins of cancer were systemic and constitutionalor localized in nature.
This dispute is one which has reappeared in different dress ever since. The humoral theory is the classic case of a constitutional (diathesis) view. It is constitutional because the source of thedisease it describes is systemic. A tumor may appear at a certain location, but it is the state of the whole body that is responsible for thehumoral imbalance (dyskrasis), thus causing the cancer. The loss ofsupport for the humoral theory by the end of the eighteenth centurymarks the end of the first period of cancer biology but not the end ofconstitutional theories of cancer.
Another constitutional theory of cancerwas upheld, for example, by Paget, who in 1853 attributed cancer totwo factors: a morbid material circulating systemically in the vascularsystem and an inherited predisposition to the reception of this impetustoward cancer (Triolo 1965)—a view which resembles current notionsof “genetic susceptibility.”A localized etiology of cancer can be based either upon an externalcause that acts locally or a discrete endogenous cause.
Only the formerwas entertained toward the end of the eighteenth century. Based onstudies of scrotal cancer in chimney sweeps, Percival Pott (1775)(Haggard & Smith 1938) introduced the idea that cancer could be theresult of environmental influence.1 In 1776, Bernard Peyrilhe, following120Chapter 4suit, suggested that cancer was a local process, which when presentingdiffusely did so by having spread through the lymphatics. Despite Pottand Peyrilhe, the predominant view until the 1830s was still that ofcancer as a constitutional disease with localized expression in the formof clotted and degenerated lymph (Haggard & Smith 1938).The idea that cancer could be based upon an endogenous, local causewas a direct outgrowth of those late seventeenth and early eighteenthcentury advances in histology, cytology, and embryology which mark thebeginning of the second period and the commencement of modernbiology.
The central figure and acknowledged doyen of this new biologyof cancer was Johannes Müller, whose neo-Kantian “teleomechanist”approach to developmental morphology was described in chapter 1.Cancer can be viewed as a local and endogenous aberration when it isanalyzed in terms of following the developmental epigenesis of the organism from (1) germs to germ layers, from (2) germ layers to tissues andorgans, and from (3) tissues and organs to whole systems. It is againworth considering—but now from the angle of cancer biology—the pathby which a neo-Kantian research logic led to Müller’s pioneering workin histopathology, and its canonization by Virchow.The extension of a teleomechanist program can be seen in the workof Blumenbach’s student Christoph Girtanner.
In his 1796 publicationÜber das Kantische Prinzip für die Naturgeschichte, he “introduced thenotion of the Stammgattung, defined as a generative stock of Keime undAnlagen which determined certain limits of structural adaptation andwhich under appropriate environmental conditions became manifest asdifferent but related species (Gattungen)” (Lenoir 1982).Carl Friedrich Kielmyer, who studied in Göttingen from 1786 to 1788,gave an influential series of lectures in the 1790s in which, drawing notjust upon comparative anatomy but also animal ethology, pathology,and paleontology, he attempted to adumbrate a research programoriented toward a general theory of animal organization (Physik desThierreiches).
Most importantly he introduced the idea of analyzingthe unity of the generative stock of Keime und Anlagen through comparative embryology. Examining the patterns of embryological development, Kielmyer envisoned an opportunity to elucidate the dynamicDialectics of Disorder: Normalization and Pathology as Process121path of animal organization itself. He imagined paths of development tobe the source of phylogenetic innovation, but like Kant and Blumenbach,he did not assume a full chain of Being.Many species have apparently emerged from other species, just as the butterflyemerges from the caterpillar . .
. They were originally developmental stages andonly later achieved the rank of independent species; they are transformed developmental stages (Lenoir 1982, p. 43).The beginnings of a modern theory of embryonic germ layers can betraced to Ingnaz Döllinger who, although influenced early in his careerby Schelling, turned away from a transcendental approach and towardthe Göttingen School. Döllinger defined the task of physiology as thatconsisting of two principal fields of study: morphology, which is thegeneral study of organic form, and histology (Lenoir 1982). The germlayer concept was introduced in 1817 by Döllinger’s student Pander(Rather 1978) and further generalized by another student, Karl Ernst vonBaer.
Along with Johannes Müller, von Baer became the seminal figurein the formulation of a developmental morphology structured by theteleomechanist outlook. Von Baer, like many other young Germans earlyin the nineteenth century, was also influenced by the eminent Frenchanatomist Georges Cuvier.Cuvier was not from the teleomechanist tradition but shared with it adesire to find the laws of organic form through a comparison of taxaguided by a regard for the functional unity of the whole organism. Hewas thus an adamant opponent of the romantic Naturphilosophen, whosought to understand morphology on the basis of isolated organs subjected to a kind of geometrical intuitionism. Transcendental morphologists attempted to order a continuous chain of taxa on the basis ofgeometrical transformations of an individual organ. Cuvier, by contrast,was a functionalist. He analyzed animal taxa with an eye to understanding the functional priority of the whole organism and on this basisgrouped all animals into four basic categories, or “embranchments.”There was no contunuity between these embranchments, each represented a unique and distinctive space of mophological possibility andpermutations within each embranchment (that is, the differences betweencomponent taxa) were understood to reflect functional requirements.122Chapter 4Von Baer accepted Cuvier’s classificatory framework and imported it intothe research program of a teleomechanistically guided developmentalmorphology.What prefigured a type, or embranchment, for von Baer was acommon stock of Keime and Anlagen contained in the germ.
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