Moss - What genes cant do - 2003 (522929), страница 33
Текст из файла (страница 33)
Thismodel of cancer is one in which cells from somatic tissue becomeautonomous due to a mutation.The first somatic mutation hypothesis was credited to Boveri by virtueof his publication of “Zur Frage der Enstehung maligne” (1914). Hebased his ideas on the earlier cytological studies of von Hansemannon chromosomal irregularities associated with cancer. These particularirregularities, however, were also found to occur in the absence ofcarcinogenesis.
Boveri himself never observed tumors cytogenetically.Nonetheless, he attributed cancer to the formation of an aberrantchromatin complex.The somatic mutation hypothesis was a direct expression of thatgene-centered pattern of interpretation that I have also referred to asthe “phylogenetic turn.” The combination of Mendel’s laws and deVries’s mutation theory provided the theoretical foundation of thesomatic mutation hypothesis. It was additionally revised by Bauer in1928 in order to accommodate Muller’s work on inducing mutations in Drosophilia by X-ray exposure (Lawley 1994). As geneticresearch increasingly took center stage among twentieth-century American biologists, the holistic-developmental understanding of cellularautonomy became marginalized.Animal studies in experimental carcinogensis, which presupposed onlythe somatic mutation model, emerged as significant research programs.While such studies established the ability to induce experimental cancerswith carcinogens in the laboratory, they did not necessarily lend empirical support to the somatic mutation hypothesis.
Data that wouldarguably militate against the somatic mutation model were alsorecorded. In some of the earliest studies in experimental carcinogensis(1906), a German pathologist found that a dye, scharlach R, when dissolved in olive oil and injected beneath rabbit epidermis, would causecells to behave as if malignant. This finding of the production of anapparent squamous cell carcinoma was readily reproducible by otherinvestigators, but rather than being an irreversible processes, consistentDialectics of Disorder: Normalization and Pathology as Process131with a mutational hypothesis, the cells reverted to a normal state asthe influence of the dye wore off (Rous 1959). Contrary findings suchas this, however, proved to be no match for the growing gene-centered,antidevelopmental momentum.What was needed in order to harden the somatic mutation hypothesis was a reliable correlation between carcinogenesis and mutagenesis,but this proved to be elusive.
No chemical mutagen was well establisheduntil after World War II, and because the one that had emerged—mustard gas—was used as an agent of chemical warfare, publication ofany findings pertaining to it had been forcibly delayed. Prior to the availability of mustard gas the only established means for inducing mutationwas through X-ray exposure, a method discovered by H. J. Muller andapplied to Drosophilia genetics beginning in the 1920s. Muller, however,did not begin to apply this to cancer research until the 1950s.
At thattime he observed that “cancers induced by overexposure of a part of thebody to radiation often fail to show up until some 10 to 20 years afterthe cessation of the irradiation” (Lawley 1994).In addition to the experience of latency in X-ray induced cancer, observations of a strong correlation between advanced age and cancer incidence led to a “multi-hit” theory of cancer causation.
In this modelcancer is never the result of a single somatic mutation; rather, somenumber of sequential mutations are required for carcinogenesis. Initially,Muller and others proposed that as many as six mutations were necessary. But the problem with that theory is that spontaneous somaticmutation is understood to be a rare event. In order for six sequentialmutations to accumulate there would have to be an adequate amount oftime for each newly mutated cell to expand clonally, that is, give rise tonew generations of genetically identical cells such that there were enoughsecond generation cells (with the first mutation) that the chance of oneof these acquiring another mutation was higher than negligible.
Thetime frame required for five such sufficiently large clonal expansions,however, appeared to be inconsistent with the possibility of cancer’soccurring within a human lifetime. This caused the cancer research community to shift down to a two-hit model and yet “it became evident fromstudies of the development of specific types of cancer that often morethan two genetic changes are involved” (Lawley 1994).132Chapter 4Proponents of the somatic mutation theory of multistep carcinogenesishad adopted the nomenclature suggested by Peyton Rous during the1940s. Rous distinguished between initiation, which was a necessary butnot sufficient precondition for carcinogenesis, and promotion, which,given an initiated state, could end the latency period, resulting in thebeginning of phenotypic transformation and finally the progressivemalignant transformation of the cancerous tissue.
Rous himself,however, was never convinced by the somatic mutation hypothesis. Inhis studies of 1941 he found the initiation of tumors in skin painted withtar to be reversible. If skin painting was interrupted, the tumors disappeared but could be induced to reappear at precisely the same sites withrenewed application. Additionally, he found that the priming, or initiating, effect could also be achieved through the use of noncarcinogenicstimuli, such as the application of turpentine or the process of woundhealing in response to the boring of holes in rabbit ears (Lawley 1994).With words highly reminiscent of the irritation hypothesis of Virchowet al., Rous observed that:The great majority of carcinogens are merely provocative: they convert normalcells into tumor cells but have no further essential role and are degraded or leftbehind as the changed cells multiply.
Their relation to the neoplastic state maybe likened to that of ignition to combustion: a fire can be kindled in any one ofnumerous ways but, with this done, its decisive share in events is ended. Theanalogy can be pushed further: flames differ according to their ingredients andtumors differ according to the type of cell involved (Rous 1959).Addressing the somatic hypothesis more directly Rous proclaimed that“the somatic mutation hypothesis, after more than half a century,remains an analogy . .
.” (Rous 1959). Nor was Rous alone in his assessments. In his comprehensive review of the somatic mutation hypothesisBurdette (1955) concluded that “a general correlation between mutagenicity and carcinogenicity cannot be proposed from present evidence.”This opinion was echoed nearly 15 years later by Leslie Foulds in hisauthoritative review of the state of the art (Foulds 1969).Over a half a century of studies indicated that some of the mostcarcinogenic agents were not mutagenic, and that some of the mostmutagenic agents were not carcinogenic. Rous, while characterizing theeffects of carcinogens as being merely provocative, having no influenceon the nature of the cancer that resulted, offered by contrast evidenceDialectics of Disorder: Normalization and Pathology as Process133of “neoplastic viruses” which did appear to influence the nature of thecancer that followed.
He suggested that rather than somatic mutations“the neoplastic effects of the neoplastic viruses may be due to their ownactivity which is reproduced and transmitted” (Rous 1959).Even cancer biology can have its ironies. The somatic mutationhypothesis, as we will see, reached its high water mark, not by use of Xray induced mutation or through the use of chemical carcinogenesis butrather by way of studies using a neoplastic virus. And the neoplastic virusused was the very one named in honor of the founding father of tumorvirology, Peyton Rous.Oncogenes and OncogenesisThe development of the oncogene concept emerged from, and has beenclosely tied to, the history of tumor virology. The first virus clearly shownto be the cause of tumors in an animal was isolated from chickens byPeyton Rous in 1911. However, this and subsequent findings in tumorvirology had been treated as separate areas of research from that ofthe work in experimental carcinogenesis discussed above.
The notionof a tumor etiology from viral infection did not fit in with the prevalentthinking of oncologists. Fowl tumors were typically dismissed asbeing somehow irrelevant to mammalian, and especially human,cancer (Huxley 1958).The turn toward neoplastic viruses for insights into a general theoryof cancer causation received a fateful boost with the efforts of HarryRubin, who joined the laboratory of Renato Delbecco at Cal Tech in1953 in order to establish a quantitative basis for analyzing virallyinduced tumors (Rubin 1955).
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