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Understanding cancer as a formless phenomenon
Medical Hypotheses (2002) 59(1), 68–75 ª 2002 Elsevier Science Ltd. All rights reserved. doi: 10.1016/S0306-9877(02)00111-1, available online at http://www.idealibrary.com
Understanding cancer as a formless phenomenon A. Aranda-Anzaldo noma del Estado de Me xico, Toluca, Mexico Laboratorio de Biologıa Molecular, Facultad de Medicina, Universidad Auto
Summary Complex living organisms possess qualities that cannot be reduced to the simple addition of quantities. Among such qualities are a specific form and a specific organization. Thinking about morphological aspects is a prime example of the qualitative approach to biological matters. Such a morphogenetic perspective has been continuously developed, both theoretically and experimentally, along the past century, even though it is now rather marginal within a mainstream dominated by molecular biology. However, the morphogenetic outlook can be applied to the understanding of complex biological phenomena, such as cancer. This phenomenon is currently explained as a cellular problem caused by specific gene mutations and/or specific loss of gene regulation. Nevertheless, cancer is a problem that affects the whole organism. Contemporary research based on the genetic paradigm of cancer causation has led to paradoxes and anomalies that cannot be explained within such a reductionist paradigm. Here it is proposed that real, non-experimental, sporadic cancer may be understood as a conflict between an organized morphology (the organism) and a part of such a morphology that drifts towards an amorphous state (the tumour). Thus, rare, sporadic cancer in children can be the result of early disruption of the developmental constraints before the organism has achieved its morphological maturity. While common sporadic cancer in aged individuals may ensue as a result of the weakening or exhaustion of the developmental constraints that determine the morphological stability of the organism, once the organism is past its reproductive prime. ª 2002 Elsevier Science Ltd. All rights reserved.
INTRODUCTION Ontogeny is the individual development of an organism from the fertilized egg to the adult. Such a development implies the process of morphogenesis, consisting in the formation of biological structure by changing the spatial relationships of cells or tissues, or in other words: the process of bringing about changes in form in the developing embryo, so as to eventually achieve the full organic form which is proper to an individual organism of a given species. Individuation is a system’s ability to attain pattern and form from an initial condition in Received 13 June 2001 Accepted 1 November 2001 Correspondence to: Prof. Armando Aranda-Anzaldo, Laboratorio de Biologıa Molecular, Facultad de Medicina, UAEM, Apdo. Postal 428, C.P. x., Me xico. Phone: 52-7-2173552 ext: 113; Fax: 52-750000, Toluca, Edo. Me 2174142; E-mail: [email protected]
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which these properties are absent. It is, therefore, an aspect of epigenesis that characterizes ontogeny (1). Individuation is possible because the elements of the embryonic system can organize responses according to the requirements of the specific developmental conditions that exist, rather than according to a rigidly determined plan. Yet, final individuation implies that all constituents of the organism (cells, tissues, organs) are structurally and functionally integrated into a single complex whole. Such an integration and organization must be respected and maintained during the organism’s life if the organism is to survive. Thus replacement or regeneration of tissues must be guided by a general and constant normating principle, which harmoniously integrates the parts into a whole. The enormous amount of experimental evidence demonstrating this phenomenon of individuation, posed the need of finding and explaining the source and nature of the integrative ability that is manifested during individuation. It must be considered that the process of individuation continues after birth
Understanding cancer as a formless phenomenon
and it reaches completion when the organism reaches full sexual maturity and competence. Yet, once the organism is past its reproductive prime, a steady decay of the living system ensues and there is no apparent need for maintaining the constraints that guarantee the morphological stability of the organism. Otherwise, longlived, morphological stable individuals will reduce the rate of turnover within the species and may significantly reduce the variation potential of the species (2). THE MORPHOGENETIC FIELD The unit of organization that embodies the attributes of positional information in individuating systems is the morphogenetic or embryonic field. The field constitutes an embryonic system or part of such a system, that contains elements that acquire their potential properties in relation to a common source of positional information but can also re-establish the informational system, its constituent elements, and their responses following the disturbance of spatial relationships within the system. It follows then that the elements that comprise a field can exist on several structural levels. The egg of a regulative embryo is a single field: the primary field. The processes of cleavage and primary determination subdivide the primary field into smaller internal secondary fields, whose regulatory powers are restricted to a certain type of determination. These fields are equated with organforming areas and display their regulatory powers through the control of regional individuation. Thus, fields exist at both the cellular and supracellular level. A striking property of fields is that they can anticipate the need for potential formal properties independently of its apparent properties. Thus fields provide an operational definition of organic wholeness as the state of organization towards which the regulatory powers of the field are directed. Organ-forming areas are examples of fields. The limb- and eye-forming areas are dependent on field properties for their development. In each of these areas, the field, as a whole, is determined to become a given organ, but the cells within it are individually restricted as to the part of that organ they can make. Their final differentiation is controlled solely by their position within the field. Fields determine gene function, since the positional information of the field is converted into distinctive patterns of gene function. Also, they persist long after the morphogenetic processes associated with them have been completed, as shown by the formation of supernumerary organs after the normal organ has appeared. Field properties are concentrated in a centre, although the physical nature of such a centre is rather difficult to pinpoint, since cells located in the centre or region of maximal field properties do not differ from those in peª 2002 Elsevier Science Ltd. All rights reserved.
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ripheral areas of the field. Hence, their properties derive from their location and not from intrinsic constituents. Fields can recognize different spatial relationships and they regulate growth as well as differentiation. Therefore, generation of a particular structure in an organism depends not only on the properties of the elements making up the structure (cells in this case) but upon additional influences affecting the spatial order that emerges from cell–cell interactions. Embryonic or morphogenetic fields provide the constraints on cellular function that are necessary for differentiation and individuation. Embryological systems cannot be reduced beyond their constituent fields without the disappearance of the very properties that characterize ontogeny. The egg is a field that can be subdivided only to the extent that it preserves its field properties. Later in development, the original single field of the egg becomes subdivided into smaller, more restricted fields, which have essentially the same basic properties operating on a smaller scale. (for a thorough discussion of morphogenetic fields see: (3–6).) THE FORMLESS NATURE OF MALIGNANT TUMOURS Malignant tumours display two main characteristics: cellular abnormalities and invasion of the surrounding tissues. The standard cellular criteria include a local increase in cell number, loss of the normal regular arrangement of cells, variation in cell shape and size, increase in nuclear size and density of staining (both of which reflect an increase in total DNA), an increase in mitotic activity (increased cell division), and the presence of abnormal mitoses and chromosomes. However, the only definitive evidence of malignancy is invasion of underlying tissues. The tumour cells destroy and replace normal tissues, also they invade the blood and lymphatic vessels and then, they may be carried to other parts of the body and develop into secondary tumours (metastases) in distant sites. This type of spread is the major problem in the treatment of malignant tumours since a tumour that remains localized to its site of origin can usually be removed surgically or destroyed by radiation. Malignant tumours have no well defined capsule and the tumour cells grow in a much more disorganized form than is found in benign tumours (7). Malignant tumours represent dynamic entities where there is a gradual acquisition of new characters as the tumour develops. This process is called tumour progression and the general trend is for tumours to go from bad to worse, showing a movement towards a more aggressive behaviour and an increase in their ability to invade. All cells in a single malignant tumour are not identical but there is a range of populations of cells expressing many different characters (phenotypes). Cells in a tumour may show differences in structure, morphology, growth rate, Medical Hypotheses (2002) 59(1), 68–75
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karyotype or behaviour. This diversity is a consequence of tumour progression (8). However, metastasis is an inefficient process and the majority of tumour cells released into the circulation do not give rise to secondary tumours. There is no specific morphogenetic field associated with cancer. Cancer morphogenesis is aberrant. Malignant tumours show no defined tissue architecture. In fact, solid tumour growth leads to the production of aberrant masses known as spheroids, so poorly irrigated that the cells occupying the central regions of such spheroids become necrotic for lack of oxygen and nutrients. Also, the blood vessels in solid tumours show aberrant configurations that lead them to bleed rather easily (9). Thus, a malignant tumour is going nowhere from the morphogenetic point of view. Phenomenologically speaking, a malignant tumour is meaningless because it cannot survive as a separate entity with defined morphology, in that sense it is completely different from a true parasite which may survive the demise of its current host and it has developed strategies for its introduction into new hosts. There is no natural way for introducing a tumour into a new host. Complex systems such as multicellular living organisms are more than the sum of their elements or parts. They possess qualities that cannot be reduced to the simple addition of quantities. Among such qualities are a specific form and a specific organization. Cancer cells do not respect morphology nor the organization of the host. They grow beyond their expected boundaries, they occupy the wrong places within the organism. Indeed, there is no place for the malignant tumour within the organism, that is the main problem associated with malignant tumours. A cancer cell is wrong in relation to the rest of the organism, yet it performs its cellular functions rather efficiently, but such cells cannot form a coherent whole. The tumour itself never becomes organized at least into a semi-autonomous system divided into well-defined parts with more or less specialized functions. Tumour progression is characterized by chaotic cycles of mass growth followed by cellular destruction. The more malignant the cells of a tumour are, the farthest the tumour is from showing any degree of morphological organization. Metastasis is quite an inefficient process, most tumour outgrowths are bound for spontaneous destruction or involution due to the lack of internal organization, a situation that impairs the flow of oxygen and nutrients into the tumour. CURRENT EXPERIMENTAL APPROACHES DO NOT ADDRESS THE CAUSES OF SPORADIC CANCER For rather obvious reasons, cancer research favours the study of model systems where brief exposure to a strong Medical Hypotheses (2002) 59(1), 68–75
carcinogen or outright genetic manipulation produces a high incidence of cancer within weeks or months. But most naturally occurring cancers arise at a slow rate after incubation periods of many years. Cancer is currently understood as a genetic or cellular disease which results either from the over-expression or lack of expression of certain genes, but also from the abnormal activity or lack of activity of the proteins coded by such altered genes. Explicit definitions of cancer as a genetic disease can be found in widely read reference sources (10–13). Many experimental protocols and the known epidemiology of cancer clearly show that a single mutation in a single gene is not enough to cause cancer. In 1999 it was shown that at least four independent genetic events are necessary for malignant transformation of normal human cells in vitro (14). However, another group realized similar manipulations, targeting the same four genetic functions, without achieving any success in transforming primary human cells (15). It is known that the mutation rates of somatic cells are very low, and the mutation rates of most types of cancer cells in culture are usually not greater than those of non-malignant cells (16). Therefore, it is highly unlikely that such four experimentally induced genetic events (mutations), might occur spontaneously within a single cell in the appropriate order and fashion (since some are inactivating mutations while others must be activating mutations). A simple estimate, based on the known mutation rate of somatic human cells of around 10 12 per nucleotide per generation (17,18), suggests the actual impossibility of such a stepwise accumulation of four independent mutations within a single cell and within the average life span of a human being (2). Moreover, a cell that is accumulating sporadic tumour-promoting mutations is usually surrounded by normal cells that can suppress the propensity of the mutant cell to proliferate. Thus, it has been suggested that the transition from normal to transformed cell requires the previous acquisition of inherent genetic instability (19). But in order for cancer to progress such an instability must be a feature of a group of cells that become a ‘field of cancerization’ that might promote tumour formation. In standard neo-Darwinian theory it is assumed that populations adapt through the appearance and subsequent fixation of beneficial mutations that increase the fitness of the individuals. In large populations such as cells in culture, beneficial mutations may arise frequently enough that two or more are present in independent lineages. In the asexual system the lineages created by these beneficial mutations will compete with one another, so that only those with the largest effect on fitness shall be fixed. This phenomenon is known as clonal interference. Thus, asexual populations must fix beneficial mutations sequentially (20). It is rather comª 2002 Elsevier Science Ltd. All rights reserved.
Understanding cancer as a formless phenomenon
mon that transient but frequent beneficial mutations do not achieve fixation because the presence of other interfering beneficial mutations within the population (21). Experiments designed to evaluate the effect of clonal interference, show that the larger the population size is (which means, the stronger the possible clonal interference). then the larger the magnitude of the beneficial effect needed to fix a mutation is. A very important observation concerning the evolution of asexual populations (such as cells), is that resident populations (for example, normal cells) are protected from invaders (such as tumour cells) simply because of their numerical advantage. Thus, a supposedly high-fitness clone seeded at a low frequency into a resident population of low-fitness variants will be displaced by the low-fitness competitors (22,23). Indeed, the high-fitness clone needs to achieve a certain initial frequency threshold in order to out-compete the low-fitness variants in the resident population. Therefore, one of the key steps towards sporadic cancer must be the development of a field of mutant cells (24). It is obvious that whichever factors are responsible for establishing a field of cancerization, such factors must be acting against the normal local and global constraints that characterize the morphogenetic field of the affected organism. Experiments with cells transformed by oncogenes that are over-expressed by means of strong, heterologous promoters (such as viral promoters), are rather misleading as models for cancer development. For example, in primary cancers mutated ras genes are expressed at the same rate as their normal counterparts in normal proliferating cells. Actually, there is no evidence that any of the so-called oncogenes is expressed at a higher rate in a primary cancer cell than in its normal counterpart (25–28). Moreover, often the model tumours are lymphomas, leukaemias or sarcomas which altogether represent less than 10% of naturally occurring tumours, while almost 90% of human tumours are epithelial in origin (29). Recent technological advances that make the comparison of the gene-expression profiles of thousands of genes feasible, suggest that many of the so-called oncogenes are actually non-expressed or lowly expressed in tumour tissues (30–33). The gene expression patterns of 8,102 genes has been compared in tumour samples from different patients presenting breast cancer of a similar hystological type and stage. The results show that gene expression patterns of two tumour samples from the same individual were always more similar to each other than either was to any other sample from a different patient. Thus suggesting that each tumour is gentically different and therefore, there is no common or typical pattern of gene expression characteristic of a specific kind of cancer (33). ª 2002 Elsevier Science Ltd. All rights reserved.
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Currently, there are more than 100 oncogenes and at least 17 tumour suppressor genes have been described, though so far, only four qualify as bonafide tumour suppressors (34–37). Indeed, the criteria for considering a gene as a tumour suppressor are far from being universally established (38). It is likely that many more shall be discovered; all these genes are involved either in cellsignalling, control of the cell cycle or control of gene expression. Basically, all kinds of genes which are not coding for essential metabolic enzymes or essential structural proteins are likely to be found in a mutated state in one or another form of cancer, or in one or another type of cell transformed in vitro. This is because such mutations do not put at risk the survival of the individual cell (at least in the short term). Most mutations that are really incompatible with cellular life are those in genes which code for key metabolic enzymes or structural proteins. Indeed, the somatic mutations commonly observed in tumour cells may be a consequence rather than the cause of cancer, since such mutations occur in gene functions that are rather irrelevant for both the individual and species survival once the organism is past its reproductive prime. The ultimate fate of a gene that ceases to be useful is to accumulate mutations until it is no long recognizable (39). The gradual accumulation of mutations in the absence of selective pressure is called genetic drift (40). Once the organism has contributed offspring it becomes dispensable as a vehicle for survival and then genetic drift in absence of strong natural selection might ensue. Yet, only the cells displaying mutations in functions that are not critical for cell survival shall be available for sampling, while mutations in key cellular functions lead to cell death. This situation produces the false impression that the observed somatic mutations are the cause of cancer. To extrapolate conclusions from the observation of very rare cancer-prone syndromes (such as Li-Fraumeni syndrome or familial retinoblastoma), in order to explain the causality of the commonly occurring cancers can be quite misleading. This is because the mutations causally associated with such rare syndromes, may be consequences but not causes in the case of the sporadic cancers (2). CHROMOSOME INSTABILITY AND NUCLEAR MORPHOLOGY Now there is important evidence that genome-wide instability precedes the appearance of mutations in key proto-oncogenes and the eventual development of certain common forms of cancer (41–44). It has been observed that in most colorectal cancers and probably in many other cancer types, a chromosomal instability leading to aneuploidy is observed. This seems to be an
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early feature of the transformed cells (41). The source of such instability has been variously attributed. Either to mutations in genes controlling the repair of base mismatches in DNA (45). or to mutations in genes controlling the assembly of the mitotic spindle, thus leading to abnormal partitioning of the post-G2 4n chromosome complement between the daughter cells (42–46). It has been shown that aneuploidy (variation in the modal chromosome number), which at least for the last 100 years has been regarded as the most common feature of malignant tumour cells (47), correlates 100% with cell transformation induced by non-genotoxic agents unable to cause mutations in the cellular DNA (48). Moreover, the four artificially induced genetic events, apparently necessary for transforming primary human cells (14), were not directly responsible for the transformed cell phenotype. since it took more than 60 population doublings to generate the tumour cells. Indeed, the tumour cells were clonal even though the gene transfers were polyclonal (49). Thus, the truly basic feature was that the resulting tumour cells were aneuploid. Therefore, aneuploidy appears to be a basic characteristic of tumour cells that needs not to be related to mutations (either specific or non-specific) in the DNA sequence. Indeed, theoretical models suggest that the metabolic imbalance resulting from the aneuploid condition typical of tumour cells, could be the actual cause of cell transformation to a malignant state, without the need for any specific kind of oncogene or tumour-suppressor gene mutation (31,49). Tight control of cell ploidy is important for as long as the organism reaches and passes the reproductive age, thereafter such a control becomes non-relevant for both individual and species fitness (2). For example, the number of abnormal metaphases in older hepatectomized mice is much higher when compared to the number observed in younger animals (50). Aneuploidy, translocations and chromosome end-to-end fusions have been shown to be higher in lymphocytes and fibroblasts of elderly humans compared with younger ones (51). The available evidence suggests that ageing is associated with an overall reduction of genome stability. Our current knowledge of the higher-order structure within the cell nucleus shows that chromosome disposition inside the nucleus is highly organized and that the genetic material seems to maintain a set of constant specific interactions with the nuclear substructure, according to the cell type and the state of cell differentiation. Such interactions are very important for nuclear physiology but also. represent topological parameters which define a complex nuclear morphology (52–56). Therefore, chromosome instability and aneuploidy represent major alterations of the internal nuclear morphology. These alterations may be the evidence, at the
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cellular level, of perturbed interactions between the would-be tumour cells and the morphogenetic field the whole organism. It is known that any factor that alters the topological parameters within the cell nucleus leads to wholesale perturbation of nuclear functions, including gene expression (57–59). SPONTANEOUS REGRESSION OF CANCER IS INCOMPATIBLE WITH GENETIC CAUSALITY If cancer were truly a phenomenon due to the accumulation of mutations in a few key genes, then once the threshold has been crossed, there should be no way back towards normality. Yet, this conclusion is not consistent with the thousands of spontaneous cancer regressions quoted in the specialized literature (60). Such regressions cannot be attributed to the action of a hypothetical ‘immune surveillance’ since no difference in primary tumour development and incidence has been observed between athymic nude mice lacking T cells, and syngenic wild-type mice (61,62). Moreover, if malignancy is not a strictly genetic phenomenon, there should be some evidence for its reversibility. In leopard frogs, isolated nuclei from Lucke carcinoma cells (a kidney tumour induced by a herpesvirus) have been introduced into activated, enucleated frog eggs. Following nuclear transplantation, a small proportion of the nuclei allowed the development of tadpoles with normal, differentiated tissues (63). Mouse teratocarcinomas contain pluripotential embryonal carcinoma cells. The introduction of such cells into the embryonic blastocyst allows incorporation into the inner cell mass, and hence to the embryo. Using genetic markers it has been shown that the embryonal carcinoma cells contribute to most of the normal tissues of the mouse, although such mice have a higher incidence of teratocarcinomas. It has also been found that the descendants of embryonal cell lines can form a normal germ line (64,65). Thus, heritable normal behaviour can be restored to certain pluripotent cancer cells by transplantation, or cultivation, in a suitable environment. It is highly unlikely that the restored normal cellular behaviour results from the specific reversion of multiple specific gene mutations that are claimed to be the cause of cancer. A very interesting finding is that malignant neoplasms arise when normal rat ovarian tissue is transplanted into normal rat spleen (66). Thus, normal tissue situated in the wrong location within the context of the organism, degenerates into a tumour. On the other hand, tumour cells introduced into a blastocyst become normal and contribute to the formation of organized bodily structures (64,65). These facts are quite paradoxical, considering that within the early embryo there is an elevated amount of growth factors that should
ª 2002 Elsevier Science Ltd. All rights reserved.
Understanding cancer as a formless phenomenon
speed up the growth of the tumour cells, because such cells already require less growth factors than normal cells in order to stimulate their growth. Moreover, there is no obvious way that the simple change in the location of the ovarian cells might be inducing the somatic mutations which, according to the standard paradigm, are claimed to be the causal origin of cancer. Yet, these results can be understood on the one hand, as a normalization of the tumour cells by the action of a strong morphogenetic field associated with a developing system. On the other hand, as evidence that the loss of coherence (artificially induced in this case) between a set of bodily cells and the morphogenetic field of an adult organism (about to exhaust its developmental potential), induces tumour formation. ON THE NEED OF THEORETICAL ENTITIES IN BIOMEDICINE Currently, among the natural sciences, biomedicine is the last bulwark of naive empiricism, characterized by an almost indiscriminate accumulation of observational and experimental data, which flood an amazing number of journals, but with few theoretical frameworks that may help to make sense of such data. It remains to be explored by sociologists and historians of science why biomedical scientists are so uncomfortable with theoretical entities. Thus, in cosmology and physics, one may speak of ‘superstrings’, ‘time-warps’, ‘gluons’ or ‘charmed quarks’, without worrying about the fact that such entities are not endowed with a ‘rock-hard’ materiality. Instead, the outstanding criteria for assuming the existence of such entities is whether they allow us to understand and to predict the behaviour of physical systems. On the other hand, the only ‘deep’ theory sustaining most of contemporary biology is Darwinian evolution, supported by observation of fossils, stratigraphic data, the properties of contemporary organisms and more recently, by some biochemical and molecular data. Nevertheless, evolutionary biology is weakly predictive, being closer to history. Indeed, for many a critic, biological science is mostly storytelling, a bundle of ‘just so’ stories (67). Moreover, molecular biologists, spend most of the time looking at dark bands and spots in gels and thinking that such spots correspond, for example, to ‘rock-hard’ interactions between proteins and DNA. Without considering that such molecular interactions are closer to the quantum-mechanical level of measurement and explanation, than to the ‘width, length and weight’ approach of macroscopic experience. Perhaps this rather obsessive attachment to empirical evidence in the biomedical sciences (which -vis the widespread aclooks rather incongruous vis-a ceptation of Darwin’s narrative), is a remainder of late positivism and its fear of metaphysical entities. ª 2002 Elsevier Science Ltd. All rights reserved.
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Yet as shown in Margenau’s analysis of deep physical theories, the explanatory and predictive success of these theories is based on introducing many levels of abstraction, from objects to microscopic entities to particles to force fields to probability distribution functions, etc. (68). All these theoretical constructs are based on metaphysical requirements that are applied de facto by scientists, when choosing between constructs and theories, without necessarily thinking about their philosophical implications. The metaphysical criteria identified by Margenau’s are logical fertility, multiple connections, permanence and stability, extensibility, causality, and simplicity and elegance. Logical fertility requires that the constructs shall be formulated as to permit logical manipulations. The theoretical structure of science consists of a set of connections between constructs (be it formal, that is mathematical, or epistemic). Permanence and stability mean that the elements of the theory may not be arbitrarily altered to fit experience. The extensibility of constructs is a property that allows generalization of results, and the principle of causality asserts that a given state is invariably followed in time by another specifiable state. Finally, simplicity and elegance apply when two theories present themselves as competent explanations of a given complex of sensory experience, then science decides in favour of the simpler one (this corresponds to Ockham’s razor). Currently, the theory of the morphogenetic field might satisfy most of the aforementioned metaphysical principles save the principle of causality. Thus, its current level of explanation is rather phenomenological, but science has other examples of phenomenological theories and ‘laws’ (for example, the second principle of thermodynamics). Indeed, principles such as the ‘central dogma’ of molecular biology (information flows from DNA to RNA to protein) have already been modified, under pressure of empirical evidence, in an ad hoc way (information might flow from DNA to RNA and then back to DNA, via reverse transcription, and then to protein). Thus failing to satisfy the metaphysical criteria of stability and permanence. While ‘laws’ such as Mendel’s laws, apply only to a limited number of biological entities (sexually reproducing beings) which also carry non-Mendelian genetic traits (such as the transposons). Moreover, the status of the principle of natural selection, which sustains Darwinian evolution, is still a matter of debate (69). CONCLUSION The morphogenetic field, as a working principle, theoretical construct or abstract descriptive tool, is closer to any criteria of scientific rationality than any empirical Medical Hypotheses (2002) 59(1), 68–75
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gathering of gene-product interactions (such as those described in the genetic paradigm for cancer). The concept of morphogenetic field applied to the problem of cancer gives us clues to a possible intelligible ontology for such a phenomenon, which is lacking altogether in the current genetic paradigm. Since wholesale affectation of an organism’s organization, by local molecular disturbances affecting a limited number of cells, is assumed but it is never explained by such a paradigm. The alternative view presented in this paper, suggests that cancer is first of all an organic problem that cannot be exclusively reduced to the cellular, genetic or molecular level.Secondly, such a view suggests that cancer might be the result of a conflict between an organized morphology (the organism) and a part of such a morphology that drifts towards an amorphous state (the tumour). A fully developed morphogenetic perspective on cancer is being published elsewhere (70). Yet as a summing up conclusion it is worth to remember the following words by Sir David Smithers: Cancer is no more a disease of cells than a traffic jam is a disease of cars. A lifetime study of the internal combustion engine would not help anyone to understand our traffic problems’ (71).
ACKNOWLEDGMENTS xico (grant: 33539-N) and UAEM Supported by CONACYT-Me (grant: 1447/2000).
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34. Bishop J. M. Molecular themes in oncogenesis. Cell 1991; 64: 235–248. 35. Marshall C. J. Tumor suppressor genes. Cell 1991; 64: 313–326. 36. Kinzler K. W., Vogelstein B. Gatekeepers and caretakers. Nature 1997; 386: 761–763. 37. Pennisi E. New tumor suppressor found twice. Science 1997; 275: 1876–1878. 38. Clurman B., Groudine M. Killer in search of a motive?. Nature 1997; 389: 122–123. 39. Lewin B. In: Genes; vol. VII. Oxford: Oxford University Press, 2000: p. 77. 40. Watson J. D., Gilman M., Witkowski J., Zoller M. In: Recombinant DNA, 2nd ed. New York: Freeman–Scientific American Books, 1992: p. 443. 41. Lengauer C., Kinzler K. W., Vogelstein B. Genetic instability in colorectal cancers. Nature 1997; 386: 616–620. 42. Cahill D. P., Lengauer C., Yu J., Riggins G. J., Willson J. K. V., Markowitz S. D. et al. Mutations of mitotic checkpoint genes in human cancers. Nature 1998; 392: 300–303. 43. Fodde R., Kuipers J., Rosenberg C. et al. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 2001; 3: 433–438. 44. Kaplan K. B., Burds A. A., Swedlow J. R., Bekir S. S., Sorger P. €thke I. S. A role for the adenomatous polyposis coli K., Na protein in chromosome segregation. Nat Cell Biol 2001; 3: 429–432. 45. Richards B., Zhang H., Phera G., Meuth M. Conditional mutator phenotypes in hMSH2-deficient tumor cell lines. Science 1997; 277: 1523–1526. 46. Michel L. S., Liberal V., Chatterjee A. et al. MAD2 haploinssuficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 2001; 409: 355–359. 47. Boveri T. Zur Frage der Enstehung Malignant Tumoren. Jena: Gustav Fisher Verlag, 1914. 48. Li R., Yerganian G., Duesberg P., Kraemer A., Willer C., Rausch C. et al. Aneuploidy correlated 100% with chemical transformation of Chinese hamster cells. Proc Natl Acad Sci USA 1997; 94: 14506–14511. 49. Li R., Sonik A., Stindl R., Rasnick D., Duesberg P. Aneuploidy vs. gene mutation hypothesis of cancer: recent study claims mutation but is found to support aneuploidy. Proc Natl Acad Sci USA 2000; 97: 3236–3241. 50. Curtis H., Crowley C. Chromosome aberrations in liver cells in relation to the somatic mutation theory of ageing. Radiat Res 1963; 19: 337–344. 51. Ly D. H., Lockhart D. J., Lerner R. A., Schultz P. G. Mitotic misregulation and human ageing. Science 2000; 287: 2486– 2492. 52. Aranda-Anzaldo A. On the role of chromatin higher-order structure and mechanical interactions in the regulation of gene expression. Speculat Sci Technol 1989; 12: 163–176. 53. Pienta K. J., Coffey D. S. Cellular harmonic information transfer through a tissue tensegruty-matrix system. Med Hypotheses 1991; 34: 88–95.
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54. Razin S. V., Gromova I. I., Iarovaia O. V. Specificity and functional significance of DNA interaction with the nuclear matrix: new approaches to clarify old questions. Int Rev Cytol 1995; 162B: 405–449. 55. Maniotis A. J., Bojanowski K., Ingber D. Mechanical continuity and reversible chromosome disassembly within intact genomes removed from living cells. Int Cell Biochem 1997; 65: 114–130. 56. Marshall W. F., Straight A., Marko J. F., Swedlow J., Dernburg A., Belmont A. et al. Interphase chromosomes undergo constrained diffusional motion in living cells. Curr Biol 1997; 7: 930–939. 57. Aranda-Anzaldo A., Dent M. A. R. Loss of DNA supercoiling and organization in cells infected by herpes simplex virus type 1. Res Virol 1997; 148: 397–408. 58. Aranda-Anzaldo A. The normal association between newly replicated DNA and the nuclear matrix is abolished in cells infected by herpes simplex virus type 1. Res Virol 1998; 149: 195–208. 59. Aranda-Anzaldo A., Orozco-Velasco F., Garcıa-Villa E., Gariglio P. p53 is a rate-limiting factor in the repair of higher-order DNA structure. Biochim Biophys Acta 1999; 1446(3): 181–192. 60. Challis G. B., Stam H. J. The spontaneous regression of cancer. A review of cases from 1900 to 1987. Acta Oncol 1990; 29(5): 545–550. 61. Stutman O. Spontaneous tumors in nude mice: effect of the viable yellow gene. Exp Cell Biol 1979; 47: 129–135. 62. Stutman O. Chemical carcinogenesis in nude mice: comparison between nude mice from homozygous and heterozygous matings and effect of age and carcinogen dose. J Natl Cancer Inst 1979; 2: 353–358. 63. Weiss R. A. Understanding carcinogenesis. In: L. M. Franks, N. M. Teich (eds). Introduction to the Cellular and Molecular Biology of Cancer. Oxford: Oxford University Press, 1991: 510–514. 64. Papaioannou V. E., Gardner R. L., McBurney M. W., Babinet B., Evans M. J. Participation of cultured teratocarcinoma cells in mouse embryogenesis. J Embryol Exp Morphol 1978; 44: 93–104. 65. Illmensee K., Stevens L. C. Teratomas and chimeras. Sci Amer 1979; 240(4): 120–132. 66. Biskind M. S., Biskind G. S. Development of tumors in the rat ovary after transplantation in the spleen. Proc Soc Exp Biol Med 1944; 55: 176. 67. McCloskey D. N. Once upon a time there was a theory. Sci Amer 1995; 272(February): 19. 68. Margenau H. The Nature of Physical Reality. Woodbridge: Ox Bow Press, 1977. 69. Aranda-Anzaldo A. On natural selection and Hume’s second problem. Evol Cognition 1998; 4(2): 156–172. 70. Aranda-Anzaldo A. Towards a morphogenetic perspective on cancer. Riv Biol/Biol Forum 2002; 95(1): 35–62. 71. Smithers D. W. Lancet 1962; i: 443.
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Understanding cancer as a formless phenomenon A. Aranda-Anzaldo noma del Estado de Me xico, Toluca, Mexico Laboratorio de Biologıa Molecular, Facultad de Medicina, Universidad Auto
Summary Complex living organisms possess qualities that cannot be reduced to the simple addition of quantities. Among such qualities are a specific form and a specific organization. Thinking about morphological aspects is a prime example of the qualitative approach to biological matters. Such a morphogenetic perspective has been continuously developed, both theoretically and experimentally, along the past century, even though it is now rather marginal within a mainstream dominated by molecular biology. However, the morphogenetic outlook can be applied to the understanding of complex biological phenomena, such as cancer. This phenomenon is currently explained as a cellular problem caused by specific gene mutations and/or specific loss of gene regulation. Nevertheless, cancer is a problem that affects the whole organism. Contemporary research based on the genetic paradigm of cancer causation has led to paradoxes and anomalies that cannot be explained within such a reductionist paradigm. Here it is proposed that real, non-experimental, sporadic cancer may be understood as a conflict between an organized morphology (the organism) and a part of such a morphology that drifts towards an amorphous state (the tumour). Thus, rare, sporadic cancer in children can be the result of early disruption of the developmental constraints before the organism has achieved its morphological maturity. While common sporadic cancer in aged individuals may ensue as a result of the weakening or exhaustion of the developmental constraints that determine the morphological stability of the organism, once the organism is past its reproductive prime. ª 2002 Elsevier Science Ltd. All rights reserved.
INTRODUCTION Ontogeny is the individual development of an organism from the fertilized egg to the adult. Such a development implies the process of morphogenesis, consisting in the formation of biological structure by changing the spatial relationships of cells or tissues, or in other words: the process of bringing about changes in form in the developing embryo, so as to eventually achieve the full organic form which is proper to an individual organism of a given species. Individuation is a system’s ability to attain pattern and form from an initial condition in Received 13 June 2001 Accepted 1 November 2001 Correspondence to: Prof. Armando Aranda-Anzaldo, Laboratorio de Biologıa Molecular, Facultad de Medicina, UAEM, Apdo. Postal 428, C.P. x., Me xico. Phone: 52-7-2173552 ext: 113; Fax: 52-750000, Toluca, Edo. Me 2174142; E-mail: [email protected]
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which these properties are absent. It is, therefore, an aspect of epigenesis that characterizes ontogeny (1). Individuation is possible because the elements of the embryonic system can organize responses according to the requirements of the specific developmental conditions that exist, rather than according to a rigidly determined plan. Yet, final individuation implies that all constituents of the organism (cells, tissues, organs) are structurally and functionally integrated into a single complex whole. Such an integration and organization must be respected and maintained during the organism’s life if the organism is to survive. Thus replacement or regeneration of tissues must be guided by a general and constant normating principle, which harmoniously integrates the parts into a whole. The enormous amount of experimental evidence demonstrating this phenomenon of individuation, posed the need of finding and explaining the source and nature of the integrative ability that is manifested during individuation. It must be considered that the process of individuation continues after birth
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and it reaches completion when the organism reaches full sexual maturity and competence. Yet, once the organism is past its reproductive prime, a steady decay of the living system ensues and there is no apparent need for maintaining the constraints that guarantee the morphological stability of the organism. Otherwise, longlived, morphological stable individuals will reduce the rate of turnover within the species and may significantly reduce the variation potential of the species (2). THE MORPHOGENETIC FIELD The unit of organization that embodies the attributes of positional information in individuating systems is the morphogenetic or embryonic field. The field constitutes an embryonic system or part of such a system, that contains elements that acquire their potential properties in relation to a common source of positional information but can also re-establish the informational system, its constituent elements, and their responses following the disturbance of spatial relationships within the system. It follows then that the elements that comprise a field can exist on several structural levels. The egg of a regulative embryo is a single field: the primary field. The processes of cleavage and primary determination subdivide the primary field into smaller internal secondary fields, whose regulatory powers are restricted to a certain type of determination. These fields are equated with organforming areas and display their regulatory powers through the control of regional individuation. Thus, fields exist at both the cellular and supracellular level. A striking property of fields is that they can anticipate the need for potential formal properties independently of its apparent properties. Thus fields provide an operational definition of organic wholeness as the state of organization towards which the regulatory powers of the field are directed. Organ-forming areas are examples of fields. The limb- and eye-forming areas are dependent on field properties for their development. In each of these areas, the field, as a whole, is determined to become a given organ, but the cells within it are individually restricted as to the part of that organ they can make. Their final differentiation is controlled solely by their position within the field. Fields determine gene function, since the positional information of the field is converted into distinctive patterns of gene function. Also, they persist long after the morphogenetic processes associated with them have been completed, as shown by the formation of supernumerary organs after the normal organ has appeared. Field properties are concentrated in a centre, although the physical nature of such a centre is rather difficult to pinpoint, since cells located in the centre or region of maximal field properties do not differ from those in peª 2002 Elsevier Science Ltd. All rights reserved.
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ripheral areas of the field. Hence, their properties derive from their location and not from intrinsic constituents. Fields can recognize different spatial relationships and they regulate growth as well as differentiation. Therefore, generation of a particular structure in an organism depends not only on the properties of the elements making up the structure (cells in this case) but upon additional influences affecting the spatial order that emerges from cell–cell interactions. Embryonic or morphogenetic fields provide the constraints on cellular function that are necessary for differentiation and individuation. Embryological systems cannot be reduced beyond their constituent fields without the disappearance of the very properties that characterize ontogeny. The egg is a field that can be subdivided only to the extent that it preserves its field properties. Later in development, the original single field of the egg becomes subdivided into smaller, more restricted fields, which have essentially the same basic properties operating on a smaller scale. (for a thorough discussion of morphogenetic fields see: (3–6).) THE FORMLESS NATURE OF MALIGNANT TUMOURS Malignant tumours display two main characteristics: cellular abnormalities and invasion of the surrounding tissues. The standard cellular criteria include a local increase in cell number, loss of the normal regular arrangement of cells, variation in cell shape and size, increase in nuclear size and density of staining (both of which reflect an increase in total DNA), an increase in mitotic activity (increased cell division), and the presence of abnormal mitoses and chromosomes. However, the only definitive evidence of malignancy is invasion of underlying tissues. The tumour cells destroy and replace normal tissues, also they invade the blood and lymphatic vessels and then, they may be carried to other parts of the body and develop into secondary tumours (metastases) in distant sites. This type of spread is the major problem in the treatment of malignant tumours since a tumour that remains localized to its site of origin can usually be removed surgically or destroyed by radiation. Malignant tumours have no well defined capsule and the tumour cells grow in a much more disorganized form than is found in benign tumours (7). Malignant tumours represent dynamic entities where there is a gradual acquisition of new characters as the tumour develops. This process is called tumour progression and the general trend is for tumours to go from bad to worse, showing a movement towards a more aggressive behaviour and an increase in their ability to invade. All cells in a single malignant tumour are not identical but there is a range of populations of cells expressing many different characters (phenotypes). Cells in a tumour may show differences in structure, morphology, growth rate, Medical Hypotheses (2002) 59(1), 68–75
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karyotype or behaviour. This diversity is a consequence of tumour progression (8). However, metastasis is an inefficient process and the majority of tumour cells released into the circulation do not give rise to secondary tumours. There is no specific morphogenetic field associated with cancer. Cancer morphogenesis is aberrant. Malignant tumours show no defined tissue architecture. In fact, solid tumour growth leads to the production of aberrant masses known as spheroids, so poorly irrigated that the cells occupying the central regions of such spheroids become necrotic for lack of oxygen and nutrients. Also, the blood vessels in solid tumours show aberrant configurations that lead them to bleed rather easily (9). Thus, a malignant tumour is going nowhere from the morphogenetic point of view. Phenomenologically speaking, a malignant tumour is meaningless because it cannot survive as a separate entity with defined morphology, in that sense it is completely different from a true parasite which may survive the demise of its current host and it has developed strategies for its introduction into new hosts. There is no natural way for introducing a tumour into a new host. Complex systems such as multicellular living organisms are more than the sum of their elements or parts. They possess qualities that cannot be reduced to the simple addition of quantities. Among such qualities are a specific form and a specific organization. Cancer cells do not respect morphology nor the organization of the host. They grow beyond their expected boundaries, they occupy the wrong places within the organism. Indeed, there is no place for the malignant tumour within the organism, that is the main problem associated with malignant tumours. A cancer cell is wrong in relation to the rest of the organism, yet it performs its cellular functions rather efficiently, but such cells cannot form a coherent whole. The tumour itself never becomes organized at least into a semi-autonomous system divided into well-defined parts with more or less specialized functions. Tumour progression is characterized by chaotic cycles of mass growth followed by cellular destruction. The more malignant the cells of a tumour are, the farthest the tumour is from showing any degree of morphological organization. Metastasis is quite an inefficient process, most tumour outgrowths are bound for spontaneous destruction or involution due to the lack of internal organization, a situation that impairs the flow of oxygen and nutrients into the tumour. CURRENT EXPERIMENTAL APPROACHES DO NOT ADDRESS THE CAUSES OF SPORADIC CANCER For rather obvious reasons, cancer research favours the study of model systems where brief exposure to a strong Medical Hypotheses (2002) 59(1), 68–75
carcinogen or outright genetic manipulation produces a high incidence of cancer within weeks or months. But most naturally occurring cancers arise at a slow rate after incubation periods of many years. Cancer is currently understood as a genetic or cellular disease which results either from the over-expression or lack of expression of certain genes, but also from the abnormal activity or lack of activity of the proteins coded by such altered genes. Explicit definitions of cancer as a genetic disease can be found in widely read reference sources (10–13). Many experimental protocols and the known epidemiology of cancer clearly show that a single mutation in a single gene is not enough to cause cancer. In 1999 it was shown that at least four independent genetic events are necessary for malignant transformation of normal human cells in vitro (14). However, another group realized similar manipulations, targeting the same four genetic functions, without achieving any success in transforming primary human cells (15). It is known that the mutation rates of somatic cells are very low, and the mutation rates of most types of cancer cells in culture are usually not greater than those of non-malignant cells (16). Therefore, it is highly unlikely that such four experimentally induced genetic events (mutations), might occur spontaneously within a single cell in the appropriate order and fashion (since some are inactivating mutations while others must be activating mutations). A simple estimate, based on the known mutation rate of somatic human cells of around 10 12 per nucleotide per generation (17,18), suggests the actual impossibility of such a stepwise accumulation of four independent mutations within a single cell and within the average life span of a human being (2). Moreover, a cell that is accumulating sporadic tumour-promoting mutations is usually surrounded by normal cells that can suppress the propensity of the mutant cell to proliferate. Thus, it has been suggested that the transition from normal to transformed cell requires the previous acquisition of inherent genetic instability (19). But in order for cancer to progress such an instability must be a feature of a group of cells that become a ‘field of cancerization’ that might promote tumour formation. In standard neo-Darwinian theory it is assumed that populations adapt through the appearance and subsequent fixation of beneficial mutations that increase the fitness of the individuals. In large populations such as cells in culture, beneficial mutations may arise frequently enough that two or more are present in independent lineages. In the asexual system the lineages created by these beneficial mutations will compete with one another, so that only those with the largest effect on fitness shall be fixed. This phenomenon is known as clonal interference. Thus, asexual populations must fix beneficial mutations sequentially (20). It is rather comª 2002 Elsevier Science Ltd. All rights reserved.
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mon that transient but frequent beneficial mutations do not achieve fixation because the presence of other interfering beneficial mutations within the population (21). Experiments designed to evaluate the effect of clonal interference, show that the larger the population size is (which means, the stronger the possible clonal interference). then the larger the magnitude of the beneficial effect needed to fix a mutation is. A very important observation concerning the evolution of asexual populations (such as cells), is that resident populations (for example, normal cells) are protected from invaders (such as tumour cells) simply because of their numerical advantage. Thus, a supposedly high-fitness clone seeded at a low frequency into a resident population of low-fitness variants will be displaced by the low-fitness competitors (22,23). Indeed, the high-fitness clone needs to achieve a certain initial frequency threshold in order to out-compete the low-fitness variants in the resident population. Therefore, one of the key steps towards sporadic cancer must be the development of a field of mutant cells (24). It is obvious that whichever factors are responsible for establishing a field of cancerization, such factors must be acting against the normal local and global constraints that characterize the morphogenetic field of the affected organism. Experiments with cells transformed by oncogenes that are over-expressed by means of strong, heterologous promoters (such as viral promoters), are rather misleading as models for cancer development. For example, in primary cancers mutated ras genes are expressed at the same rate as their normal counterparts in normal proliferating cells. Actually, there is no evidence that any of the so-called oncogenes is expressed at a higher rate in a primary cancer cell than in its normal counterpart (25–28). Moreover, often the model tumours are lymphomas, leukaemias or sarcomas which altogether represent less than 10% of naturally occurring tumours, while almost 90% of human tumours are epithelial in origin (29). Recent technological advances that make the comparison of the gene-expression profiles of thousands of genes feasible, suggest that many of the so-called oncogenes are actually non-expressed or lowly expressed in tumour tissues (30–33). The gene expression patterns of 8,102 genes has been compared in tumour samples from different patients presenting breast cancer of a similar hystological type and stage. The results show that gene expression patterns of two tumour samples from the same individual were always more similar to each other than either was to any other sample from a different patient. Thus suggesting that each tumour is gentically different and therefore, there is no common or typical pattern of gene expression characteristic of a specific kind of cancer (33). ª 2002 Elsevier Science Ltd. All rights reserved.
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Currently, there are more than 100 oncogenes and at least 17 tumour suppressor genes have been described, though so far, only four qualify as bonafide tumour suppressors (34–37). Indeed, the criteria for considering a gene as a tumour suppressor are far from being universally established (38). It is likely that many more shall be discovered; all these genes are involved either in cellsignalling, control of the cell cycle or control of gene expression. Basically, all kinds of genes which are not coding for essential metabolic enzymes or essential structural proteins are likely to be found in a mutated state in one or another form of cancer, or in one or another type of cell transformed in vitro. This is because such mutations do not put at risk the survival of the individual cell (at least in the short term). Most mutations that are really incompatible with cellular life are those in genes which code for key metabolic enzymes or structural proteins. Indeed, the somatic mutations commonly observed in tumour cells may be a consequence rather than the cause of cancer, since such mutations occur in gene functions that are rather irrelevant for both the individual and species survival once the organism is past its reproductive prime. The ultimate fate of a gene that ceases to be useful is to accumulate mutations until it is no long recognizable (39). The gradual accumulation of mutations in the absence of selective pressure is called genetic drift (40). Once the organism has contributed offspring it becomes dispensable as a vehicle for survival and then genetic drift in absence of strong natural selection might ensue. Yet, only the cells displaying mutations in functions that are not critical for cell survival shall be available for sampling, while mutations in key cellular functions lead to cell death. This situation produces the false impression that the observed somatic mutations are the cause of cancer. To extrapolate conclusions from the observation of very rare cancer-prone syndromes (such as Li-Fraumeni syndrome or familial retinoblastoma), in order to explain the causality of the commonly occurring cancers can be quite misleading. This is because the mutations causally associated with such rare syndromes, may be consequences but not causes in the case of the sporadic cancers (2). CHROMOSOME INSTABILITY AND NUCLEAR MORPHOLOGY Now there is important evidence that genome-wide instability precedes the appearance of mutations in key proto-oncogenes and the eventual development of certain common forms of cancer (41–44). It has been observed that in most colorectal cancers and probably in many other cancer types, a chromosomal instability leading to aneuploidy is observed. This seems to be an
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early feature of the transformed cells (41). The source of such instability has been variously attributed. Either to mutations in genes controlling the repair of base mismatches in DNA (45). or to mutations in genes controlling the assembly of the mitotic spindle, thus leading to abnormal partitioning of the post-G2 4n chromosome complement between the daughter cells (42–46). It has been shown that aneuploidy (variation in the modal chromosome number), which at least for the last 100 years has been regarded as the most common feature of malignant tumour cells (47), correlates 100% with cell transformation induced by non-genotoxic agents unable to cause mutations in the cellular DNA (48). Moreover, the four artificially induced genetic events, apparently necessary for transforming primary human cells (14), were not directly responsible for the transformed cell phenotype. since it took more than 60 population doublings to generate the tumour cells. Indeed, the tumour cells were clonal even though the gene transfers were polyclonal (49). Thus, the truly basic feature was that the resulting tumour cells were aneuploid. Therefore, aneuploidy appears to be a basic characteristic of tumour cells that needs not to be related to mutations (either specific or non-specific) in the DNA sequence. Indeed, theoretical models suggest that the metabolic imbalance resulting from the aneuploid condition typical of tumour cells, could be the actual cause of cell transformation to a malignant state, without the need for any specific kind of oncogene or tumour-suppressor gene mutation (31,49). Tight control of cell ploidy is important for as long as the organism reaches and passes the reproductive age, thereafter such a control becomes non-relevant for both individual and species fitness (2). For example, the number of abnormal metaphases in older hepatectomized mice is much higher when compared to the number observed in younger animals (50). Aneuploidy, translocations and chromosome end-to-end fusions have been shown to be higher in lymphocytes and fibroblasts of elderly humans compared with younger ones (51). The available evidence suggests that ageing is associated with an overall reduction of genome stability. Our current knowledge of the higher-order structure within the cell nucleus shows that chromosome disposition inside the nucleus is highly organized and that the genetic material seems to maintain a set of constant specific interactions with the nuclear substructure, according to the cell type and the state of cell differentiation. Such interactions are very important for nuclear physiology but also. represent topological parameters which define a complex nuclear morphology (52–56). Therefore, chromosome instability and aneuploidy represent major alterations of the internal nuclear morphology. These alterations may be the evidence, at the
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cellular level, of perturbed interactions between the would-be tumour cells and the morphogenetic field the whole organism. It is known that any factor that alters the topological parameters within the cell nucleus leads to wholesale perturbation of nuclear functions, including gene expression (57–59). SPONTANEOUS REGRESSION OF CANCER IS INCOMPATIBLE WITH GENETIC CAUSALITY If cancer were truly a phenomenon due to the accumulation of mutations in a few key genes, then once the threshold has been crossed, there should be no way back towards normality. Yet, this conclusion is not consistent with the thousands of spontaneous cancer regressions quoted in the specialized literature (60). Such regressions cannot be attributed to the action of a hypothetical ‘immune surveillance’ since no difference in primary tumour development and incidence has been observed between athymic nude mice lacking T cells, and syngenic wild-type mice (61,62). Moreover, if malignancy is not a strictly genetic phenomenon, there should be some evidence for its reversibility. In leopard frogs, isolated nuclei from Lucke carcinoma cells (a kidney tumour induced by a herpesvirus) have been introduced into activated, enucleated frog eggs. Following nuclear transplantation, a small proportion of the nuclei allowed the development of tadpoles with normal, differentiated tissues (63). Mouse teratocarcinomas contain pluripotential embryonal carcinoma cells. The introduction of such cells into the embryonic blastocyst allows incorporation into the inner cell mass, and hence to the embryo. Using genetic markers it has been shown that the embryonal carcinoma cells contribute to most of the normal tissues of the mouse, although such mice have a higher incidence of teratocarcinomas. It has also been found that the descendants of embryonal cell lines can form a normal germ line (64,65). Thus, heritable normal behaviour can be restored to certain pluripotent cancer cells by transplantation, or cultivation, in a suitable environment. It is highly unlikely that the restored normal cellular behaviour results from the specific reversion of multiple specific gene mutations that are claimed to be the cause of cancer. A very interesting finding is that malignant neoplasms arise when normal rat ovarian tissue is transplanted into normal rat spleen (66). Thus, normal tissue situated in the wrong location within the context of the organism, degenerates into a tumour. On the other hand, tumour cells introduced into a blastocyst become normal and contribute to the formation of organized bodily structures (64,65). These facts are quite paradoxical, considering that within the early embryo there is an elevated amount of growth factors that should
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speed up the growth of the tumour cells, because such cells already require less growth factors than normal cells in order to stimulate their growth. Moreover, there is no obvious way that the simple change in the location of the ovarian cells might be inducing the somatic mutations which, according to the standard paradigm, are claimed to be the causal origin of cancer. Yet, these results can be understood on the one hand, as a normalization of the tumour cells by the action of a strong morphogenetic field associated with a developing system. On the other hand, as evidence that the loss of coherence (artificially induced in this case) between a set of bodily cells and the morphogenetic field of an adult organism (about to exhaust its developmental potential), induces tumour formation. ON THE NEED OF THEORETICAL ENTITIES IN BIOMEDICINE Currently, among the natural sciences, biomedicine is the last bulwark of naive empiricism, characterized by an almost indiscriminate accumulation of observational and experimental data, which flood an amazing number of journals, but with few theoretical frameworks that may help to make sense of such data. It remains to be explored by sociologists and historians of science why biomedical scientists are so uncomfortable with theoretical entities. Thus, in cosmology and physics, one may speak of ‘superstrings’, ‘time-warps’, ‘gluons’ or ‘charmed quarks’, without worrying about the fact that such entities are not endowed with a ‘rock-hard’ materiality. Instead, the outstanding criteria for assuming the existence of such entities is whether they allow us to understand and to predict the behaviour of physical systems. On the other hand, the only ‘deep’ theory sustaining most of contemporary biology is Darwinian evolution, supported by observation of fossils, stratigraphic data, the properties of contemporary organisms and more recently, by some biochemical and molecular data. Nevertheless, evolutionary biology is weakly predictive, being closer to history. Indeed, for many a critic, biological science is mostly storytelling, a bundle of ‘just so’ stories (67). Moreover, molecular biologists, spend most of the time looking at dark bands and spots in gels and thinking that such spots correspond, for example, to ‘rock-hard’ interactions between proteins and DNA. Without considering that such molecular interactions are closer to the quantum-mechanical level of measurement and explanation, than to the ‘width, length and weight’ approach of macroscopic experience. Perhaps this rather obsessive attachment to empirical evidence in the biomedical sciences (which -vis the widespread aclooks rather incongruous vis-a ceptation of Darwin’s narrative), is a remainder of late positivism and its fear of metaphysical entities. ª 2002 Elsevier Science Ltd. All rights reserved.
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Yet as shown in Margenau’s analysis of deep physical theories, the explanatory and predictive success of these theories is based on introducing many levels of abstraction, from objects to microscopic entities to particles to force fields to probability distribution functions, etc. (68). All these theoretical constructs are based on metaphysical requirements that are applied de facto by scientists, when choosing between constructs and theories, without necessarily thinking about their philosophical implications. The metaphysical criteria identified by Margenau’s are logical fertility, multiple connections, permanence and stability, extensibility, causality, and simplicity and elegance. Logical fertility requires that the constructs shall be formulated as to permit logical manipulations. The theoretical structure of science consists of a set of connections between constructs (be it formal, that is mathematical, or epistemic). Permanence and stability mean that the elements of the theory may not be arbitrarily altered to fit experience. The extensibility of constructs is a property that allows generalization of results, and the principle of causality asserts that a given state is invariably followed in time by another specifiable state. Finally, simplicity and elegance apply when two theories present themselves as competent explanations of a given complex of sensory experience, then science decides in favour of the simpler one (this corresponds to Ockham’s razor). Currently, the theory of the morphogenetic field might satisfy most of the aforementioned metaphysical principles save the principle of causality. Thus, its current level of explanation is rather phenomenological, but science has other examples of phenomenological theories and ‘laws’ (for example, the second principle of thermodynamics). Indeed, principles such as the ‘central dogma’ of molecular biology (information flows from DNA to RNA to protein) have already been modified, under pressure of empirical evidence, in an ad hoc way (information might flow from DNA to RNA and then back to DNA, via reverse transcription, and then to protein). Thus failing to satisfy the metaphysical criteria of stability and permanence. While ‘laws’ such as Mendel’s laws, apply only to a limited number of biological entities (sexually reproducing beings) which also carry non-Mendelian genetic traits (such as the transposons). Moreover, the status of the principle of natural selection, which sustains Darwinian evolution, is still a matter of debate (69). CONCLUSION The morphogenetic field, as a working principle, theoretical construct or abstract descriptive tool, is closer to any criteria of scientific rationality than any empirical Medical Hypotheses (2002) 59(1), 68–75
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gathering of gene-product interactions (such as those described in the genetic paradigm for cancer). The concept of morphogenetic field applied to the problem of cancer gives us clues to a possible intelligible ontology for such a phenomenon, which is lacking altogether in the current genetic paradigm. Since wholesale affectation of an organism’s organization, by local molecular disturbances affecting a limited number of cells, is assumed but it is never explained by such a paradigm. The alternative view presented in this paper, suggests that cancer is first of all an organic problem that cannot be exclusively reduced to the cellular, genetic or molecular level.Secondly, such a view suggests that cancer might be the result of a conflict between an organized morphology (the organism) and a part of such a morphology that drifts towards an amorphous state (the tumour). A fully developed morphogenetic perspective on cancer is being published elsewhere (70). Yet as a summing up conclusion it is worth to remember the following words by Sir David Smithers: Cancer is no more a disease of cells than a traffic jam is a disease of cars. A lifetime study of the internal combustion engine would not help anyone to understand our traffic problems’ (71).
ACKNOWLEDGMENTS xico (grant: 33539-N) and UAEM Supported by CONACYT-Me (grant: 1447/2000).
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