Cancer biology features the ascription of normal functions to parts of cancers. At least some ascriptions of function in cancer biology track local normality of parts within the global abnormality of the aberration to which those parts belong. That is, cancer biologists identify as functions activities that, in some sense, parts of cancers are supposed to perform, despite cancers themselves having no purpose. The present paper provides a theory to accommodate these normal function ascriptions—I call (...) it the Modeling Account of Normal Function (MA). MA comprises two claims. First, normal functions are activities whose performance by the function-bearing part contributes to the self-maintenance of the whole system and, thereby, results in the continued presence of that part. Second, MA holds that models of system-level activities that are (partly) constitutive of self-maintenance are improved by including a representation of the relevant function-bearing part and by making reference to the activity/activities that part performs which contribute(s) to those system-level activities. I contrast MA with two other accounts that seek to explicate the ascription of normal functions in biology, namely, the organizational account and the selected effects account. Both struggle to extend to cancer biology. However, I offer ecumenical readings which allow them to recover some ascriptions of normal function to parts of cancers. So, though I contend that MA excels in this respect, the purpose of this paper is served if it provides materials for bridging the gap between cancer biology, philosophy of cancer, and the literature on function. (shrink)

The dominant position in Philosophy of Science contends that downward causation is an illusion. Instead, we argue that downward causation doesn’t introduce vicious circles either in physics or in biology. We also question the metaphysical claim that “physical facts fix all the facts.” Downward causation does not imply any contradiction if we reject the assumption of the completeness and the causal closure of the physical world that this assertion contains. We provide an argument for rejecting this assumption. Furthermore, this (...) allows us to reconsider the concept of diachronic emergence. (shrink)

We show that as game theory was transferred from mathematical oncology to experimental cancer biology, a new mode of inquiry was created. Modeling was replaced by measuring. The game measured by a game assay can serve as a bridge that allows knowledge to flow backward from target (cancer research) to source (game theory). Our finding suggests that the conformist and creative (Houkes and Zwart 2019) types of transfer need to be augmented. We conclude by introducing the expansive (...) and transformative types to get a four-tier typology of knowledge transfer. (shrink)

The existing literature on the development of recombinant DNA technology and genetic engineering tends to focus on Stanley Cohen and Herbert Boyer's recombinant DNA cloning technology and its commercialization starting in the mid-1970s. Historians of science, however, have pointedly noted that experimental procedures for making recombinant DNA molecules were initially developed by Stanford biochemist Paul Berg and his colleagues, Peter Lobban and A. Dale Kaiser in the early 1970s. This paper, recognizing the uneasy disjuncture between scientific authorship and legal invention (...) in the history of recombinant DNA technology, investigates the development of recombinant DNA technology in its full scientific context. I do so by focusing on Stanford biochemist Berg's research on the genetic regulation of higher organisms. As I hope to demonstrate, Berg's new venture reflected a mass migration of biomedical researchers as they shifted from studying prokaryotic organisms like bacteria to studying eukaryotic organisms like mammalian and human cells. It was out of this boundary crossing from prokaryotic to eukaryotic systems through virus model systems that recombinant DNA technology and other significant new research techniques and agendas emerged. Indeed, in their attempt to reconstitute 'life' as a research technology, Stanford biochemists' recombinant DNA research recast genes as a sequence that could be rewritten thorough biochemical operations. The last part of this paper shifts focus from recombinant DNA technology's academic origins to its transformation into a genetic engineering technology by examining the wide range of experimental hybridizations which occurred as techniques and knowledge circulated between Stanford biochemists and the Bay Area's experimentalists. Situating their interchange in a dense research network based at Stanford's biochemistry department, this paper helps to revise the canonized history of genetic engineering's origins that emerged during the patenting of Cohen-Boyer's recombinant DNA cloning procedures. (shrink)

The existing literature on the development of recombinant DNA technology and genetic engineering tends to focus on Stanley Cohen and Herbert Boyer's recombinant DNA cloning technology and its commercialization starting in the mid-1970s. Historians of science, however, have pointedly noted that experimental procedures for making recombinant DNA molecules were initially developed by Stanford biochemist Paul Berg and his colleagues, Peter Lobban and A. Dale Kaiser in the early 1970s. This paper, recognizing the uneasy disjuncture between scientific authorship and legal invention (...) in the history of recombinant DNA technology, investigates the development of recombinant DNA technology in its full scientific context. I do so by focusing on Stanford biochemist Berg's research on the genetic regulation of higher organisms. As I hope to demonstrate, Berg's new venture reflected a mass migration of biomedical researchers as they shifted from studying prokaryotic organisms like bacteria to studying eukaryotic organisms like mammalian and human cells. It was out of this boundary crossing from prokaryotic to eukaryotic systems through virus model systems that recombinant DNA technology and other significant new research techniques and agendas emerged. Indeed, in their attempt to reconstitute 'life' as a research technology, Stanford biochemists' recombinant DNA research recast genes as a sequence that could be rewritten thorough biochemical operations. The last part of this paper shifts focus from recombinant DNA technology's academic origins to its transformation into a genetic engineering technology by examining the wide range of experimental hybridizations which occurred as techniques and knowledge circulated between Stanford biochemists and the Bay Area's experimentalists. Situating their interchange in a dense research network based at Stanford's biochemistry department, this paper helps to revise the canonized history of genetic engineering's origins that emerged during the patenting of Cohen-Boyer's recombinant DNA cloning procedures. (shrink)

The major cause of death from cancer is the relentless growth of metastases that are resistant to conventional therapy. The pathogenesis of a metastasis is complex and requires that tumor cells complete a sequence of potentially lethal interactions with various host factors. The finding in 1973 that metastasis is selective process and the finding in 1977 that malignant neoplasms are heterogeneous and contain few preexisting metastatic subpopulations have added a new dimension to our understanding of cancer and its (...) spread. This understanding is now contributing to the design of better therapies against disseminated metastasis. (shrink)

Cancer is a paradigmatic case of a complex causal process; causes of cancer operate at a variety of temporal and spatial scales, and the respects in which these causes act and interact are diverse. There are, for instance, temporal order effects, organizational effects, structural effects, and dynamic relationships between causes operating at different temporal and spatial scales. Because of this complexity, models of cancer initiation and progression often involve deliberate choices to focus on one time scale, one (...) causal pathway, or one aspect of cancer’s dynamics. As in most of biology, modeling cancer involves simplification and idealization. At the same time, theoretical perspectives inform the construction of these models. Such perspectives might involve viewing cancer ‘as’ a genetic disease, metabolic disease, stem cell disease, an infectious disease, or a disease of tissue disorganization. This paper will argue that purportedly competing theoretical views of cancer are not at odds, but can be viewed as mutually informative. Models are most often developed in the service of asking very specific questions, and this requires limiting our view of the phenomena to a specific temporal or spatial scale, a particular cause, or a particular outcome, dynamic, or pattern. Thus, while some models may seem at odds, often they are simply concerned with different questions, or, they are complementary and mutually informative. I hope to bring this case to bear on debates among philosophers of science over perspectivism and realism, as well pluralism about the aims and scope of scientific theory. (shrink)

This is a book review of A. Aktipis' 2020 book on cancer and the application of a social evolution framework understand what cancer is, why and how it emerges, and why it is sometimes difficult to cure.

Here we review and discuss the link between regeneration capacity and tumor suppression comparing mammals (embryos versus adults) with highly regenerative vertebrates. Similar to mammal embryo morphogenesis, in amphibians (essentially newts and salamanders) the reparative process relies on a precise molecular and cellular machinery capable of sensing abnormal signals and actively reprograming or eliminating them. As the embryo's evil twin, tumor also retains common functional attributes. The immune system plays a pivotal role in maintaining a physiological balance to provide surveillance (...) against tumor initiation or to support its initiation and progression. We speculate that susceptibility to cancer development in adult mammals may be determined by the loss of an advanced regenerative capability during evolution and believe that gaining mechanistic insights into how regenerative capacity linked to tumor suppression is postnatally lost in mammals might illuminate an as yet unrecognized route to cancer treatment. (shrink)

Despite the productivity of basic cancer research, cancer continues to be a health burden to society because this research has not yielded corresponding clinical applications. Many proposed solutions to this dilemma have revolved around implementing organizational and policy changes related to cancer research. Here I argue for a different solution: a new conceptualization of causation in cancer. Neither the standard molecular biomarker approaches nor evolutionary biology approaches to cancer fully capture its complex causal dynamics, (...) even when considered jointly. These approaches map on to Ernst Mayr’s proximate–ultimate distinction, which is an inadequate conceptualization of causation in biological systems and makes it difficult to connect developmental and evolutionary viewpoints. I propose looking to evolutionary developmental biology to overcome the distinction and integrate the proximate and ultimate causal frameworks. I use the concepts of modularity and evolvability to show how an EvoDevo perspective can be manifested in cancer translational research. This perspective on causation in cancer is better suited for integrating the complexity of current empirical results and can facilitate novel developments in the investigation and clinical treatment of cancer. (shrink)

With a previous paper (Niu & Wang, 1995), a general, hypothetical outline of the mechanism of carcinogenesis was proposed. With reference to the fact of starvation-induced hypermutation in micro-organisms, we propose that the hypoxia commonly seen in the cells at the centre of solid tumours might also result in hypermutation, and then p53-dependent programmed cell death. Like the apparently adaptive mutations in micro-organisms, only those genes (e.g. p53) that enable the cells to escape from apoptosis may be selected.

Cancer is not one, but many diseases, and each is a product of a variety of causes acting (and interacting) at distinct temporal and spatial scales, or “levels” in the biological hierarchy. In part because of this diversity of cancer types and causes, there has been a diversity of models, hypotheses, and explanations of carcinogenesis. However, there is one model of carcinogenesis that seems to have survived the diversification of cancer types: the multi-stage model of carcinogenesis. This (...) paper examines the history of the multistage theory, and uses the theory as a case study in the limits and goals of unification as a theoretical virtue, comparing and contrasting it with “integrative” research. (shrink)

This book explores a variety of conceptual and methodological questions about cancer and cancer research: Is cancer one disease, or many? If many, how many exactly? How is cancer classified? What does it mean, exactly, to say that cancer is “genetic,” or “familial”? What exactly are the causes of cancer, and how do scientists come to know about them? When do we have good reason to believe that this or that is a risk factor (...) for cancer? How is cancer a product or byproduct of multilevel evolution? Is cancer research unified? What sort of models, or theories, govern cancer research? This book takes a close look at these philosophical questions, by examining work in disciplines as diverse as cell and molecular biology, epidemiology, clinical medicine, and evolutionary biology. (shrink)

A new therapeutic strategy could break the stalemate in the war on cancer by targeting not all cancerous cells but the small fraction that lie at the root of cancers. Lucie Laplane offers a comprehensive analysis of cancer stem cell theory, based on an original interdisciplinary approach that combines biology, biomedical history, and philosophy.

In this paper we explore the rise of ‘the breast cancer gene’ as a field of medical, cultural and personal knowledge. We address its significance in the Norwegian public health care system in relation to so-called biological citizenship in this particular national context. One of our main findings is that, despite its claims as a measure for health and disease prevention, gaining access to medical knowledge of BRCA 1/2 breast cancer gene mutations can also produce severe instability in (...) the individuals and families affected. That is, although gene testing provides modern subjects with an opportunity to foresee their biological destiny and thereby become patients in waiting, it undoubtedly also comes with difficult existential dilemmas and choices, with implications that resonate beyond the individual and into different family and love relations. By elaborating on this finding we address the question of whether the empowerment slogan, which continues to be advocated through various health, BRCA and breast cancer discourses, reinforces a naïve or an idealized notion of the actively responsible patient: resourceful enough to seek out medical expertise and gain sufficient knowledge, on which to base informed decisions, thereby reducing the future risk of developing disease. In contrast to this ideal, our Norwegian informants tell a different story, in which there is no apparent heroic mastery of genetic fates, but rather a pragmatic attitude to dealing with a dire situation over which they have little control, despite having complied with medical advice through national guidelines and follow-up procedures for BRCA 1/2 carriers. In conclusion we claim that the sense of safety that gene testing and its associated medical solutions allegedly promise to provide proved illusory. Although BRCA-testing offers the potential for protection from adverse DNA-heritage, administered through possibilities for self-monitoring and self-management of the body, the feeling of ‘being in good health’ has hardly been reinforced by the emergence of gene technology. (shrink)

Research on diseases such as cancer reveals that primary mechanisms, which have been the focus of study by the new mechanists in philosophy of science, are often subject to control by other mechanisms. Cancer cells employ the same primary mechanisms as healthy cells but control them differently. I use cancer research to highlight just how widespread control is in individual cells. To provide a framework for understanding control, I reconceptualize mechanisms as imposing constraints on flows of free (...) energy, with control mechanisms operating on flexible constraints in primary mechanisms. I argue that control mechanisms themselves often form complex, integrated networks. (shrink)

The concept ‘hereditary breast cancer’ is commonly used to delineate a group of people genetically at risk for breast cancer—all of whom also having risk for other cancers. People carrying pathogenic variants of the BRCA1 and BRCA2 genes are often referred to as those having predisposition for ‘hereditary breast cancer’. The two genes, however, are when altered, associated with different risks for and dying from breast cancer. The main risk for dying for carriers of both genes (...) is from ovarian cancer. These biological facts are of philosophical interest, because they are the facts underlying the public debate on BRCA1/2 genetic testing as a model for the discussion of how to implement genetic knowledge and technologies in personalized medicine. A contribution to this public debate describing inherited breast cancer as ‘biological citizenship’ recently printed in Med Health Care and Philos illustrated how fragmented and detached from the biological and socio-political facts this debate sometimes is. We here briefly summarize some of the biological facts and how they are implemented in today’s healthcare based on agreed philosophical, ethical and moral principles. The suggestion of a ‘biological citizenship’ defined by hereditary breast cancer is incorrect and ill-advised. ‘Identity politics’ focusing hereditary breast cancer patients as a group based on a bundle of ill-defined negative arguments is well known, but is supported neither by scientific nor philosophical arguments. To those born with the genetic variants described, the philosophical rule of not doing harm is violated by unbalanced negative arguments. (shrink)

Cancer is not one, but many diseases, and each is a product of a variety of causes acting at distinct temporal and spatial scales, or ‘‘levels’’ in the biological hierarchy. In part because of this diversity of cancer types and causes, there has been a diversity of models, hypotheses, and explanations of carcinogenesis. However, there is one model of carcinogenesis that seems to have survived the diversification of cancer types: the multi-stage model of carcinogenesis. This paper examines (...) the history of the multistage theory, and uses the theory as a case study in the limits and goals of unification as a theoretical virtue, comparing and contrasting it with ‘‘integrative’’ research. (shrink)

Paradoxically, DNA sequence polymorphisms in cancer risk loci rarely correlate with the expression of cancer genes. Therefore, the molecular mechanism underlying an individual's susceptibility to cancer has remained largely unknown. However, recent evaluations of the correlations between DNA methylation and gene expression levels across healthy and cancerous genomes have revealed enrichment of disease‐related DNA methylation variations within disease‐associated risk loci. Moreover, it appears that transcriptional enhancers embedded in cancer risk loci often contain DNA methylation sites that (...) closely define the expression of prominent cancer genes, despite the lack of significant correlations between gene expression levels and the surrounding disease‐associated polymorphic sequences. We suggest that DNA methylation variations may obscure the effect of co‐residing risk sequence alleles. Analysis of enhancer methylation data may help to reveal the regulatory circuits underlying predisposition to cancers and other common diseases.Editor's suggested further reading in BioEssays DNA methylation reprogramming in cancer: Does it act by re‐configuring the binding landscape of Polycomb repressive complexes? Abstract. (shrink)

The aim of this paper is to assess the relevance of somatic evolution by natural selection to our understanding of cancer development. I do so in two steps. In the first part of the paper, I ask to what extent cancer cells meet the formal requirements for evolution by natural selection, relying on Godfrey-Smith’s (2009) framework of Darwinian populations. I argue that although they meet the minimal requirements for natural selection, cancer cells are not paradigmatic Darwinian populations. (...) In the second part of the paper, I examine the most important examples of adaptation in cancer cells. I argue that they are not significant accumulations of evolutionary changes, and that as a consequence natural selection plays a lesser role in their explanation. Their explanation, I argue, is best sought in the previously existing wiring of the healthy cells. (shrink)

The presence and role of microbes in human cancers has come full circle in the last century. Tumors are no longer considered aseptic, but implications for cancer biology and oncology remain underappreciated. Opportunities to identify and build translational diagnostics, prognostics, and therapeutics that exploit cancer's second genome—the metagenome—are manifold, but require careful consideration of microbial experimental idiosyncrasies that are distinct from host‐centric methods. Furthermore, the discoveries of intracellular and intra‐metastatic cancer bacteria necessitate fundamental changes in describing (...) clonal evolution and selection, reflecting bidirectional interactions with non‐human residents. Reconsidering cancer clonality as a multispecies process similarly holds key implications for understanding metastasis and prognosing therapeutic resistance while providing rational guidance for the next generation of bacterial cancer therapies. Guided by these new findings and challenges, this Review describes opportunities to exploit cancer's metagenome in oncology and proposes an evolutionary framework as a first step towards modeling multispecies cancer clonality. Also see the video abstract here: https://youtu.be/-WDtIRJYZSs. (shrink)

The Mongol in Our Midst F G Crookshank Originally published in 1925. "A brilliant piece of speculative induction" Saturday Review Combining anthropology, psychology, geography, science and medicine, this volume was a ground-breaking study in the area of race, ethnicity and eugenics, when first published and has to be read in the appropriate historical, social and scientific context of the early twentieth century. 120 pp, 24 b&w plates Prometheus or Biology and the Advancement of Man H S Jennings Originally published (...) in 1925 "This volume is one of the most remarkable that has yet appeared in this series." Times Literary Supplement "An exceedingly brilliant book." New Leader This volume provides a lucid summary of the striking advances of the early 20 th century in biological knowledge, genetics, and the theory of evolution. 88pp Metanthropos or the Body of the Future Ronald Campbell Macfie Originally published in 1928 "An exceptionally stimulating book…" Saturday Review "Should certainly be read by a large public." The Lancet Drawing on the history of evolution and geology, this volume examines the role of society on physical, emotional and psychological changes in the population of Western Europe during the early twentieth century, whilst attempting to predict genetic developments of the future. 88pp. Pygmalion or the Doctor of the Future R M Wilson Originally published in 1925 "No doctor worth his salt would venture to say that Dr.Wilson was wrong." Daily Herald "Dr Wilson has added a brilliant essay to this series." Times Literary Supplement The author foresees an evolution in the personality of the doctor, who will become less of a scientist, more of a humanist, and use every spiritual agency, as well as every practical measure, to restore the human body and soul to health. 66pp. The Conquest of Cancer H W S Wright Originally published in 1925 "Eminently suitable for general reading. The problem is fairly and lucidly presented." F G Crookshank Whilst affirming that the causes and treatment of cancer will never be solved by the efforts of the medical profession alone, this volume provides an accessible source of information on cancer and proposes routine examination for those people aged 40 and over as the best means of defence against cancer. 82pp. (shrink)

"The author tells a history of the study of cancer-causing viruses from the early twentieth century to the development of an HPV vaccine for cervical cancer in 2006. He profiles the "cancer virus hunters" who made breakthroughs in tumor virology"--.

According to objective Bayesianism, an agent’s degrees of belief should be determined by a probability function, out of all those that satisfy constraints imposed by background knowledge, that maximises entropy. A Bayesian net offers a way of efficiently representing a probability function and efficiently drawing inferences from that function. An objective Bayesian net is a Bayesian net representation of the maximum entropy probability function. In this paper we apply the machinery of objective Bayesian nets to breast cancer prognosis. Background (...) knowledge is diverse and comes from several different sources: a database of clinical data, a database of molecular data, and quantitative data from the literature. We show how an objective Bayesian net can be constructed from this background knowledge and how it can be applied to yield prognoses and aid translation of clinical knowledge to genomics research. (shrink)

The technique of nuclear transplantation – popularly known as cloning – has been integrated into several different histories of twentieth century biology. Historians and science scholars have situated nuclear transplantation within narratives of scientific practice, biotechnology, bioethics, biomedicine, and changing views of life. However, nuclear transplantation has never been the focus of analysis. In this article, I examine the development of nuclear transplantation techniques, focusing on the people, motivations, and institutions associated with the first successful nuclear transfer in metazoans (...) in 1952. The conflict between embryologists and geneticists over the mechanisms of differentiation motivated Robert Briggs to pursue nuclear transplantation experiments as a way to resolve the debate. Briggs worked at the Lankenau Hospital Research Institute, a research facility devoted to the study of cancer. The goal of understanding cancer would play a role in the development of the technique, and the story of nuclear transplantation sheds light on the role that biomedical contexts play in biological research in the second half of the twentieth century. (shrink)

The current mainstream in cancer research favours the idea that malignant tumour initiation is the result of a genetic mutation. Tumour development and progression is then explained as a sort of micro-evolutionary process, whereby an initial genetic alteration leads to abnormal proliferation of a single cell that leads to a population of clonally derived cells. It is widely claimed that tumour progression is driven by natural selection, based on the assumption that the initial tumour cells acquire some properties that (...) endow such cells with a selective advantage over the normal cells from which the tumour cells are derived. The standard view assumes that the transformed bodily cell somehow acquires "responsiveness" to natural selection independently of the whole organism to which the cell belongs. Yet, it is never explained where such an acquired capacity to respond to natural selection by the individual bodily cell comes from. This situation poses many difficult questions that so far have been left unanswered. For example, there is no explanation why some cells belonging to an organised whole and as such having no independent capacity for survival, apparently become 'independent' entities, able to respond to selective pressures in an autonomous fashion and then to be evaluated by natural selection. Hereunder it is argued that such a qualitative change cannot be the consequence of specific genetic mutations. Moreover, it is shown that natural selection is unlikely to be acting within the organism during tumour development and progression and that tumour evolution is a random, non-adaptive process, driven by no fundamental biological principle. Thus, mutations in the so-called oncogenes and tumour suppressor genes observed in epithelial cancers (that constitute more than 90% of all cancers) are not the result of selection for better cellular growth or survival under restrictive conditions. Instead, here it is suggested that they are the consequence of genetic drift acting upon gene functions that become non-relevant, either for the individual or the species fitness, once the organism is past its reproductive prime and as such, they also become superfluous for cell survival in the short term. It is proposed that the origin of cancer is epigenetic and it is a consequence of the need for a continued turnover of the individuals that constitute a species. (shrink)

In 2015, Tomasetti and Vogelstein published a paper in Science containing the following provocative statement: “… only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells.” The paper—and perhaps especially this rather coy reference to “bad luck”—became a flash point for a series of letters and reviews, followed by replies and (...) yet further counterpoints. In this paper, I critically assess Tomasetti and Vogelstein's argument, discuss the meaning of “luck” (or, better: “chance”) in the context of the debate, and use this case study to address larger questions about methodological criteria for causal explanations of population level patterns in biomedicine. (shrink)

Cancer biologists ascribe normal functions to parts of cancer. Normal functions are activities that parts of systems are in some minimal sense supposed to perform. Cancer biologists’ finding normality within the abnormality of cancer pose difficulties for two main approaches to normal function. One approach claims that normal functions are activities that parts are selected for. However, some parts of cancers that have normal functions aren’t selected to perform them. The other approach claims that normal functions (...) are part-activities typical for the system and that contribute to survival/reproduction. However, cancers are too heterogeneous to establish what’s typical across a type. (shrink)

Since the 1970s, the origin of cancer is being explored from the point of view of the Somatic Mutation Theory (SMT), focusing on genetic mutations and clonal expansion of somatic cells. As cancer research expanded in several directions, the dominant focus on cells remained steady, but the classes of genes and the kinds of extra-genetic factors that were shown to have causal relevance in the onset of cancer multiplied. The wild heterogeneity of cancer-related mutations and phenotypes, (...) along with the increasing complication of models, led to an oscillation between the hectic search of 'the' few key factors that cause cancer and the discouragement in face of a seeming 'endless complexity'. To tame this complexity, cancer research started to avail itself of the tools that were being developed by Systems Biology. At the same time, anti-reductionist voices began claiming that cancer research was stuck in a sterile research paradigm. This alternative discourse even gave birth to an alternative theory: the Tissue Organization Field Theory (TOFT). A deeper philosophical analysis shows the serious limits of both reductionist and anti-reductionist positions and of their polarization. This book demonstrates that a radical philosophical reflection is necessary to drive cancer research out of its impasses. At the very least, this will be a reflection on the assumptions of different kinds of cancer research, on the implications of what cancer research has been discovering over 40 years and more, on a view of scientific practice that is most able to make sense of the cognitive and social conflicts that are seen in the scientific community (and in its results), and, finally, on the nature of living entities with which we entertain this fascinating epistemological dance that we call scientific research. The proposed Dynamic and Relational View of carcinogenesis is a starting point in all these directions. (shrink)

A major challenge for The Cancer Genome Atlas (TCGA) Project is solving the high level of genetic and epigenetic heterogeneity of cancer. For the majority of solid tumors, evolution patterns are stochastic and the end products are unpredictable, in contrast to the relatively predictable stepwise patterns classically described in many hematological cancers. Further, it is genome aberrations, rather than gene mutations, that are the dominant factor in generating abnormal levels of system heterogeneity in cancers. These features of (...) class='Hi'>cancer could significantly reduce the impact of the sequencing approach, as it is only when mutated genes are the main cause of cancer that directly sequencing them is justified. Many biological factors (genetic and epigenetic variations, metabolic processes) and environmental influences can increase the probability of cancer formation, depending on the given circumstances. The common link between these factors is the stochastic genome variations that provide the driving force behind the cancer evolutionary process within multiple levels of a biological system. This analysis suggests that cancer is a disease of probability and the most‐challenging issue to the TCGA project, as well as the development of general strategies for fighting cancer, lie at the conceptual level. BioEssays 29:783–794, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

In recent cancer research, strong and apparently conflicting epistemological stances have been advocated by different research teams in a mist of an ever-growing body of knowledge ignited by ever-more perplexing and non-conclusive experimental facts: in the past few years, an 'organicist' approach investigating cancer development at the tissue level has challenged the established and so-called 'reductionist' approach focusing on disentangling the genetic and molecular circuitry of carcinogenesis. This article reviews the ways in which 'organicism' and 'reductionism' are used (...) and opposed in this context, with an aim at clarifying the debate. Methodological, epistemological and ontological implications of both approaches are discussed. We argue that the 'organicist/reductionist' opposition in the present case of carcinogenesis is more a matter of diverging heuristics than a claim about theoretical or ontological (ir)reducibility. As a matter of fact, except for the downward causation claim, which we question, we argue that the organicist arguments are compatible with the reductionist approach. Moreover, we speculate that both approaches, which currently focus on specific entities i.e., genes versus tissues, will need to shift their conceptual frameworks to studying complex arrays of relationships potentially ranging over several levels of entities, as is the case with 'systems biology'. (shrink)

Parallels between cancer and ecological systems have been increasingly recognized and extensively reviewed. However, a more unified framework of understanding cancer as an evolving dynamical system that undergoes a sequence of interconnected changes over time, from a dormant microtumor to disseminated metastatic disease, still needs to be developed. Here, we focus on several examples of such mechanisms, namely, how in cancer niche construction a metabolic adaptation and consequent change to the tumor microenvironment becomes an important factor in (...) evasion of the predator, facilitating disease progression; how tumor establishment and propagation is driven by the tumor’s own keystone species, the cancer stem cells; and how the succession of stages of metastatic dissemination can be informed by ergodic theory and forest ecology. (shrink)

The highly structured mechanisms of cancers, their tendency to occur as a response to environmental stress, and the existence of oncogenes, suggest that neoplasticity may represent more than a biological disfunction. It is proposed that cancer exists as a phylogenetic mechanism serving to promote hyperevolution, albeit at the expense of the ontogeny, that is similar to a process recently discovered in bacterial mutations. Cell-surface-associated nucleic acid in tumorigenic cells and sperm cell vectorization of foreign DNA indicate the existence of (...) essential mechanisms necessary to the occurrence of cancer mediated hyperevolution. An analysis of the proposed mechanism indicates that for mutagenesis of chemical cytology, stress induced neoplasticity confers an evolutionary advantage of more than two orders of magnitude. (shrink)

The clonal evolution model and the cancer stem cell model are two independent models of cancers, yet recent data shows intersections between the two models. This article explores the impacts of the CSC model on the CE model. I show that CSC restriction, which depends on CSC frequency in cancer cell populations and on the probability of dedifferentiation of cancer non-stem cells into CSCs, can favor or impede some patterns of evolution and some processes of evolution. Taking (...) CSC restriction into account for the CE model thus has implications for the way in which we understand the patterns and processes of evolution, and can also provide new leads for therapeutic interventions. (shrink)

This paper explores the epistemology of extrapolation from model organisms to humans in molecular medicine. We take into account two common views on the issue, the homology view and the disanalogy view. In response to both interpretations, we argue that the foundational basis of extrapolations cannot simply be provided by homology and that relevant disanalogies can, thanks to the techniques of molecular biology, be experimentally controlled and exploited to allow useful and reliable extrapolations. The case of "humanised mice" in (...) the context of cancer stem cell research provides evidence of how animal models can be construed to approximate bona fide causal analogue models of human diseases. To supplement this view we show how the epistemology of model organisms needs to take into account the engineering side of molecular medicine. Model organisms are often manipulated to create analogies or remove disanalogies with the target system. We maintain that highlighting this feature is fundamental to explain what warrants extrapolation in the search for the molecular causes of disease. (shrink)

This article provides an ethnographic account of how Big Data biology is produced, interpreted, debated, and translated in a Big Data-driven cancer clinical trial, entitled “Personalized OncoGenomics,” in Vancouver, Canada. We delve into epistemological differences between clinical judgment, pathological assessment, and bioinformatic analysis of cancer. To unpack these epistemological differences, we analyze a set of gazes required to produce Big Data biology in cancer care: clinical gaze, molecular gaze, and informational gaze. We are concerned with (...) the interactions of these bodily gazes and their interdependence on each other to produce Big Data biology and translate it into clinical knowledge. To that end, our central research questions ask: How do medical practitioners and data scientists interact, contest, and collaborate to produce and translate Big Data into clinical knowledge? What counts as actionable and reliable data in cancer decision-making? How does the explicability or translatability of genomic Big Data come to redefine or contradict medical practice? The article contributes to current debates on whether Big Data engenders new questions and approaches to biology, or Big Data biology is merely an extension of early modern natural history and biology. This ethnographic account will highlight how genomic Big Data, which underpins the mechanism of personalized medicine, allows oncologists to understand and diagnose cancer in a different light, but it does not revolutionize or disrupt medical oncology on an institutional level. Rather, personalized medicine is interdependent on different styles of thought, gaze, and practice to be produced and made intelligible. (shrink)

In spite of the advances in our knowledge of cancer biology, most cancers remain not curable with present therapies. Current treatments consider cancer as resulting from uncontrolled proliferation and are non‐specific. Although they can reduce tumour burden, relapse occurs in most cases. This was long attributed to incomplete tumour elimination, but recent developments indicate that different types of cells contribute to the tumour structure, and that the tumour's cellular organization would be analogous to that of a normal (...) tissue, with a main mass of differentiating cells sensitive to anti proliferative agents, together with a small percentage of quiescent, resistant stem cells responsible for replenishing the tumour: the Cancer Stem Cells (CSCs). Anti‐CSCs targeted therapeutic agents would prevent tumour regeneration. New mouse models tailored to exploit this novel concept will be critical to develop CSC‐based anti‐cancer therapies. Here we review the biological basis and the therapeutic implications of the stem‐cell model of cancer. BioEssays 29:1269–1280, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Thousands of candidate cancer biomarkers have been proposed, but so far, few are used in cancer screening. Failure to implement these biomarkers is attributed to technical and design flaws in the discovery and validation phases, but a major obstacle stems from cancer biology itself. Oncogenomics has revealed broad genetic heterogeneity among tumors of the same histology and same tissue (or organ) from different patients, while tumors of different tissue origins also share common genetic mutations. Moreover, there (...) is wide intratumor genetic heterogeneity among cells within any single neoplasm. These findings seriously limit the prospects of finding a single biomarker with high specificity for early cancer detection. Current research focuses on developing biomarker panels, with data assessment by machine‐learning algorithms. Whether such approaches will overcome the inherent limitations posed by tumor biology and lead to tests with true clinical value remains to be seen. (shrink)

In recent years the argument has been made that malignant tumors represent complex dynamic and self‐organizing biosystems. Furthermore, there is increasing evidence that collective cell migration is common during invasion and metastasis of malignant tumors. Here, we argue that cancer systems may be capable of developing multicellular collective patterns that resemble evolved adaptive behavior known from other biological systems including collective sensing of environmental conditions and collective decision‐making. We present a concept as to how these properties could arise in (...) tumors and why the emergence of such swarm‐like patterns would confer advantageous properties to the spatiotemporal expansion of tumors, and consequently, why understanding and ultimately targeting such collectivity should be of interest for basic and clinical cancer research alike. (shrink)

DNA methylation is a repressive epigenetic mark vital for normal development. Recent studies have uncovered an unexpected role for the DNA methylome in ensuring the correct targeting of the Polycomb repressive complexes throughout the genome. Here, we discuss the implications of these findings for cancer, where DNA methylation patterns are widely reprogrammed. We speculate that cancer‐associated reprogramming of the DNA methylome leads to an altered Polycomb binding landscape, influencing gene expression by multiple modes. As the Polycomb system is (...) responsible for the regulation of genes with key roles in cell fate decisions and cell cycle regulation, DNA methylation induced Polycomb mis‐targeting could directly drive carcinogenesis and disease progression.Editor's suggested further reading in BioEssays Unmasking risk loci: DNA methylation illuminates the biology of cancer predisposition Abstract. (shrink)

Patient-derived xenografts are currently promoted as new translational models in precision oncology. PDXs are immunodeficient mice with human tumors that are used as surrogate models to represent specific types of cancer. By accounting for the genetic heterogeneity of cancer tumors, PDXs are hoped to provide more clinically relevant results in preclinical research. Further, in the function of so-called “mouse avatars”, PDXs are hoped to allow for patient-specific drug testing in real-time. This paper examines the circulation of knowledge and (...) bodily material across the species boundary of human and personalized mouse model, historically as well as in contemporary practices. PDXs raise interesting questions about the relation between animal model and human patient, and about the capacity of hybrid or interspecies models to close existing translational gaps. We highlight that the translational potential of PDXs not only depends on representational matching of model and target, but also on temporal alignment between model development and practical uses. Aside from the importance of ensuring temporal stability of human tumors in a murine body, the mouse avatar concept rests on the possibility of aligning the temporal horizons of the clinic and the lab. We examine strategies to address temporal challenges, including cryopreservation and biobanking, as well as attempts to speed up translation through modification and use of faster developing organisms. We discuss how featured model virtues change with precision oncology, and contend that temporality is a model feature that deserves more philosophical attention. (shrink)

In the last decades, Systems Biology (including cancer research) has been driven by technology, statistical modelling and bioinformatics. In this paper we try to bring biological and philosophical thinking back. We thus aim at making diferent traditions of thought compatible: (a) causality in epidemiology and in philosophical theorizing—notably, the “sufcient-component-cause framework” and the “mark transmission” approach; (b) new acquisitions about disease pathogenesis, e.g. the “branched model” in cancer, and the role of biomarkers in this process; (c) the (...) burgeoning of omics research, with a large number of “signals” and of associations that need to be interpreted. In the paper we summarize frst the current views on carcinogenesis, and then explore the relevance of current philosophical interpretations of “cancer causes”. We try to ofer a unifying framework to incorporate biomarkers and omic data into causal models, referring to a position called “evidential pluralism”. According to this view, causal reasoning is based on both “evidence of diference-making” (e.g. associations) and on “evidence of underlying biological mechanisms”. We conceptualize the way scientists detect and trace signals in terms of information transmission, which is a generalization of the mark transmission theory developed by philosopher Wesley Salmon. Our approach is capable of helping us conceptualize how heterogeneous factors such as micro and macro-biological and psycho-social—are causally linked. This is important not only to understand cancer etiology, but also to design public health policies that target the right causal factors at the macro-level. (shrink)

Recent studies of prostate cancer and other tumor types have revealed significant support, as well as unexpected complexities, for the application of concepts from normal stem cell biology to cancer. In particular, the cell of origin and cancer stem cell models have been proposed to explain the heterogeneity of tumors during the initiation, propagation, and evolution of cancer. Thus, a basis of intertumor heterogeneity has emerged from studies investigating whether stem cells and/or non‐stem cells can (...) serve as cells of origin for cancer and give rise to tumor subtypes that vary in disease outcome. Furthermore, analyses of putative cancer stem cells have revealed the genetically diverse nature of cancers and expanded our understanding of intratumor heterogeneity and clonal evolution. Overall, the principles that have emerged from these stem cell studies highlight the challenges to be surmounted to develop effective treatment strategies for cancer. (shrink)

This book proposes the foundation of the relational approach to biology, rejecting the deterministic and reductionist approach of molecular biology. Although biology has made enormous progress in the last seventy years, onto genesis is still conceived as a “revelation” of information (DNA). Recovering the geometric tradition, relational biology conceives scientific and epistemological tools (cause, probability, space etc.) of science in a new way. If probabilistic biology and organicism still proposes a biology based on physics, (...) with a fundamental invariant, relational biology is based on variation: its fundamental invariant is variation, one of the most important elements of life. This is an indispensable book for academics who consider biology from a new theoretical approach, in particular for those working in the domains of cancer, ontogenesis and evolution. (shrink)