Pierre-Luc Germain

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer.

In its last round of publications in September 2012, the Encyclopedia Of DNA Elements (ENCODE) assigned a biochemical function to most of the human genome, which was taken up by the media as meaning the end of ‘Junk DNA’. This provoked a heated reaction from evolutionary biologists, who among other things claimed that ENCODE adopted a wrong and much too inclusive notion of function, making its dismissal of junk DNA merely rhetorical. We argue that this criticism rests on misunderstandings concerning the nature of the ENCODE project, the relevant notion of function and the claim that most of our genome is junk. We argue that evolutionary accounts of function presuppose functions as ‘causal roles’, and that selection is but a useful proxy for relevant functions, which might well be unsuitable to biomedical research. Taking a closer look at the discovery process in which ENCODE participates, we argue that ENCODE’s strategy of biochemical signatures successfully identified activities of DNA elements with an eye towards causal roles of interest to biomedical research. We argue that ENCODE’s controversial claim of functionality should be interpreted as saying that 80 % of the genome is engaging in relevant biochemical activities and is very likely to have a causal role in phenomena deemed relevant to biomedical research. Finally, we discuss ambiguities in the meaning of junk DNA and in one of the main arguments raised for its prevalence, and we evaluate the impact of ENCODE’s results on the claim that most of our genome is junk

The notion of biological function is fraught with difficulties—intrinsically and irremediably so, we argue. The physiological practice of functional ascription originates from a time when organisms were thought to be designed and remained largely unchanged since. In a secularized worldview, this creates a paradox which accounts of functions as selected effect attempt to resolve. This attempt, we argue, misses its target in physiology and it brings problems of its own. Instead, we propose that a better solution to the conundrum of biological functions is to abandon the notion altogether, a prospect not only less daunting than it appears, but arguably the natural continuation of the naturalisation of biology.

In response to Germain argument that evolution by natural selection has a limited explanatory power in cancer, Lean and Plutynski have recently argued that many adaptations in cancer only make sense at the tumor level, and that cancer progression mirrors the major evolutionary transitions. While we agree that selection could potentially act at various levels of organization in cancers, we argue that tumor-level selection is unlikely to actually play a relevant role in our understanding of the somatic evolution of human cancers.

The ways in which other animal species can be informative about human biology are not exhausted by the traditional picture of the animal model. In this paper, I propose to distinguish two roles which laboratory organisms can have in biomedical research. In the more traditional case, organisms act as surrogates for human beings, and as such are expected to be more manageable replicas of humans. However, animal models can inform us about human biology in a much less straightforward way, by being used as measuring devices—what I call their instrumental role. I first characterize this role and provide criteria for it, before illustrating it with some examples from biomedical research, especially cancer research. In such an instrumental role, phenotypes are not expected to phenocopy human phenomena, but instead have the purely instrumental value of detecting or measuring differences. I argue that the instrumental role is more prevalent than might first be suspected, and that some characteristics of contemporary biomedical research are increasingly shifting the use of laboratory organisms to the instrumental role. Finally, in light of the distinction proposed, I discuss the meaning of the expression “animal model”.

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.

What has been called the new mechanistic philosophy conceives of mechanisms as the main providers of biological explanation. We draw on the characterization of the p53 gene in molecular oncology, to show that explaining a biological phenomenon implies instead a dynamic interaction between the mechanistic level—rendered at the appropriate degree of ontological resolution—and far more general explanatory tools that perform a fundamental epistemic role in the provision of biological explanations. We call such tools “explanatory frameworks”. They are called frameworks to stress their higher level of generality with respect to bare mechanisms; on the other hand, they are called explanatory because, as we show in this paper, their importance in explaining biological phenomena is not secondary with respect to mechanisms. We illustrate how explanatory frameworks establish selective and local criteria of causal relevance that drive the search for, characterisation and usage of biological mechanisms. Furthermore, we show that explanatory frameworks allow for changes of scientific perspective on the causal relevance of mechanisms going beyond the account provided by the new mechanistic philosophy