ToC

1. Ingredients for Human Cancer: The Mechanism of Natural SelectionPredrag ŠustarDepartment of Philosophy, University of Rijeka, Croatia(psustar@ffri.hr)

2. ToC • Introduction • Natural Selection • Natural Selection as a Mechanism • A Tip from Cancer Research 5. Conclusion.

3. 1. Introduction • Scientific Looseness about Natural Selection (NS): NS is most usually characterized as a cause, force, process, mechanism, factor, principle. • Philosophical Options for the issue of what, after all, NS is: (i) NS as a force:

4. 1. Introduction (1) a wide reading; (2) a narrow reading; (3) an interactionist reading; (ii) NS as a statistical consequence (for a more detailed recent overview of both (i) and (ii), see Brunnander 2007); (iii) NS as a mechanism.

5. 1. Introduction • In this paper, I will examine the account of NS as a mechanism. • In particular, I will try to single out a more adequate mechanistic approach to the nature of NS than most recently advanced by Barros 2008. • Namely, I will argue that distinctive features of NS can be best accounted for as a so-called ‘process-mechanism’.

7. 1. Introduction • My main case-study, to which I will refer in making clearer the nature of NS, will be throughout the paper cancer research, more specifically, the scientific area of so-called ‘cancer as a micro-evolutionary process’ (Alberts et al. 2002). • Basically, there are the following two reasons for this choice of case-study: (1) the accessibility of evidence; (2) the proximity of NS, as a putative scientific mechanism, to mechanisms in a less controversial sense.

8. 2. Natural Selection • Below follows a schematic summary of NS, which also represents a consensus scheme in philosophical literature (see, in particular, Skipper and Millstein 2005) and here specifically refers to the occurrence of NS in tumorigenesis and cancerogenesis more broadly:

9. 2. Natural Selection I Initial Conditions 1. A population of biological entities (B) exist. [‘B’ is to be replaced by the name of some biological entity, most usually by certain individual organisms, e.g., Darwin’s finches, or, in the case of so-called ‘clonal evolution’ (see the corresponding figure below), by a cell and its cell-line. The above feature conforms to the so-called ‘substrate neutrality’ of NS.]

10. 2. Natural Selection 2. Bs vary according to forms of T, which are heritable. [‘T’ is to be replaced by some determinable biological trait; in our case, this could be, for instance, the capacity to thrive in highly reduced aerobic conditions, which characterize the situation within (human) tumors; specifically, with regard to secondary tumors (metastases), T can refer, e.g., to a certain cellular mechanism through which corresponding Bs colonize new tissues;]

11. 2. Natural Selection 3. Bs are in environment E with critical factor F. [‘E’ is to be replaced by the description of the total environment related to ‘B’. ‘F’ is to be replaced by the description of a critical factor in ‘E’; consider again the examples given in the case of ‘T’;]

12. 2. Natural Selection II Interaction 1. Bs in virtue of the varying forms of T interact differently with environment E. 2. Critical factor F affects that interaction. [(i) This is the so-called “causal crux” of NS. Exactly this point is probing the applicability of mechanistic approaches to NS.]

14. 2. Natural Selection III The Cascade of Downstream Effects Type of Effect (1): differential reproductive rates of Bs across forms of T in E. Type of Effect (2): (1) may lead to differential representation in the population of Bs across forms of T in E. Type of Effect (3): (2) may lead to the predominance of Bs with a certain form of T over other forms of T in E.

15. 3. Natural Selection as a Mechanism • This Section examines the main current views on NS, as schematized above, in the mechanistically oriented strand of the philosophy of science. • I will proceed here as follows: (3.1) Description of requirements according to which something is classified as a mechanism; (3.2) Analysis of the way in which Barros 2008 fits NS into a mechanistic framework; (3.3) Objections to the strong mechanistic program on the nature of NS.

16. 3. Natural Selection as a Mechanism (3.1) Description of Requirements: • Organization, i.e., this requirement is concerned basically with the following two claims: (1) mechanisms are comprised of various elements and (2) these elements are structured in some way (see Skipper and Millstein 2005; Glennan 2008; Barros 2008).

17. 3. Natural Selection as a Mechanism • Productive continuity, i.e., this requirement relates to the fact that mechanisms are productive of phenomena or behaviors from start or set-up to finish or termination conditions (see MDC 2000; Glennan 2008). [Examples: I will illustrate this mechanistic requirement by referring to some of the most typical examples of mechanisms both in biology/medicine and technology.]

18. 3. Natural Selection as a Mechanism • Regularity, i.e., this requirement refers to a specific quality of the way through which mechanisms are productive of change, more precisely, of phenomena or behaviors. That quality is understood by the main accounts of mechanisms as ‘regular, but not exceptionless’ (see Glennan 2008; MDC 2000).

19. 3. Natural Selection as a Mechanism (3.2) Analysis of Barros’ Mechanistic Interpretation of NS: • Barros 2008 figure for NS (Barros 2008, 316, Figure 3)

21. 3. Natural Selection as a Mechanism • Barros’ definition of NS as a mechanism: “NS is a multi-stage mechanismthat tends to increase the prevalence of a beneficial trait within a population over time.” (317) “NS therefore is a two-level, multi-stage stochastic mechanism that explains the phenomenon of adaptation. It is two-level because the phenomenon of adaptation cannot be fully explained using either individual or population level mechanisms alone.” (318; italics added)

22. 3. Natural Selection as a Mechanism (3.3) Objections to Barros’ account: • Despite its importance, the requirement of regularity is only one of the three requirements that, jointly, characterize an object as a mechanism. • Furthermore, the stage of “causal crux” itself appears to be a deterministic event, whereas the cascade of distinct types of causal outcomes – downstream of this crux – are probabilistic events.

23. 3. Natural Selection as a Mechanism • However, more intuitively, NS does not meet the organizational requirement that distinguishes mechanisms. In fact, mechanisms are a kind of tightly packed structures performing some function or, more briefly, they are “complex systems” (Glennan 2002). Consider in that respect the standard case-studies on which the main accounts of mechanisms are build up: mouse-trap, synaptic depolarization, protein synthesis.

24. 4. A Tip from Cancer Research (4.1) In tumorigenesis and cancerogenesis more broadly, we have the following general situation as far as the behavior of cells is concerned: • there are mechanisms that involve certain cells in a particular function (e.g., the mechanism by which a cell of a tumor colonizes foreign tissues; see the following figure);

26. 4. A Tip from Cancer Research • However, on the other hand, the same cell or cell line is involved in a causal chain of events, which in some important respects resembles the mechanisms in the above sense (see again the scheme of NS and corresponding figure for clonal evolution).

28. 4. A Tip from Cancer Research (4.2) The distinction between the above two basic kinds of mechanisms in tumorigenesis and cancerogenesis is correctly captured by the distinction between the so-called system-mechanisms and process-mechanisms (see, e.g., Glennan 2002). Since we have already seen that Barros’ account, which is an instantiation of a system-mechanism view, does not apply to the nature of NS, I will examine in the remainder of the paper whether NS can be classified as a certain variety of process-mechanism.

29. 4. A Tip from Cancer Research (4.3) Glennan’s account of process-mechanisms (P-Mch). These are the main features: • P-Mch is a unique causal chain of events. • P-Mch is a causal nexus within which a particular event brings about other particular event (e.g., the assassination of Archduke Ferdinand brings about the outbreak of WW I).

30. 4. A Tip from Cancer Research • P-Mch does not form a stable configuration tobe calleda system. • P-Mch does not form a type with distinct tokens. • P-Mch does not reliably produce behaviors, i.e., it is not robust. My final task: clarify similarities and differences between the above account of process-mechanisms and the nature of NS, as contributing to the onset of human cancers.

31. 4. A Tip from Cancer Research (4.4) In the above list of features, the third and fifth features do not appear particularly problematic. Thus, those features also apply to the occurrence of NS in neo-plasms. However, the remaining three features of process-mechanisms, as they are sketched by Glennan’s account of mechanisms, are problematic for the following reasons: • the similarity between the 1st and 4th features; • the right understanding of the 2nd feature; (iii) their applicability to the nature of NS.

32. 4. A Tip from Cancer Research • According to Glennan’s account, process-mechanisms can only be unique causal chains of events (e.g., the chain of events leading to the outbreak of WW I). In other words, there are no types of causal chains to which those tokens could belong, whatsoever. (ii) However, the 2nd feature above reasonably suggests the opposite view: unique causal chains do, in fact, fit within a corresponding causal nexus.

33. 4. A Tip from Cancer Research (iii) Now, if we accordingly interpret process-mechanisms, then their resulting features can also apply in discovering the nature of NS. For NS is both a unique causal chain of events (e.g., clonal evolution leading to the colonization from a primary colorectal tumor in a certain human individual) and, more importantly, a kind of process that has distinctive mechanistic aspects, such as the basic interaction at the “causal crux”, and the three types of downstream causal effects, intertwined in a certain manner.

34. 5. Conclusion • Consequence of the proposed understanding of the nature of NS: NS conceived as argued above is operative and evidentially supported explanatory vehicle for distinct important biological phenomena of interest to us. This is the most immediate consequence of the analysis conducted in this paper.

35. References Alberts et al. (2007), Molecular Biology of the Cell; Barros (2008), “Natural Selection as a Mechanism”, Philosophy of Science (PhoS), 75: 306-322; Brunnander (2007), “What is Natural Selection?”, Biology and Philosophy, 22: 231-246; Glennan (2008), “Mechanisms” in Psillos and Curd (2008), 376-384; Glennan (2002), “Rethinking Mechanistic Explanation”, PhoS, 69: S342-S353; Machamer et al. (2000), “Thinking about Mechanisms”, PhoS, 67: 1-25; Skipper and Millstein (2005), “Thinking about Evolutionary Mechanisms: Natural Selection”, St. Hist. Phil. Bio. Biomed. Sc., 36: 327-347.