Rosenberg Redux: How not to be a reductionist in developmental biology Laura Franklin-Hall
1. Introduction
The first round of debate on biological reductionism focused on the relationship between Classical and molecular genetics, with some participants maintaining the autonomy of Classical genetics and others arguing that molecular genetics could provide a reduction of the classical (Schaffner 1993), a replacement for it (Hull 1974), or explanatory extension of it (Kitcher 1984). Although the dispute had no clear victor, Alex Rosenberg (1997a 1 , 1997b, 2006) inaugurated a second round of reductionist discussion in the philosophy of biology, this time concerning the reductive relationship between developmental biology and molecular biology. Rosenberg argued that the science of development is reducible to molecular biology, recommending that the appropriate test for the reducibility of development is what he terms, after Lewis Wolpert (1994), the computability of the embryo based on “the total description of the fertilized egg--the total DNA sequence and the location of all proteins and RNA”(449). Rosenberg has suggested that the computability of the embryo should be understood in terms of the complexity of the function that, at least theoretically, maps molecular inputs to developmental outcomes. This function must be decidable, decomposable, and “relatively simple”(451). Using examples from Drosophila segmentation and eye development, Rosenberg has tried to show that biological development fulfills these conditions, and that molecular causes bring about embryonic morphologies in “a straight line manner”(453). Here I will develop Rosenberg’s proposed computability conditions and will argue that, correctly applied, they do not suggest that developmental phenomena are reducible to molecular 1 All unspecified page numbers refer to this text. 1

biology. Authors such as Robert (2004), Laubichler and Wagner (2001), and Frost-Arnold (2004) have also taken aim at Rosenberg’s reducibility claims. However, they have done so by rejecting, rather than applying, Rosenberg’s particular—and perhaps idiosyncratic—account of reducibility.
2 I hope to show that even on Rosenberg’s own terms, contemporary developmental biology does not reduce to a structural, lower-level science. I begin by explaining Rosenberg’s account of developmental computability. I then revisit his examples from Drosophila development that have been thought to illustrate the reducibility of development, arguing that they fail to indicate that development occurs as Rosenberg requires. I propose that the persuasiveness of Rosenberg’s position depends on his tendency to systematically mis-describe the developmental explanandum as well as the molecular explanans. In the following chapter (5) I develop an alternative account of reducibility in developmental biology, one claiming that reductionism fails when higher-level structures called modules are causally responsible for developmental events. I explain what I take to be the advantages of this “modular” account of biological anti-reductionism over traditional accounts that emphasize either causal democracy or traditional multiple-realizability.
2. Reduction as Computability
The biologist Lewis Wolpert’s work provided the inspiration for recent claims that development is reducible to molecular biology. In a two page opinion piece in Science, Wolpert (1994) considers whether we might one day be able to “compute the embryo,” to predict how an embryo will develop based on “a total description of the fertilized egg” (572).
3 Although 2 The one exception to this is Keller (1999). 3 Interestingly, although Rosenberg argues that to explain development based on molecular biology we only have to be able to “compute the embryo,” Wolpert is not of the same opinion. He only thinks that a full molecular description of the egg will allow us to “predict” embryonic changes, not that it will let us explain them. For example, he is impressed by how few 2

Wolpert is cautiously optimistic about the prospects for success, he does not explain what kind of computation would suffice, noting only that it would involve programming a computer “to simulate some aspects of development”(572). This statement is of course merely suggestive. Rosenberg recognizes that a reduction of developmental biology would involve not just simulating development, but doing so in terms of a lower-level science such as molecular biology.
4 In general, Rosenberg rejects the standard Nagel-type inter-theoretic reduction, owing partly to the fact that he believes that biology does not posit the laws required for a reduction, 5 but merely “almost invariable”(448) sequences of developmental changes. Thus, Rosenberg envisions an explanatory reduction of these developmental generalizations to the molecular level. A computational “explanatory” reduction begins, Rosenberg imagines, at a molecular level description of the embryo at conception. Based on knowledge of molecular interactions, the scientist, using her computer, should eventually be able to predict how all the molecules will be arranged later in time. The full account of such changes will provide an explanation. We are told that only certain kinds of molecules will be required for such a computation – DNA, RNA and proteins.
6 “principles” and “special concepts” that are required to “understand development,” such as “fate maps, asymmetric division, induction, competence, positional information, determination and lateral inhibition”(1994, 571), none of which are molecular, but rather functional, concepts. 4 Many computer models compute developmental change in terms of higher-level processes, such as the transformations in highly abstracted “cells” (for some examples, see Kumar 2003). Although these might well be explanatory, they are not necessarily reductive. 5 “[I]n developmental biology at least there are no deep explanatory generalizations….For there are no explanatory generalizations at higher levels of organization”(447-8). 6 Technically, there is no reason for Rosenberg to restrict his explanatory base in such a way (Frost-Arnold 2004). Thus, following changes he makes to this account in his 2006, we can assume that such a computation could call on information about all (molecular) aspects of the developing organism. 3

Rosenberg does insist that the function from molecules to embryo used in the explanation fulfill certain standards. In particular, it should be decomposable and relatively simple (451). Decomposability requires that, where non-molecular “cellular machinery” plays a part in the explanation, that machinery itself should be explainable using molecularly-described processes. As Rosenberg sees it, this is tantamount to rejecting the explanatory use of “downward causal forces, undisaggregatable functional units, or for the matter vital forces and entelechies”(450). He intends with this to rule out computational models that use functions that are not either based on local interaction between molecules in the embryo, or decomposable to such items. Rosenberg also insists that the function from molecules to embryo be “relatively simple.” He characterizes this as meaning that developmental phenomena are only explained when the “vast diversity of forms” are explained by “a tractable base of a relatively small number of regulatory and structural genes (and their protein products) combined by a similarly small number of combination rules”(451).
7 This is a significant restriction to place on reductive molecular explanations of developmental biology. Importantly, the simplicity requirement, since it is based on parameters such as the number of molecules and the number of combination rules, makes the reducibility of development an empirical claim about biology, rather than merely about the nature of explanation itself. If it turns out that there is no such small set of regulatory structures and genes, 7 This is similar to views of reduction promoted by other authors. Britten (2003) writes that the real question about the reduction of developmental biology isn’t about either epistemological or ontological reduction: “The issue is not antireductionism, however. It is a direct question of whether genes with large information context exist. I am exited by the prospect of proving the grand principle that biology depends just on the details”(Britten 2003, 85). 4

Rosenberg admits that “we can surrender all hope of any completeness and generality in understanding how diversity in development if possible, let alone actual”(451).
8 Restrictions on a reductive explanation for Rosenberg 9 Explanans “relatively regulatory and structural genes and their protein products” “a small number of combination rules” Table 1 small number of Explanandum “the vast diversity of forms” Based on this schematic account of reduction, Rosenberg concludes that work coming out of developmental labs indicates that developmental phenomena are reducible to molecular biology – the vast diversity of forms are explainable based on a small number of molecules and their interactions. To evaluate this claim, we can now examine actual developmental phenomena cited by Rosenberg and clarify the restrictions Rosenberg places on a successful reduction.
3. Examples: the fly and the eye
8 To say that the claim is empirical is not to say that it doesn’t require philosophical commitments. As we will see, potentially controversial views about causation are required to determine which molecules in the embryo are necessary to explain the development of the embryo. 9 The discussion surrounding Rosenberg’s paper seems to has completely abandoned this claim on the limits on a reducible function, possibly because Rosenberg himself seems to have abandoned it when he suggests that the only way that anti-reductionism might turn out to be correct is if there ends up being downward causation between higher-level functional kinds and the molecular level. It could be true that there is no neat set of rules governing the molecular level supporting the explanation of the embryonic level without having to enter the quagmire of downward causation. In any case, Rosenberg’s attempt to understand the nature of the reducing function is probably a step in the right direction and its place in his argument ought to be emphasized. 5

The main examples of reductive explanations in development to molecular biology are 1) early drosophila development, based on work by Christiane Nusslein-Volhard and Eric Wieschaus (see their [1980]) and Lewis Wolpert, and 2) eye development, based on Walter Gehring’s work [1998]. To account for early drosophila development, Rosenberg provides the following explanation-sketch.
10 Beginning in the 1960’s, Wolpert hypothesized that a concentration gradient set up by the diffusion of molecules from a source on one side of the embryo could explain the differentiation of cells in different parts of the embryo, in a model known as the French Flag Model. No such molecules were known, but Wolpert predicted their existence and preemptively named them “diffusible morphogens.” According to the model, different concentrations of the diffusible morphogens could “switch on different developmental patterns in different parts of the embryo”(451). Three different patterns, reminiscent of a French flag, would result if there were two threshold levels above which the diffusible morphogen activated alternate developmental genes. Figure 1 Researchers then uncovered a particular molecule that appeared to be just such a morphogen, illustrating the French Flag model in action. This molecule was bicoid. The mRNA 10 Similar sketches of this story can be found in any developmental biology textbook. I use Wolpert (2007) and Gilbert (2007) as general references. 6

of the bicoid gene is localized at the anterior end in the unfertilized Drosophila egg. When this is translated to protein after fertilization, it diffuses towards the posterior end, leading to a bicoid concentration gradient from the anterior to the posterior end of the young larva. The bicoid protein then serves as a “positional signal.” Most importantly, it acts as the transcriptional activator of another gene, hunchback, leading to the expression of hunchback in the front half of the embryo. The activation of second tear genes, called gap genes, by hunchback and bicoid combined, leads to the expression of still other genes, such as Krüppel, giant, and knirps, in particular bands. For example, Kruppel is expressed in the midsection of the embryo in which there is both bicoid expression and low levels of hunchback expression. As Rosenberg explains it, “the bicoid gene expresses a protein which turns on and/or turns off some twenty five segmentation genes”(452). Eventually, the embryo is segmented into narrow bands of gene expression, with each band eventually developing the proper appendages, such as antennae, legs, and eyes.
11 This seemed to be an obvious example of a molecular-level explanation of a developmental process. Maternal Factors Gap Factors Pair-rule Factors Segment-polarity Factors Figure 2 11 These bands determine gene expression in the larvae, and it is only in the imago that such organs develop. 7

Rosenberg believes that based on such explanations, developmental biology has “discharged” the old teleology of embryology, a discipline in which an explanation of early drosophila segmentation would take place by citing that the cellular differentiation was “needed to direct subsequent differentiation throughout the embryo”(452). Obviously such cascades do not explain development in a teleological manner. Yet this isn’t all that is required for them to be acceptable reductive explanations according to the standards discussed above. Does the bicoid cascade of gene expression satisfy Rosenberg’s demands that the reducing science account for “the vast diversity of forms using “a relatively small number of [molecules]” and “a small number of combination rules”? Answering this question requires spelling out the example in more detail and on stating more clearly what the explanans and explanandum are supposed to be. Let us begin with the explanandum.
12 This particular example does not provide an explanation that accounts for the vast diversity of embryonic forms. However, hoping for as much could be demanding more from the reduction than Rosenberg’s account requires. Does the account maintain 1) that the vast diversity of forms are explained by one small set of molecules and combination rules [  x(Sx   y(Fy  xEy))], or, 2) merely that each form should be explainable by some small set of molecules and combination rules, but not that there be one set of molecules that explain all forms [  y(Fy   x(Sx  xEy))]?
13 It seems safe to reject 1), either 12 Rosenberg does not state exactly what the bicoid cascade is explaining, so we have some flexibility in characterizing it. 13 One might also wonder how forms should be individuated. Is Rosenberg suggesting that the form of an entire organism (including the hands, the heart, etc.) should all be explained in this simple way, or that each part of the form (each hand, heart, etc.) should be amenable to such an account? 8

as an interpretation of Rosenberg or a statement of fact. There is no reason to think that there is any small set of molecules and rules that explains the vast diversity of forms.
14 But possibility 2, which maintains that there is a small set of molecules/rules explaining every form, can further be distinguished into sub-varieties, a) one maintaining that similar forms should be explained based on the same molecular interactions across species, b) and another one insisting that forms in a particular species (or even a particular organism) be explained by the restricted set of molecules/rules. Although he modifies his views at times, Rosenberg does suggest that he believes 2a), that the development of general categories of form found in a variety of organisms – such as head shape, limb development, or organ morphology – should be each explainable by a small set of molecules and mechanisms. First, this view is apparent from Rosenberg’s account of eye development, in which he emphasizes that that an individual gene and the protein it expresses, eyeless, in addition to the set of proteins that eyeless activates, explain eye development in a variety of organisms from fruit fly to mouse to squid to planarian (454). Rosenberg seems to be looking for an explanation of the eye across species, not merely within one. Second, Rosenberg likens the generative explanatory potential of these molecular explanations to the explanatory potential of computationalism in philosophy of mind. Computationalism, Rosenberg says “is overwhelming attractive in cognitive science because it enables us to explain the power to encode and decode an indefinitely large class of signals on the basis of a finite stock of recognizable elements”(450-1). Based on this parallel, just as a large class of signals can all be explained by a “finite stock of elements,” an “indefinitely large” class 14 Nevertheless, it does sometime sound like Rosenberg is making this stronger and implausible claim. 9

of forms should be so explained based on, in his developmental description, a small set of elements.
15 With this view of the explanadum in mind, the kind of animal “form” that seems to be explained in the bicoid example is the process of anterior/posterior differentiation. It is of course a pervasive fact across the animal kingdom that differentiation of form takes place along the head-tail axis, and we can understand Rosenberg as providing an explanation of it. Yet the explanation given does not elucidate much of what goes into making one part of the embryo the front, such as how the eyes and antennae develop, or the back, with the appropriate pear-shape and wings correctly attached. Instead, what appears to be explained is how different parts of the embryo obtain rather general information about where they are situated along the A-P axis. Here we can see that although Rosenberg implies that his “simple” explanations will account for “forms,” form itself is not explained. The explanandum has been changed from this more traditional embryological goal to a narrower one, that is, to understand “the control of gene activity in time and space”(Nusslein-Vohlard 2006, 21), in particular, to the control of gene activity along the A-P axis in the early embryo. As Davies (2005, 3) has noted, contemporary developmental biologists frequently substitute one explanandum for the other (differentiation for morphogenesis), suggesting that the project of understanding development is tantamount to understanding cellular differentiation. Yet we have no reason to think that actually explaining morphogenesis will be anything as simple as explaining how certain genes can be turned on or off along the A-P axis. According 15 Of course the difference between the developmental and the computationalist case is that while Rosenberg insists that the “finite stock” of explanatory elements be small, some computationalists do not make that requirement. Fodor (1998), for example, claims that we have huge library of innate concepts for everything from doorknobs to pandas. In as much as such a large set of elements are required for explanations, they cease to fulfill Rosenberg’s appealing simplicity requirement. 10

to Davies, morphogenesis, as opposed to the signaling of differentiation, is “a formidably difficult problem….involving the interaction of thousands of different molecules….This makes it much more complicated to study…than differentiation”(3). Davies explains that morphogenesis itself is normally treated in developmental biology texts as a “black box” and that it appears that the box is full of rather complex cellular mechanisms, the likes of which Rosenberg does not mention. To make the black box transparent would involve not merely explaining how one cell knows what kind of cell to differentiate into, in this case based on bicoid concentrations, but also to explain how that differentiation takes place and how the differentiation affects form.
16 Of course, this need not be a disaster for Rosenberg’s project. Perhaps he ought to rephrase his explanandum, as applied to development, as one which insists that “cellular differentiation” be explained by “a small number of molecules.” Let us explore whether his claim make more sense against this somewhat more modest—although still impressive—goal. Although the details of Rosenberg’s example come from drosophila, we can assume, again given his statement of the explanandum, that the bicoid story applies to many other animals with anterior/posterior differentiation. After all, he states that the example is intended to “sketch some of the results that sustain”(451) optimism about the existence of a function that satisfies the table 1 conditions. Yet, unfortunately the bicoid story does not cleanly apply to most organisms with A-P axes. The French-Flag model above applies uniquely to a small number of “anomalous” insects whose early embryo’s pass through a syncytial blastoderm stage, a stage in which the embryo is composed of a large, multi-nucleated cells and does not possess internal cellular boundaries. This 16 Wolpert himself is very clear that he is not explaining form. He distinguishes between what he explains, “the spatial organization of cellular differentiation,” from “the two other processes in development, cellular differentiation and changes in form”(1981, 441). 11

stage is crucial to the mechanism because the protein (bicoid) must be able to diffuse across the entire embryo and thus determine anterior-posterior differentiation based on the different concentrations found in different areas. And although developmental biologists have found remarkable similarities in the genes and proteins responsible for this determination across the animal kingdom, most require a much more complex story to explain differentiation since, in most organisms, inter-cellular communication – usually through a G-protein coupled signaling mechanism – is required to communicate between cells so as to provide information about their relative positions. Thus, the suggestion that there are only a small number of genes and proteins, and interactions between them, required to explain development becomes implausible. In most organisms, there is no equivalent to the bicoid protein which can act as an individual signature of A/P axis position.
17 Thus, it seems that the real explanandum in Rosenberg’s case has to be narrowed to 1) a specific form, e.g. eye, liver, etc. (rather than all organismal form), 2) cellular differentiation (rather than the physical production of morphology), 3) in the fruit fly or other syncytial organism (rather than a diverse group of them). This need not spell disaster for Rosenberg’s explanatory program. His original statement of the explanandum might have been somewhat optimistic, and some of his reductionist ambitions might need to, as he suggests, “be curtailed.” But he might still be right that, at the very least, this explanandum can be explained by “a tractable base of a relatively small number of regulatory and structural genes (and their protein products) combined by a similarly small number of combination rules”(451). In fact, to make the reductionist task even easier and to prevent disputes about the exact breadth of the explanandum, 17 Not only is cross-cellular communication required in some organisms to orient the A/P axis, but there others, such as the frog, which don’t use a gradient mechanism at all to determine cellular A/P position. 12

let us further simplify it by taking it to be the development of a particular organism.
18 Rosenberg’s challenge will be to merely explain this particular developmental event in terms of his chosen explanatory base. Determining whether even this is possible involves taking a closer look at the explanans. Rosenberg’s explanans includes molecules which compose the organism and rules for combining them. These should both be “of relatively small number”. Evaluating the plausibility of this claim is made difficult by the fact that Rosenberg (1997a, 1997b, 2006) does not provide any explicit statement of what he thinks molecular biology, the science that is thought to reduce/explain developmental generalizations, looks like. Are the basic objects of molecular biology molecules described chemically in terms of atoms and their topological connections? Or are they molecular species defined in functional terms, such as transcriptional activators? Depending on how molecular species are described it can easier or harder for the simplicity requirement to be fulfilled. Because of this lacuna in Rosenberg’s account, interpreters such as Frost-Arnold (2004) have proposed a way of understanding the science of molecular biology for use in Rosenberg’s project. Frost-Arnold notes that the reducing realm has not been a point of debate: A reductionist about development would have to maintain that the mechanisms or rules that govern interactions between molecules are sufficient to derive or ‘explain’ in some sense the regularities at the developmental level of description (in combination with the 18 Rosenberg ends up asserting that he is only seeking an “existence proof” which aims to show that there are some developmental processes which can be explained using the principles that Rosenberg and Wolpert demand. Thus, it makes sense for us to consider the viability of even token molecular explanation here. 13

F-terms). What sorts of ‘mechanisms’ are these in the case of molecular biology? I will not go into detail about this, since neither Rosenberg nor Laubichler and Wagner do. [my italics](Frost-Arnold 2004) 19 To fill the gap, Frost-Arnold uses Sahotra Sarkar’s description of the reducing language of molecular biology from his [1998]. This language is called “macro-molecular physics”(p. 136), and is described by the following four rules: i) Weak interactions rule: “the interactions that are critical in molecular explanations are very weak”(p. 149). ii) Structure determines function: “the behavior of biological macromolecules can be explained from their structures”(p. 148). iii) The importance of molecular shape: “these structures, in turn, can be characterized entirely by molecular size and, especially, shape, and some general properties (such as hydrophobicity) of the different regions”(p. 149). iv) Lock-and-key fit for molecular interactions: “molecules such as protein molecules forming larger structures or enzymes interacting with substrates interact when there is a lock-and-key fit between the two surfaces”(p. 150).
20 How could these rules play a part in an explanation of development? Sarkar envisions molecular biologists treating the DNA-RNA-protein system as a network of chemical reactions, in each case attempting to write down a system of differential equations describing the processes that they would like to explain. Sarkar says correctly that the main difficulty with such an 19 Note that Frost-Arnold puts aside the simplicity requirement in his account of Rosenberg’s reductionism. He takes the explanatory task of developmental reduction to be the ability to explain developmental events based on any number of molecules and rules for combining them. 20 Sarkar’s emphasis on molecular shape is consistent with the fact that he takes the central successes of the molecular revolution to be explanations of 1) the allosteric hemoglobin molecule and 2) Linus Pauling’s explanation of the shape of proteins based on α-helices and β sheets. On the other hand, Sarkar dismisses the importance of Jacob/Monod-style explanations for the context-dependent up- and down-regulation of gene expression. These are the kinds of explanations that are, in my understanding, now taken as central to molecular biology, and are the basis on which the systems biology community functions. 14

account is that each explanation must call upon a rather large number of variables. These variables have to keep track of, among many other factors, the concentrations (and the sub cellular locations) of each type of DNA, RNA and protein that could potentially arise in the cell, “not just the ones that emerge during normal gene expression, but also those that could arise through errors”(218). Internal to Sarkar’s account, one might worry that however complicated biological explanations of development might be on his terms, they actually should be even more complicated. Sarkar’s reduction emphasizes only the DNA, RNA and protein concentrations and interactions. Yet, lots of inorganic cofactors modulate the rate at which enzymes catalyze the DNA/RNA/Protein reactions. In part, this is through changes the ions affect in the shapes of proteins. If this is how Sarkar hopes his explanations to look, he will need his explanatory base to include all molecules of the developing embryo, not merely the interactions of the big three. This is, of course, not a serious problem. However, it does show the extent to which such explanations would surely fail Rosenberg’s “simplicity” test. More interestingly, perhaps, is the possibility that Sarkar (and hence Rosenberg) mis describes the how these sort of systems of differential equations actually explain biological (and thus developmental) events. Do the chemical networks actually explain developmental events in terms of the shapes of molecules and their lock-and-key fit interactions? There is reason to think they don’t. Scientists often have no knowledge of the mechanism of action of a given enzyme, that is, of the location or shape of the active site and how the substrates are bound to the active site, yet they still produce perfectly good accounts of the interactions of those molecules in the Sarkar-style. This is because one needs to know only the functional effect of one enzyme on a candidate reaction in order to produce these explanations, and not actually to understand their 15

physical interactions. It is true, presumably, that a full account of why a particular enzyme affected a molecular interaction in such-and-such a way could itself be explained by facts about molecular shape. However, given the dearth of such facts used in simulations of molecular networks, a further argument is certainly needed for us to believe that these molecular details are really required for a full biological explanation. The potential irrelevance of the exact shapes and even the quantitative fine-tuning of molecular interactions in explaining development has been brought out by work by von Dassow and coworkers (2000) in their investigations into the networks of genes responsible for segmenting the drosophila embryo – the segment polarity genes. They began their investigation using an explanatory strategy very similar to the one Sarkar describes – finding all the parameters that affect the interactions of the relevant molecules such as binding rates and cooperativity coefficients, and plugging them into systems of equations meant to model the molecules system under scrutiny. However, once Dassow’s team produced a network with the proper topology – with the correct qualitative connections of up and down regulation between elements – it turned out that it the “fine-tuning” of the various parameters didn’t matter. The patterns of gene expression characteristic of embryos after segmentation would be produced just by virtue of the network topology and not because of the fine details of the molecular interactions.
21 Furthermore, it isn’t clear that Rosenberg’s examples—which serve the rhetorical purpose of showing us how simple a non-functional, physical reduction of developmental biology would be--actually use Sarkar’s “macro-molecular” physics in explanations of 21 This doesn’t mean that all molecular networks are robust in this sense. For those developmental systems that lack this kind of robustness, it is easier to make a case that the details of molecular interaction as Sarkar envisions them are necessary for a full explanation of development. 16

development. Rosenberg certainly purports to give a fully molecular account of development, but at times it seems he does not. The Rosenberg/Wolpert explanation of developmental events is not posed in terms of rate equations and chemical conversions, but instead in terms of transcription factor and transcription factor binding sites, functional concepts. Rosenberg’s explanation, for example, explains how certain genes “turn on” or “turn off” other genes (452), and also how certain molecules “signal” to others their position in the embryo. These connections are always qualitative topological explanations, such those found in many-a biology paper. Even allowing that “signaling” language is purely metaphorical, Rosenberg’s basic understanding of the relationship between genes is in terms of the functionally described network of interactions that they are involved in. Of course, this use of functional language in the explanation of development is not surprising. Rosenberg requires that only a few rules govern the interaction between genes and molecules. The only way that these rules would be few is if they are phrased at a functional level, in terms of Jacob/Monod-like gene expression pathways. This is also the way that prominent developmental biologists suggest that development be explained. In her recent book on the topic, Christiane Nusslein-Volhard explains that if we hope to explain development, we should actually not look at “the attributes and characteristics of molecules so much as with their role in development”(2006, xii). But this is precisely what Rosenberg’s account purports to eliminate – the use of functional concepts in the explanation of developmental events. But let us grant that molecular-interaction explanations should be reduced to the shape and fit between the central varieties of molecules, and that it is necessary to attend to the details of these molecular interactions – rather than merely to their topology or their functional roles -- in order to produce a satisfying explanation. Does such an explanation satisfy Rosenberg’s 17

requirement that explanations call on a small number of genes and proteins, coupled with a small number of rules governing their interactions? It is easy to understand what a failure of this requirement would look like: the discovery that one needed a full molecular model of the cell in order to explain developmental generalizations. Sarkar himself comments that it is perfectly possible that such an “explanation” might yield nothing “except a morass of inchoate detail”(226). He suggests that if explanations looked like this, this could show the limitations of this sort of reductionist explanation in molecular biology. So, in order for Rosenberg’s strategy to succeed, he needs to be able to pick out individual molecules and the interactions which account for the developmental explanandum, cellular differentiation, while leaving the countless other molecules that play a part in the embryo in the background. It isn’t the case that the activities of a small number of molecules could ever be sufficient for cellular differentiation in a developing organism. Developmental genes, just like all other genes, important in “directing” organismal development can only take effect against a background of cell physiology, and within a particular embryonic environment. This is not a problem unique to developmental explanation. Among many others, Lisa Gannett (1999) has argued that causal explanation in biology always involves the foregrounding of particular kinds of causes and the backgrounding of others. Rarely, if ever, can we say that any cause is necessary and sufficient for any effect. When we take causes to be mere difference makers, we are faced with an overabundance of causes; we focus in on particular difference makers by changing which we put in the foreground and which we hold fixed in the background, leading to different attributions of cause for the same apparent effect. Traditionally, the foregrounding / backgrounding problem in developmental biology has been confronted by those interested in understanding whether DNA should be considered a 18

“master molecule” controlling development: why say that DNA is The Controller when particular environments are also necessary for all biological events as well? After all, just as changing genes against a fixed environmental background can change developmental output, so can changing aspects of the environment when the genetic background is held fixed. Critics of Rosenberg’s account, such as Robert (2004), have rejected the reductionist project precisely because of worries about how to partition the developing embryo into causal/explanatory foreground (molecular) and enabling background (environmental). One might wonder whether this should be enough of a reason to reject the reductionist program. After all, these issues affect almost any attempt to provide causal explanation, including the seemingly straight-forward claim that the striking of a match was the cause of a forest fire, considering, for example, that oxygen was also required. In any case, let us put aside the frequently-discussed environmental concerns for now, and try to determine whether even within the embryo’s skin we can successfully locate the developmentally relevant molecules. Rosenberg’s task is both easier and harder than that of she who insists that, among all the molecules in the body, the “master DNA molecule” controls the progress of development, and thus explains it. It is easier because he has allowed himself to use different kinds of molecules – DNA, RNA and protein – in his explanation of development. The task is harder because he insists that only a small subset of these kinds of molecules, and simple rules according to which they interact, are needed to explain development. One set of molecules (or molecular interactions) that it would be tempting to separate off from those responsible for development are those required for maintenance of life independent of development, such as metabolism and membrane stabilization. Geneticists frequently partition genes into different categories, such as housekeeping genes (those that are “constitutively 19

active”) and genes required for special categories of tasks. This project, of course, isn’t completely straightforward, due to the fact that many genes/proteins that are required for normal physiology in adulthood are also required for different reasons during some phases of development. But let us put aside this concern, and assume that we can focus on the developmentally relevant genes and provide an explanation of development based on these genes. Even focusing on genes/molecules that scientists think are responsible for cellular differentiation in development, it does not appear that only a “small number” are required in these processes. According to Rosenberg’s sources, over 2500 genes are required in the cellular differentiation of the eye. Coupling that with all the protein products of these genes, it does not appear that we can tell a simple story of their behavior in terms of a “small number of molecules.” Attending to all molecules needed even for cellular differentiation, and putting aside concerns about how these are distinguished from “housekeeping genes,” still leaves us with a rather large molecular burden. It seems that Rosenberg must believe that we can focus in on particular developmental molecules which are the “really important” ones. The best indication we get of how Rosenberg thinks these developmental molecules can be separated from the others comes from Rosenberg’s description of eye development. Rosenberg says that there are a few genes uniquely responsible for producing complex organs, such as eyes, and that function “in a straight line manner”(453).
22 The crucial piece of evidence for this “straight-line” causation by a small set of molecules was provided by the work of Walter Gehring. Gehring (1998) showed that when the homeotic gene Eyeless is expressed in somatic Drosophila cells, it causes the growth of complete eyes no matter 22 Ghering himself is often more circumspect. He writes in his [2000] that “the eye morphogenetic pathway is by no means linear but rather a complex genetic network”(175). 20

where in the body it is activated. These ectopic eyes are functional, and are composed of cornea, pseudocone, cone cell, etc. The gene (or its protein product) that initiates the eye-producing cascade has been called, suggestively, a “master-control” gene, whose activation is “necessary and sufficient to trigger a cascade of genes”[my italics] giving rise to eyes. By looking for the master-control genes, which are seen as regulatory bottlenecks, we can locate the molecules necessary to explain development from those that are not so necessary. Such bottlenecks do seem impressive. The Eyeless trigger leads to the activation of perhaps, according to Rosenberg, all the genes required for eye morphogenesis which are “all under direct or indirect control of eyeless”. Rosenberg notes that similar genes are found in vertebrates, and that eyeless can activate vertebrate eye development even though vertebrate eyes look completely different. He suggests that this is a good example of a system that fulfills the restrictions on reduction given earlier: “These results suggest that one of the most complex of organs is built by the switching on of a relatively small number of the same genes, across a wide variety of species”. A problem with this strategy of explanation is apparent when we make a parallel with the explanation of artifact behavior. If we believe that the real explanation of developmental events comes from the activity of the master control genes, we should also believe that the real explanation for the behavior of a computer lies is the turning on of that computer – the flicking of the switch. But the turning on of the computer actually seems to explain almost nothing of its activity. It is more akin to the background conditions necessary for the activity of the circuits in the computer or the program running on it, more like oxygen than it is akin to the striking of the match. Rosenberg needs to provide an account of why these molecular triggers should be considered explanations of development. 21

Once we attend to the down-stream effects of the master-control genes, we see that accounting for the activity of the genes that they “control” will not be a simple task and will involve us in a rather complex explanation involving far more that the “small number of molecules” allowed. Eye development is thought to be effected by a network of 3000-5000 genes (Thaker and Kankel 1992), all of whose expression is tightly regulated in a tight and complex network (Chen and Mardon 2005). More worrying, biologists believe that only a “small portion” of the genes affecting eye development have actually been identified (Chen and Mardon 2005, 286). Without having even worried about whether a “small number of mechanisms” are required to explain the interaction between molecules, it looks as though an explanation of eye development will not fulfill Rosenberg’s reductionist desiderata. Rosenberg might emphasize at this point that even if lots of molecules are needed for cellular differentiation, molecules like eyeless are “bottleneck” molecules, should be thought of as the “important” because of their promiscuous effects. Changing the concentrations or locations of these explanatory developmental molecules during development will affect the morphology of the embryo (without affecting background physiology) is a way unparalleled by genes activated downstream from them. There is something right about this strategy, but its usefulness should not be overblown. It appears that the bicoid protein can be said to have “promiscuous effects” in this sense. Experiments show that a drosophila that does not express any bicoid lacks anterior structures entirely. This is because, lacking bicoid expression, hunchback expression is not correctly concentrated in the anterior end, and thus cannot activate the appropriate gene expression in the anterior of the organism. 22

But, if our goal is to explain sometime slightly more fine-grained, such as the location of particular segments in the embryo rather than merely explaining the brute presence or absence of anterior regions, the story becomes more complicated. As Wolpert notes in his [2007], although it is clear that bicoid activates hunchback, measurement of the bicoid gradient has revealed that while it has different strength at a given A-P location from one embryo to another, “the spatial positioning of expression of zygotic hunchback remains the same”(58). This indicates that there is a mechanism which maintains developmental robustness in hunchback expression, something which can’t be explained merely by pointing to the causal link between bicoid and hunchback concentrations. Figure 2: (from Patel and Lall (2002)) This shows that the supposedly “straight-line” causation of one developmental molecule on another is not as straight as it appears. If Rosenberg hopes to explain using a simple story the location of a particular A/P boundary, such as the boundary between the head and the torso (the labial segment and the first thorasic segment), he will not be able to point to merely bicoid expression and the down-stream affects of that expression. Although the story is still unfolding, researchers have found that only large, stable networks of molecular interactions will explain the robustness of the hunchback expression profile and all other segmental boundaries within the embryo. An explanation of the locations of these boundaries, central to the developmental patterning which Rosenberg needs to explain, is much more complex than he suggests. 23

This illustrates a principle which holds true in many developmental systems: that major developmental events are not “controlled” by simple cascades, but are buffered from genetic and environmental noise though the use of various homeostatic mechanisms. If we must include explanations of the homeostatic mechanisms, we are left with explanations which are not as clean and linear as the text-book explanations for organismal development, like those that Rosenberg provides. This doesn’t mean of course that there isn’t something right about text-book explanations. But these cascades only work because of under-reported molecules that do the dirty-work of making sure these generalization hold. An explanation that captured robustness of development would need to do one of two things – one, it would need to include molecular characterizations of all homeostatic, noise buffering systems that play a part in development; or two, it would need to take these homeostatic systems, taken as wholes, as part of the explanans, and to admit that a good explanation of development would be at the level of these homeostatic systems and their interactions, systems which are called modules (see chapter 5 for an attempt to develop this approach).
4. Consequences
If indeed I have shown that the facts of development, even those required for an explanandum as narrow as the development of an individual embryo, fail to satisfy Rosenberg’s restrictions on computable reduction, this might not seem noteworthy. An argument that X is irreducible is only as interesting as the putative account of reducibility being used. Frost-Arnold (2004) has argued that with a little tweaking of Rosenberg’s account, common developmental phenomena are reducible to molecular biology. This “tweaking” involves an abandonment of 24

Rosenberg’s problematic “simplicity” standard, the one which has caused trouble over the course of this paper. But is there any value in Rosenberg’s particular, unadulterated account of reduction? Why does it matter, one might wonder, how many molecules are needed to explain development, or how many kinds of interactions they have with one another? One response to this question is that, with the triumph of physicalism, we are interested in the debate between reductionists and anti-reductionists no longer being about the presence or absence of vital forces or final causes. Judging by the number of times actual scientific results are included in philosophy papers which argue on one side or the other of the reductionism discussion, it seems that the actual results of science are important in deciding the question – a metaphysician in her armchair would not be capable of settling the dispute. Rosenberg’s requirement makes sense of both of these facts – it makes the truth of reduction a contingent matter of fact, a fact about which two physicalists might disagree, and one about which they would need to look to scientific results to adjudicate between. As Frost-Arnold modifies Rosenberg’s approach, as Rosenberg himself does in his (2006), the success of the reductionist seems almost trivial. Particularly with the explanandum narrowed to a token organism, the claim is merely that using all molecules in the cell, and attending to all the different kinds of interactions between them, it is possible to give an explanation of all developmental events. Is there anything about how the world is (rather than how explanation works) which could have lead this to be false? Of course, the desire that questions of reduction genuinely depend on the facts of development doesn’t justify the particular requirement Rosenberg places on reduction, but merely suggests that an adequate account of reductionism should leave some empirically 25

verifiable dispute between reductionists and their adversaries. Thus, we need a more specific reason to take seriously Rosenberg’s account of reduction. A weak reason to follow this account is that biologists also seem to be concerned about the complexity of the network of molecules that play a part in developmental explanations: “Life depends on the interaction of tens of thousands of genes and their protein products, orchestrated by the regulatory logic of each genome. If we are to comprehend this logic, we must hope that it can be dissected into a series of interlinked modules or networks, each of which can be studies in relative isolation”(Dearden and Akam 2000, 131). A stronger reason might be that Rosenberg’s account actually represents an attractive intermediate view on the relationship between lower-level and upper level kinds when compared with two prominent alternatives. On the one side, we can imagine a naïve developmental reductionist who believes that a successful reduction will involve showing that there are particular molecules that are causally responsible for the development of particular developmental structures. This account doesn’t work for a variety of reasons which the reader can glean from the discussion above. On the other hand, there are those that believe that a successful reduction requires no regular relationship between the molecular level and developmental kinds, just as long as there is a dependence of one on the other. That Rosenberg’s view is intermediate between these two can be seen by his emphasis on that the genes that produce complex organs, such as eyes, function “in a straight line manner”(453).
23 The importance of this “straight line” of molecular interactions is that Rosenberg’s account of development will show a close relationship between families of molecules interacting in simple ways, and the developmental structures which embryologists map. This definitely preserves a 23 Ghering himself is often more circumspect. He writes in his [2000] that “the eye morphogenetic pathway is by no means linear but rather a complex genetic network”(175). 26

kind of intelligibility that the mere dependence view lacks. Of course, we’ve seen that Rosenberg might have been overly optimistic that such small sets of developmentally responsible molecules exist, but there is no reason to doubt the attraction of such a view of reduction. If I am right and the actual details of biological development can’t be explained in the molecular way that Rosenberg suggests, we are left, rather awkwardly, without any account of developmental explanation at all. Rosenberg tells us that “in developmental biology at least there are no deep explanatory generalizations” in terms of functional biology. If, on Rosenberg’s own account, we can’t give an explanation of developmental events in terms of molecular biology either, then, is developmental biology not only not reducible but not explainable at all? No. Let us not be hasty. In the next chapter, I will present an account of developmental explanation which hopes to show how developmental events are explainable even when they are not molecularly reducible. References Britten, Roy J. (2003) “Only Details Determine,” in Origination of Organismal Form: Beyond the Gene in Developmental and Evolutionary Biology, ed. Mueller and Newman: Cambridge: MIT Press. Carroll, S. (2005) Endless forms most beautiful: The New Science of Evo-Devo. New York: Norton & Co. Chen, Rui and Graeme Mardon (2005) “Keeping an eye on the fly Genome”, Developmental Biology 28: 285-293. Davies, Jamie (2005). Mechanisms of Morphogenesis, Elsevier Academic Press: Amsterdam. Dearden, Peter and Michael Akam (2000). “Segmentation in Silico” Nature 406: 131-132. Fodor, Jerry (1998) Concepts: Where Cognitive Science Went Wrong Oxford: Oxford University Press. Frost-Arnold, G. (2004). "How to be an Anti-Reductionist about Developmental Biology: Response to Laubichler and Wagner." Biology and Philosophy 19(1): 75-91. 27

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