The fiction of function

What is the function of the human hand? What are the functions of our fingers? One could give a very incomplete list of functions of the hand: holding cups, swatting mosquitoes, etc., and similarly for fingers: wrapping around things, pressing on things, holding rings, etc. This clearly is a pointless exercise—incomplete in the extreme—yet it is essentially the goal of many function representation schemes in systems biology, often called ‘functional ontologies’. There are several problems with listing the functions of biological objects. First, any object has several functions; possibly an infinity of them! The photosynthetic PSII complex, for example, serves many ‘typical’ functions: absorbing light, abstracting electrons from water, passing these to the electron transport chain, producing protons (that energize the pH gradient, driving ATP synthase to produce ATP), and producing free oxygen. One could list all of these, or try to assign them to the subunits of PSII. But independent functions cannot generally be assigned to individual proteins in a complex; like the human hand, most systems cannot be cleanly separated into subunits that have clear individual functions, nor is the composite function a simple combination of these. Furthermore, many objects serve different functions under different circumstances. For example, in high light, PSII produces damaging reactive oxygen species (ROS). Similarly, many chaperons serve both in the folding of proteins, and in their degradation. Moreover, to try to list the complete set of functions is to exclude novel function through evolution or pathology, where objects serve new functions, often without having undergone any change in their own structure. The typical representational principle, e.g. as implemented in the Gene Ontology project (www.geneontology.org, and 2000), assigns functions to proteins (etc.) as one or a small number of decontextualized properties of objects. Let us look at the ways in which various existing databases code the function of PSII and its component proteins (or encoding genes). The Protein Data Bank (PDB) classifies the ‘Crystal Structure [of] Photosystem II’ (Zouni et al., 2001) as a ‘Photosynthesis/Electron Transport’ protein. Although their ‘molecule of the month’ list does not discuss PSII, it does list PSI as ‘These proteins capture individual light photons and use them to provide power for building sugar’. The Gene Ontology offers no molecular function for PSII (or PSI), but offers a biological process as follows: ‘Gene ontology → Biological process → Physiological process → Photosynthesis’, and at this writing (12/29/2002) lists 25 proteins under this heading. SwissProt (www.expasy.org/sprot) lists many of the individual proteins in PSII. The function of psbA, for example is given as: ‘THIS IS ONE OF THE TWO REACTION CENTER PROTEINS OF THE CHLOROPLAST PHOTOSYSTEM II’. The complex is not given an EC number of its own (but many other protein complexes are). Indeed, as I have argued, it would be very difficult to assign a single EC number to PSII as it does several very different things, nor can one assign EC numbers to the sub-proteins, as they are functionally related in complex ways. To assign particular, decontextualized functions, to biological objects is an incomplete and intractable approach to biological representation. Unfortunately, function forms the basis of scientific explanations, so it is important not to lose the concept altogether. We can approach a resolution to these problems by recognizing that biological function is an interpretation and not a property of objects; it is what amounts to a local teleological analysis in the context of a particular explanation. For example, when one is trying to explain how the pH gradient arises that drives ATP synthase, PSII plays the role (i.e. has the functional interpretation) of using light energy to break up water into O2 and H+; whereas in the context of explaining how photosynthesis creates damaging ROS, PSII has a different functional interpretation. Unfortunately, when we record or computationally represent function, we usually drop the explanatory context. Even in the case of ‘simple’ enzymes that ‘simply’ catalyze reactions I argue that assigning fixed function is an inadequate representational principle. First, there are numerous multifunctional proteins. But more simply, nearly every catalyst serves at least two functions: the forward and reverse reactions. Perhaps we can save function by recognizing the universality of the explanatory context within which functions are analyzed. To some extent, this is the approach taken by systems-level ‘pathway’ models, such as Kegg (Kanehisa et al., 2002) and BioCyc (Karp et al., 2002). This approach, however, assigns objects fixed functions, which does not permit important novelty or pathology; they are crystallized explanations, permanently fixing function by virtue of the permanence of the fixed pathways. Therefore, for the same reason that, by my argument, function cannot be fixed,