In a recent letter, John Bothwell (2006) argues that systems biology does not represent a Kuhnian paradigm shift or revolution, as some commentators claim (Palsson, 2006; Trewavas, 2006). Rather, according to Bothwell, systems biology is best described in terms of Kuhnian normal science (Appendix A1). At first pass, this debate may seem inconsequential, especially to those who practice biology. However, closer inspection of the debate, particularly in terms of what Kuhn says about paradigm shifts and their attendant revolutions, reveals that systems biology may represent a fundamental or paradigmatic shift in biology's philosophical foundation – an important element of Kuhn's disciplinary matrix (Kuhn, 1996) (Appendix A2). That shift for many – but not all – systems biologists is from a reductionistic approach to a holistic one, for investigating and explaining biological phenomena. In response to Bothwell, I examine briefly the debate over systems biology's potential revolutionary nature and discuss its possible consequences for the practice of 21st-century biology.
The emergence of systems biology over the past decade has occurred in response to the large amounts of data generated from high-throughput genomics and proteomics (Palsson, 2006). Besides the sheer amount of data, the complexity of the biological phenomena responsible for the data beckons for a different approach than the standard reductionistic approach, in order to understand and explain these data. Reductionism involves the simplification of complex phenomena in terms of their components and comes in at least three forms (Marcum & Verschuuren, 1986). The first is theoretical reductionism, in which the terms of a complex theory are formulated in terms of a simpler one. For example, photosynthetic theoretical terms are articulated in chemical and physical theoretical terms. The second form is ontological reductionism, in which complex phenomena are simplified with respect to entities and forces (Appendix A3). Again, for example, the components comprising photosynthesis are identified with respect to chemical entities and physical forces. Methodological reductionism is the third form, in which experimental protocols are utilized to investigate complex phenomena with respect to their isolated components.
As Bothwell (2006, pp. 7 and 8) acknowledges, systems biologists attempt to replace the reductionistic approach to complex biological phenomena with a holistic approach. This approach involves an epistemological or a theoretical holism, in which higher-order structures are articulated in hierarchical – rather than in reductionistic – terms (Appendix A4). He cites Hiroaki Kitano's four components of systems biology, including system structure, system dynamics, system control method and system design method, to illustrate the epistemological or theoretical nature of the holistic approach (Kitano, 2002). Moreover, holistic ontology is not concerned solely with elemental components, such as molecules, that create complex biological phenomena but with the integrity of those phenomena at a higher level of organization (Appendix A5). Finally, systems biology's methodological holism pertains to the integration of ‘-omics’ data through computational analysis, in an effort to identify ‘organizational’ laws or principles (Mesarovic et al., 2004).
The question then is whether this move by systems biologists from a reductionistic to a holistic approach, to investigate and explain complex biological phenomena, represents a Kuhnian paradigm shift or revolution – in which scientists substitute a newer incommensurable paradigm for an older one – or whether it represents Kuhnian normal science – in which scientists are simply ‘mopping up’ after a revolution. Bothwell claims the latter, for two reasons. The first is that although systems biologists do not reduce complex biological phenomena to chemistry, they do reduce them to engineering. In other words, systems and their emergent properties are simply additional components that supplement other elemental components comprising biological phenomena. Thus, there is no replacement of an older paradigm with a newer incommensurable one because there is significant – if not complete – overlap between them. The second reason is that systems biologists did not invent the notion of functional analysis, which has a history dating back to Aristotle and is exemplified by contemporary physiology.
I think Bothwell is both correct and incorrect in his assessment of the revolutionary nature of systems biology. He is correct in that some systems biologists cling to reductionism and reject holism as a guiding principle for their trade (Sorger, 2005). In this sense these biologists are engaged in normal science in that they are mopping up after the molecular biology revolution, by articulating its paradigm (Kellenberger, 2004). He is incorrect, on the other hand, in that other systems biologists utilize a holistic approach instead of a reductionistic approach, as detailed above, and extend the standard functional analysis of physiology to include dynamical nonequilibrium analysis.
Systems biology holism – as an antireductionistic approach – comes in two forms. The first is organicism, in which complex phenomena are studied strictly at higher levels of organization so that causation proceeds top-down and not, as for reductionism, bottom-up (Fujimura, 2005). This antireductionistic approach of systems biologists represents a major Kuhnian revolution or paradigm shift because the two paradigms are globally or completely incommensurable. In other words, there is little – if any – significant overlap between the two approaches in terms of their theories, experimental methodologies and problems of interest.
The second form of systems biology holism represents a synthesis between the reductionism and organicism approaches, especially in terms of causation, in which bottom-up and top-down causes are integrated reciprocally (Grizzi & Chiriva-Internati, 2006). For example, as genes are expressed they modify their cellular environment, which in turn activates additional genes, which in turn further modify the cellular environment, and so on. In Kuhnian terms, this revolution is a minor one because the incommensurability is simply local or partial in nature. In other words, there is considerable – but not complete – overlap between the two paradigms. Therefore, these systems biologists utilize both upward and downward control and share, to some extent, theories, experimental methodologies and problems of interest.
The appropriation of Kuhn's philosophy of science to biology is problematic, as Bothwell points out, because Kuhn developed his notions of scientific revolution and of normal science using historical case studies from the physical sciences. And the systems biology case study is an excellent example of the difficulties involved in using Kuhn to understand the impact of systems biology on the future course of the biological sciences. However, apart from these problems, a Kuhnian analysis does disclose several options available for 21st-century biologists with regard to systems biology.
The first option is in terms of Kuhnian normal science, in which systems biologists – who advocate a reductionistic approach – add yet another tool (e.g. computational analysis) to their toolbox for investigating and explaining complex biological phenomena. The next option is globally incommensurable organicism. The problem with this approach, unfortunately, is that there is little, if any, technology to support it. The final option is a locally incommensurable holism that integrates both reductionism and organicism, especially in terms of causal pathways. Currently, many systems biologists advocate this integrative option (Coffman, 2006). Although which of these options – if any – becomes the predominant approach for 21st-century biologists remains to be seen, systems biology does provide a feasible route for transforming 21st-century biological practice and knowledge.