Systems medicine is a promising new paradigm for discovering associations, causal relationships and mechanisms in medicine. But it faces some tough challenges that arise from the use of big data: in particular, the problem of how to integrate evidence and the problem of how to structure the development of models. I argue that objective Bayesian models offer one way of tackling the evidence integration problem. I also offer a general methodology for structuring the development of models, within which the objective (...) Bayesian approach fits rather naturally. (shrink)

If well-designed, the results of a Randomised Clinical Trial can justify a causal claim between treatment and effect in the study population; however, additional information might be needed to carry over this result to another population. RCTs have been criticized exactly on grounds of failing to provide this sort of information Evidence, inference and enquiry. Oxford University Press, New York, 2011), as well as to black-box important details regarding the mechanisms underpinning the causal law instantiated by the RCT result. On (...) the other side, so-called In Silico Clinical Trials face the same criticisms addressed against standard modelling and simulation techniques, and cannot be equated to experiments Philosophy of molecular medicine: foundational issues in research and practice, Routledge, New York, 2017; Parker in Synthese 169:483–496, 2009; Parke in Philos Sci 81:516–536, 2014; Diez Roux in Am J Epidemiol 181:100–102, 2015 and related discussions in Frigg and Reiss in Synthese 169:593–613, 2009; Winsberg in Synthese 169:575–592, 2009; Beisbart and Norton in Int Stud Philos Sci 26:403–422, 2012). We undertake a formal analysis of both methods in order to identify their distinct contribution to causal inference in the clinical setting. Britton et al.’s study :E2098–E2105, 2013) on the impact of ion current variability on cardiac electrophysiology is used for illustrative purposes. We deduce that, by predicting variability through interpolation, ISCTs aid with problems regarding extrapolation of RCTs results, and therefore in assessing their external validity. Furthermore, ISCTs can be said to encode “thick” causal knowledge —as opposed to “thin” difference-making information inferred from RCTs. Hence, ISCTs and RCTs cannot replace one another but rather, they are complementary in that the former provide information about the determinants of variability of causal effects, while the latter can, under certain conditions, establish causality in the first place. (shrink)

In 1966 Richard Levins argued that applications of mathematics to population biology faced various constraints which forced mathematical modelers to trade-off at least one of realism, precision, or generality in their approach. Much traditional mathematical modeling in biology has prioritized generality and precision in the place of realism through strategies of idealization and simplification. This has at times created tensions with experimental biologists. The past 20 years however has seen an explosion in mathematical modeling of biological systems with the rise (...) of modern computational systems biology and many new collaborations between modelers and experimenters. In this paper I argue that many of these collaborations revolve around detail-driven modeling practices which in Levins’ terms trade-off generality for realism and precision. These practices apply mathematics by working from detailed accounts of biological systems, rather than from initially idealized or simplified representations. This is possible by virtue of modern computation. The form these practices take today suggest however Levins’ constraints on mathematical application no longer apply, transforming our understanding of what is possible with mathematics in biology. Further the engagement with realism and the ability to push realistic models in new directions aligns well with the epistemological and methodological views of experimenters, which helps explain their increased enthusiasm for biological modeling. (shrink)

This paper offers a contribution to debates around integrative aspects of systems biology and engages with issues related to the circumstances under which physicists look at biological problems. We use oral history as one of the methodological tools to gather the empirical material, conducting interviews with physicists working in systems biology. The interviews were conducted at several institutions in Brazil, Germany, Israel and the U.S. Biological research has been increasingly dependent on computational methods, high-throughput technologies, and multidisciplinary skills. Quantitative scientists (...) are joining biological departments and collaborations between physicists and biologists are particularly vigorous. This state of affairs raises a number of questions, such as: What are the circumstances under which physicists approach biological problems in systems biology? What kind of interdisciplinary challenges must be tackled? The paper suggests that, concerning physicists’ move to work on biological systems, there are common reasons to move, the transition must be understood in terms of degrees, physicists have a rationale for simplifying systems, and distinct conceptions of model and modeling strategies are recurrent. We identified problems regarding linguistic clarity and integration of epistemological aims. We conclude that cultural unconformities within the systems biology community have important consequences to the flow of scientific knowledge. (shrink)

This paper offers a contribution to debates around integrative aspects of systems biology and engages with issues related to the circumstances under which physicists look at biological problems. We use oral history as one of the methodological tools to gather the empirical material, conducting interviews with physicists working in systems biology. The interviews were conducted at several institutions in Brazil, Germany, Israel and the U.S. Biological research has been increasingly dependent on computational methods, high-throughput technologies, and multidisciplinary skills. Quantitative scientists (...) are joining biological departments and collaborations between physicists and biologists are particularly vigorous. This state of affairs raises a number of questions, such as: What are the circumstances under which physicists approach biological problems in systems biology? What kind of interdisciplinary challenges must be tackled? The paper suggests that, concerning physicists’ move to work on biological systems, there are common reasons to move, the transition must be understood in terms of degrees, physicists have a rationale for simplifying systems, and distinct conceptions of model and modeling strategies are recurrent. We identified problems regarding linguistic clarity and integration of epistemological aims. We conclude that cultural unconformities within the systems biology community have important consequences to the flow of scientific knowledge. (shrink)

Systems biologists often distance themselves from reductionist approaches and formulate their aim as understanding living systems “as a whole.” Yet, it is often unclear what kind of reductionism they have in mind, and in what sense their methodologies would offer a superior approach. To address these questions, we distinguish between two types of reductionism which we call “modular reductionism” and “bottom-up reductionism.” Much knowledge in molecular biology has been gained by decomposing living systems into functional modules or through detailed studies (...) of molecular processes. We ask whether systems biology provides novel ways to recompose these findings in the context of the system as a whole via computational simulations. As an example of computational integration of modules, we analyze the first whole-cell model of the bacterium M. genitalium. Secondly, we examine the attempt to recompose processes across different spatial scales via multi-scale cardiac models. Although these models rely on a number of idealizations and simplifying assumptions as well, we argue that they provide insight into the limitations of reductionist approaches. Whole-cell models can be used to discover properties arising at the interfaces of dynamically coupled processes within a biological system, thereby making more apparent what is lost through decomposition. Similarly, multi-scale modeling highlights the relevance of macroscale parameters and models and challenges the view that living systems can be understood “bottom-up.” Specifically, we point out that system-level properties constrain lower-scale processes. Thus, large-scale modeling reveals how living systems at the same time are more and less than the sum of the parts. (shrink)

This paper offers a contribution to debates around integrative aspects of systems biology and engages with issues related to the circumstances under which physicists look at biological problems. We use oral history as one of the methodological tools to gather the empirical material, conducting interviews with physicists working in systems biology. The interviews were conducted at several institutions in Brazil, Germany, Israel and the U.S. Biological research has been increasingly dependent on computational methods, high-throughput technologies, and multidisciplinary skills. Quantitative scientists (...) are joining biological departments and collaborations between physicists and biologists are particularly vigorous. This state of affairs raises a number of questions, such as: What are the circumstances under which physicists approach biological problems in systems biology? What kind of interdisciplinary challenges must be tackled? The paper suggests that, concerning physicists’ move to work on biological systems, there are common reasons to move, the transition must be understood in terms of degrees, physicists have a rationale for simplifying systems, and distinct conceptions of model and modeling strategies are recurrent. We identified problems regarding linguistic clarity and integration of epistemological aims. We conclude that cultural unconformities within the systems biology community have important consequences to the flow of scientific knowledge. (shrink)

Building computational models of engineered exemplars, or prototypes, is a common practice in the bioengineering sciences. Computational models in this domain are often built in a patchwork fashion, drawing on data and bits of theory from many different domains, and in tandem with actual physical models, as the key objective is to engineer these prototypes of natural phenomena. Interestingly, such patchy model building, often combined with visualizations, whose format is open to a wide range of choice, leads to the discovery (...) of new concepts and control structures. Two key questions are raised by this practice: how could discoveries arise from building external representations for which there is wide latitude in choice of the components from which they are built, and thus can be considered significantly arbitrary, and how could such discoveries allow engineering a real-world prototype system. To examine these questions, we present two case studies of discoveries that emerged from the building of such computational models in the bioengineering sciences. We then develop a process model that accounts for the discovery and transfer problems raised by both these cases, focusing on the process of building the model. Specifically, to account for the discovery problem, we propose that the process of building such models gradually leads to a close coupling between the modeler’s internal processes and the external dynamic model. To account for the transfer problem, we propose that the process of building the model leads to the creation of an enactive model that is generic, which closely enacts, and thus reveals, the way the system-level behavior of the engineered prototype emerges in time through the interaction of its parts. This enactive replication process leads to the model and the prototype forming a new class, which allows concepts and control structures developed for the computational model to be transfered to the real-world prototype. We argue that this account requires rethinking correspondence in engineering sciences as a plastic and enactive relation. A closer focus on the process of building models is required to develop a general account of this emerging approach to discovery. (shrink)

In silico medicine is still forging a road for itself in the current biomedical landscape. Discursively and rhetorically, it is using a three-way positioning, first, deploying discourses of personalised medicine, second, extending the 3Rs from animal to clinical research, and third, aligning its methods with experimental methods. The discursive and rhetorical positioning in promotions and statements of the programme gives us insight into the sociability of the scientific labour of advancing the programme. Its progress depends on complex social, institutional and (...) technological conditions which are not external to its epistemology, but intricately interwoven with it. This article sets out to show that this is the case through an analysis of the process of computational modelling that is at the core of its epistemology. In this paper I show that the very notion of ‘model’ needs to be re-thought for in silico medicine, and propose a replacement, in the form of the ‘Model-Simulation-Experiment-System’ or MSE-system, which is simultaneously an epistemological, social and technological system. I argue that the MSE-system is radically mediated by social relations, technologies and symbolic systems. We need now to understand how such mediations operate effectively in the construction of robust MSE-systems. (shrink)