Validation and variability: dual challenges on the path from systems biology to systems medicine

Systems biology is currently making a bid to show that it is able to make an important contribution to personalised or precision medicine. In order to do so, systems biologists need to find a way of tackling the pervasive variability of biological systems that is manifested in the medical domain as inter-subject variability. This need is simultaneously social and epistemic: social as systems biologists attempt to engage with the interests and concerns of clinicians and others in applied medical research; epistemic as they attempt to develop new strategies to cope with variability in the validation of the computational models typical of systems biology. This paper describes one attempt to develop such a strategy: a trial with a population-of-models approach in the context of cardiac electrophysiology. I discuss the development of this approach against the background of ongoing tensions between mathematically and experimentally inclined modellers on the one hand, and attempts to forge new collaborations with medical scientists on the other. Apart from the scientific interest of the population-of-models approach for tackling variability, the trial also offers a good illustration of the epistemology of experiment-facing modelling. I claim that it shows the extent to which experiment-facing modelling and validation require the establishment of criteria for comparing models and experiments that enable them to be linked together. These 'grounds of comparability' are the broad framework in which validation experiments are interpreted and evaluated by all the disciplines in the collaboration, or being persuaded to participate in it. I claim that following the process of construction of the grounds of comparability allows us to see the establishment of epistemic norms for judging validation results, through a process of 'normative intra-action' (Rouse, 2002) that shape the social and epistemic evolution of systems approaches to biomedicine.