THE NEED FOR THERAPEUTIC OBSERVATIONS IN MAN Before any discussion of the value of clinical trials, it is worthwhile remembering why quantitative or numerical studies in man are necessary. That the need for such studies is not self evident is reflected by the fact that it is only relatively recently that numerical based arguments have achieved preeminence over insights based solely on pathophysiologic mechanisms (for reviews see Vandenbroucke1,2). Science is reductionist: science’s explanatory approach is to attempt to explain phenomena at one level of description by analysis of those forces acting at a different (“lower”) level of description. This epistemic paradigm is phenomenally successful, and despite claims to the contrary, there seems little alternative. It is equally true, but apparently not obvious, that the ability to make precise quantitative predictions from a more basic level to a higher one is often poor. It is therefore the inadequacy of the reductionist enterprise that justifies the need for collecting the results of clinical interventions. A topical example may help. We may “understand” the details of how ultraviolet radiation (UVR) interferes with cell membranes, how UVR induces changes in gene expression, and how UVR induces particular forms of DNA damage, but our insights do not allow us to make sufficiently precise predictions in the clinical arena: should we use UVB twice or three times a week; what is the risk of melanoma for patients with red hair treated with PUVA; what dosing regimen of UVR should we use for particular diseases? There is an enormous gap, and a gap that cannot be closed, between explanatory pathways of the sort popular in fields such as cell biology and the sort of quantitative predictive models we require in the clinic. An important corollary of this line of reasoning is easily neglected. Once we accept the limits on our ability to predict with sufficient rigor from a more basic level to a patient, by the same logic the idea of translational research—from bench to clinic, to use the cliche—can only provide a partial view of reality. In many instances a more fruitful approach is in the reverse direction, from clinic to bench. Ironically, because it is often thought as showing quite the opposite, the rise of human molecular genetics over the past 10 years has provided the best example of clinic to bench. The whole of positional cloning has relied on the definition of a disease at a higher level of explanation guiding the search for the respective “disease gene.” The starting point is clinical description and syndrome identification. Only once this is in place can you identify a putative genetic cause. By contrast, if all research were translational in origin we would be left trying to randomly mutate the 50,000 or so genes in the human genome and attempting to delineate particular clinical phenotypes; a task even beyond the National Institutes of Health and the most zealous enthusiasts for knock-out mouse strategies. The underlying message and rationale is quite simple: just as we can’t explain behavior on the basis of an individual synapse, we can’t explain much disease or the effects of our interventions on a particular disease without extremely accurate predictive causal pathways, which for most of molecular and cell biology we simply do not have. Clinical medicine is both complex and complicated. Instead, we need to rely on studies in humans under conditions that we can manipulate or at least reason about. Although this latter approach is often described as clinical epidemiology or “trials,” it forms the core of what has been the long-standing method of clinical discovery: the comparison of those with a particular state and those without a particular state and an inquiry into either the causal antecedents for the current state or examination of the changes in the status after intervention. The rest of this article seeks to critically appraise this approach using psoriasis as an example. From the Grant Chair of Dermatology, University of Edinburgh. Reprint requests: Professor Jonathan Rees, Systems Group, Dermatology, University of Edinburgh, First Floor, Lauriston Buildings, Lauriston Place, EH3 9YW, United Kingdom. E-mail: jonathan.rees@ed.ac.uk. J Am Acad Dermatol 2003;48:135-43. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 0 doi:10.1067/mjd.2003.19