All the King's horses and all the King's men: maybe physiology can put Humpty Dumpty back together again.

In this issue of The Journal of Physiology we launch an initiative to highlight the potential clinical implications of one or more research papers via a Clinical Perspectives article. Why are we doing this? The simple answer is that integrative physiology, and the clinical outlook that can flow from it, provides a key set of intellectual tools that can frame observations across a spectrum of biological complexity. This permits physiologists, in our role as biological integrators and story tellers, to both reach back to molecular and reductionist observations and at the same time reach forward to implications for disease risk, epidemiology and ideas about novel therapeutic strategies. From the perspective of an integrative physiologist what is missing from both the fashionable (especially with funding agencies) reductionistic and population/outcomes approaches is any sense of a larger biological narrative that links findings from differing levels of intellectual exploration into a coherent story. This is also painfully obvious for those of us who have the pleasure of teaching the very bright graduate and medical students we encounter: they have all the tools needed to tackle interesting projects, but are unable to generate the plans needed to build an ‘intellectual house’. One current and favoured approach to reconciling the reductionist and population based ends of the biomedical research spectrum involves the so-called genome wide association studies (GWAS). The goal with this approach is to link or identify specific genetic variants (or patterns of variation) with the risk or presence of a certain phenotypic trait. For many diseases highly significant gene variants confer levels of ‘risk’ that are barely above what an integrative or clinical physiologist might call the regulatory signal to noise ratio. In other words, when individuals with specific variants are subjected to a ‘physiological’ test that stresses the system of interest, those with variant A don't respond much differently from those with variant B. So it appears that the GWAS approach is sometimes little more than biological bookmaking on a grand scale and falls short of telling a compelling story. Similarly, when critical genes are knocked out, varied or manipulated in animal models, the most obvious conclusions seem to be either that redundant systems compensate to keep physiological parameters ‘normal’ in spite of the intervention, or that the gene of interest really was important because manipulating it had a lethal outcome. Systems biology claims to offer another solution to the problems highlighted above, but so far it seems obscure at best. That having been said, why then is physiology the discipline that can put this biological Humpty Dumpty back together again? The language of physiology captures concepts like homeostasis, redundancy, acute and chronic adaptations to stress, regulation, feedback and feed forward control, compensation and so forth. Using this language narratives and schemes that link the subcellular, cellular, organ and organism's integrated responses are developed. These schemes can then be framed as testable hypotheses and stimulate experiments by investigators at multiple levels. For example ideas about baroreflex control of blood pressure have led to studies ranging from the basic mechanisms of mechanotransduction in cells all the way to population based studies on hypertension. The ‘size principle’ describing how the brain and spinal cord organize motor-unit recruitment and movement is another triumph of physiological conceptualization that operates to inform experiments at every level of biological integration. So, the goal of a Journal of Physiology Clinical Perspectives article is to use physiology's unique set of intellectual tools along with an outstanding paper to explore the larger biological issues and make connections that could lead to solutions. Maybe Humpty Dumpty can live again.