Systems biology and the biology of systems.

When I sit down to write an editorial for Physiology, I flatter myself that the two or three people who will ultimately read it want to hear my thoughts on a “big” topic. It strikes me that, within the rarefied realm of academic biology, there few bigger topics, or at least few topics more all encompassing in their scope, than Systems Biology. Perhaps it is the ambiguity inherent in its name that endows Systems Biology with an aura of enormity. In the very limited, and admittedly highly idiosyncratic, surveys that I have conducted, I find that the number of definitions of Systems Biology equals or exceeds the number of individuals whose opinions I have sought. Furthermore, in my experience, the attributes of Systems Biology that are emphasized in an individual’s definition tend to correlate quite closely with that individual’s particular background and scientific interests. Systems Biology is something of a Rorschach ink blot of a discipline–it has a definable shape, but we each recognize within it different patterns and unifying themes. At this point (both) readers may be forgiven for wondering why they should care what Systems Biology is or how it is defined. After all, Systems Biology tends to be seen as belonging to the world of programmatic, multi-lab, very expensive “big science,” whereas many readers of Physiology are likely to ply their craft in smaller “mom and pop” operations. I would like to suggest that the readers of Physiology should be very interested in what constitutes Systems Biology and, more importantly, should play an active role in helping to shape its future development. There is no question that Systems Biology was born of extraordinary technological innovations that permit an enormous number of the parameters that characterize a physiological system to be interrogated simultaneously. Systems Biological approaches can generate massive data sets that reflect with some degree of completeness the composition of an aspect of a cell or organ or organism’s physiological state at a moment in time. Transcriptomes, proteomes, interactomes, metabolomes–each of these “omes” is, in fact, a snap shot of a biological system taken through the equivalent of a band-pass filter that selects for information of a particular type. The technical challenges in Systems Biology relate to the development of cleverer, cheaper, faster, and higher throughput methods through which these data sets can be acquired, stored, and annotated. The intellectual challenges in Systems Biology relate to the development of the algorithms and intuition required to extract from these data sets meaningful information and predictive hypotheses that together help us to understand how a physiological system operates and responds to its environment. It is with these intellectual challenges of Systems Biology that physiologists can and should engage. Physiologists are, after all, first and foremost scientists who study the Biology of Systems. Physiologists tend to think about connections within and among systems. Furthermore, physiologists try to link the properties of biological systems across different scales–that is, physiologists try to understand how the properties of molecules and molecular assemblies determine the properties of cells, tissues, organs, and organisms. A powerful example of the role that physiology, with its inherent focus on the Biology of Systems, can play in the development of Systems Biology can be found in the ongoing success of the Physiome Project, which is endeavoring to construct the properties of complex physiological systems through analysis of the properties of their constituent components (http://www.physiome.org.nz/, http:// nsr.bioeng.washington.edu/, http://en. wikipedia.org/wiki/Physiome). It seems to me that the data sets derived through Systems Biological approaches are most useful and exciting when they can be mined to reveal previously unknown connections between molecules or metabolic processes. Physiologists are uniquely well equipped, both by training and by predilection, to help guide the searches for those connections. Furthermore, the recognition of these connections is valuable only in so far as it produces testable hypotheses. In many cases, it falls to physiologists to use their tools and talents to assess how these connections are manifest in intact organisms and to explore the physiological consequences of their disruption. Physiologists need to take the lead in creating connections to the developing departments, programs, and institutes of Systems Biology. I believe that the future of physiology as a discipline will be tied in no small measure to its success in learning to exploit the remarkable resources that Systems Biology will create. I also think that we physiologists would do well to ensure that Systems Biologists are aware that we are the natural partners and indispensible allies upon whom they will depend to disentangle the massive skeins of data that they will continue to produce at ever greater speed. What could be more natural than Systems Biologists working in close partnership with Biologists of Systems? EDITORIAL Michael Caplan PHYSIOLOGY 25: 58, 2010; doi:10.1152/physiol.00010.2010