Seminar Abstract

“Now, What is Life, Systems Biology of Homeodynamics: neuronal adaptive compensation”

What is Life? Erwin Schrodinger’s influential little book published in 1944, challenged biology and led to decades of gene-centric research that culminated in the mapping of the human genome. It asks “how can the events in… a living organism be accounted for by physics and chemistry?” In this ‘gene’s view’ of life we have aimed to reduce diseases and functions to particular genes and molecules. It portrays life as serving the replication of genes and, at the limit in evolutionary psychology, brain functions such as behavior and cognition become merely modular products of genes selected in the Pleistocene. As a result anyone reading the popular biology literature will come away convinced that we have triumphed and that the essential problems have been solved by the ‘genetic revolution’. The impression given is that we have reduced biological systems to simple, comprehensible genetic parts and that we are now on the threshold of being about to manipulate them as we do components in electronic devices.

This impression is false: the genes are not life. My seminar will analyze the emergence of post-genomic data that compels a very different view of the dimensions of the problem of the nature of life, and how that is driving development of the new field of systems biology. In these new data the genes are not controllers but participants in massive, multi-dimensional regulatory webs. This has the effect of standing “the selfish gene” on its head, and along with it much of the rationale for genetic determinism as the explanation for function. We now must understand life as a complex web or network, interacting across levels and in an ongoing process of profound adaptive interaction with its environment. Our task now is to point the way forward, just as Schrdinger successfully did for the issues of his day. As a framework in which to consider this challenge I will present my own work on the analysis of certain brain regulatory dysfunctions involved in hypertension.

Systems Biology of Homeodynamics: neuronal adaptive compensation

Recent reports indicate that the central nervous system plays a significant role in long term regulation of blood pressure, including the development and maintenance of hypertension, by baroreflex resetting to a higher mean arterial pressure set point. The mechanisms underlying these surprising but potentially very important cardiovascular homeodynamics are largely unknown. We hypothesize that the nucleus tractus solitarius (NTS), a major center mediating central and peripheral integration in cardiovascular control, adapts to peripheral blood pressure disturbance with a molecular remodeling that may contribute to alterations of regulatory function. In order to investigate this possibility we have mounted a systems-level study of the cardiovascular NTS response to hypertension. This study involves examination of system-wide transcriptional regulation, short- and longer-term signaling behavior, and the relation of these events to neuronal outputs including electrical behavior. We use a combination of high-throughput experimental methods and computational modeling, and both of these present unique challenges, for example in development of sufficient data quality, and in the use of very small samples. Our approach involves examining these processes together as a single cellular system. The behavior of this complex system involves dynamic interactions that are difficult to predict using qualitative reasoning and there is a need for experimentally validated computational modeling approaches at the systems level. These approaches are valuable in generation of hypotheses and provide a framework for the systematic comparison of data collected across experiments. These computational approaches also require particular focus on issues of broad significance in systems biology, such as the adequate representation of the complexity within a level of analysis, and the development of feedbacks or functional links between levels of analysis. The present seminar is combination of a progress report towards our scientific question of the basis for cardiovascular homeodynamics, our development of systems biology approaches making this feasible, and contemplation of the significant remaining challenges.