The link between food and health is well document but the mechanisms by which nutrient and non-nutrient bioactives influence long-term health outcomes are not well understood. For example, how do low potency dietary signals (i.e., low concentration, low-affinity, low-specificity ligands with poor pharmacokinetics and pharmacodynamics) coordinately regulate thousands of genes in hundreds of pathways to reduce disease risk? Do dietary signals interact with the genome randomly or are these interactions targeted in a gene- or region-specific fashion?
The difficulty in integrating the diverse properties of diet with current genetic control and signal sensing mechanisms is the lack of regulatory models that incorporate the action of low potency dietary signal on the balance between health and disease. While the genomic revolution has provided an array of powerful analytical tools to investigate human health, many researchers continue to use reductionist approaches to study complex diet-genome interactions. Researchers tend to focus too much on isolating individual bioactive compounds from foods to explain their health benefits (i.e., the drug model) at the expense of discovering novel synergistic affects of combinations of dietary signals. Researchers have also relied too heavily on genetic theories of disease while ignoring important genetic modifiers such as nutrition, lifestyle, exercise and epigenetics - factors that make human health a "complex system."
At the Center of Excellence in Nutritional Genomics we are reexamining diet-genome interactions through the lens of complexity theory. As a complex system, human physiology consists of networks of nodes (i.e., genes, their products and metabolites) and edges (i.e., their interactions) at the boundary between deterministic processes and chaotic (i.e., unpredictable) processes. In response to normal or stressful nutritional inputs, highly adaptive self-organizing molecular and cellular responses emerge that promote stability, robustness and the return to homeostasis. We are calling these responses nutridynamical systems, or the time-dependent genetic, metabolic or physiological states that emerge in response to small changes in nutritional input, sometimes referred to as the sensitive dependence on initial conditions or "butterfly affect." For one type of nutritional input, self-organizing behaviors can emerge that are adaptive and produce robustness in the network (i.e., short return time to homeostasis). Qualitatively or quantitatively different nutritional inputs can produce emergent behaviors that are turbulent or chaotic. These chaotic behaviors can take longer to return to homeostasis thus increasing the likelihood that a disease state will emerge. The emergence of these behaviors can be sudden and non-linear, both common characteristics of phase transitions. These "tipping points" may help explain how low potency dietary signals can expert large effects on gene expression, particularly if they involve epigenetic remodeling of chromatin. If most chromatin resides in some metastable state between open and closed, then small dietary influences on the chromatin remodeling machinery can gently push chromatin into a state accessible to the basal transcription apparatus and its many co-regulators.
To fulfill the promise of nutritional genomics, researchers must take a more holistic approach to reconciling the diverse properties of dietary signals with our growing knowledge of gene networks, all in the context of human genetic diversity and lifestyle and cultural differences.
Ray Rodriguez, Director