Challenges in the applications of -omics strategies in nutrient-gene interaction and cancer prevention.

CS06-01

Research over the past 50-70 years has been a mono-dimensional projection of multi-dimensional biological systems. It produces locally true answers, but ignores their impact on a global scale. Until the turn of the millennium, the paradigm was (1) that single genes accounted for diseases such as cancer, and (2) the loss or overexpression of a gene had a single biochemical affect and that the mono-dimensional view was the strength of NIH-funded science. More recently, study of diet-related disease risk has involved multi- and high dimensional analyses (DNA microarrays, proteomics and metabolomics). The enthusiasm for these techniques has been overwhelming - however, the need for very careful control of experimental design, both in sample collection, sample storage, sample analysis and data interpretation was not recognized in the initial rush for success. While DNA microarrays appear to be very comprehensive, they nonetheless contain important assumptions about the true transcriptome: that (1) it is fully and correctly known, (2) the gene elements that are laid down represent the genes that are expressed, and (3) that the signals from the microarray can be converted quantitatively into meaningful expression values. Proteomics is limited by the very large dynamic range of protein abundances as well as the need to rely on largely DNA-based amino acid sequence derivation. While gene sequences, gene expression and protein abundances are all important, most of the events in a cell are regulated by small molecules generated by proteins with enzymatic activity. However, interpretation of metabolomics data may only reveal what we already know. The high dimensionality of complex biological models requires input of as much prior information as possible. The biggest limitation of all the current science (low and high dimensional) is the failure to examine system dynamics, both in time-related stimulation and analysis. But help is on its way - developments in 21st Century biology will hasten the recruitment of specialized, cross-taught, engineers, physicists and mathematicians to this new frontier.