Broad Institute
A chemistry-conscious approach to systems biology was suggested over a decade ago and has been gaining traction in the research community. Today, new sources of chemical matter, new perturbation and measurement technologies, and new computational biology advances, set the stage for more rapid maturation of systems chemical biology (SCB). As the field matures, it will produce a quantity and diversity of experimental data not previously accessible. These data will span the biological scales typically considered by either chemical or systems biology, including enzyme inhibition; macromolecule modification, stability, and lifetime; participation in complexes, pathways, or processes; perturbations of cellular function; effects on tissue, organ, and whole-organism functions; and even ecological or evolutionary outcomes. Indeed, recent work has formulated new definitions of chemical similarity based on bioactivity, including at several biological scales .
At least three new challenges emerge from the availability of heterogeneous types of data about small-molecule function:
(1) integrating datasets from different experimental and technological approaches
(2) making connections between molecular differences and changes in higher-order processes (e.g., tissue, organ, and whole-organism)
(3) correctly expressing and interpreting the context of evidence from molecular experiments (e.g., concentration, sample type, assay type)
Our epistemological approach to a Translator Knowledge Provider (KP) for Systems Chemical Biology is that modifications of macromolecules at small-molecule scales can propagate their influence through all levels of biological organization and do so in a highly context-sensitive manner. We hypothesize that this approach can meaningfully inform integration of several types of data not often combined.
Question Scope. Our KP will focus on small molecules and the systems biology of their protein targets. Initially, we will include bioactivity data from cell-based multiplexed gene-expression and cell-proliferation data using sources that can suggest new candidate targets and links to known biological process, pathways, or network modules.