Volume 7 Issue 6, June 2011

A new type of big science is emerging that involves knowledge integration and collaboration among small sciences. Because open collaboration involves participants with diverse motivations and interests, social dynamics have a critical role in making the project successful. Thus, proper 'social engineering' will have greater role in scientific project planning and management in the future.

Because of the complexity of biological systems, cutting-edge machine-learning methods will be critical for future drug development. In particular, machine-vision methods to extract detailed information from imaging assays and active-learning methods to guide experimentation will be required to overcome the dimensionality problem in drug development.

As biochemistry ventures out from its reductionist roots, concentration effects and high surface-to-volume ratios will challenge our current understanding of biological systems, with colloidal and surface chemistry leading to new insights and approaches. How must our thinking change, what new tools will we need and how will these new tools be developed?

The pharmaceutical industry is in a period of crisis due to the low number of new drug approvals relative to the high levels of R&D investment. It is argued here that improving the quality of target selection is the single most important factor to transform industry productivity and bring innovative new medicines to patients.

Riboswitches are so named because they switch gene expression on or off in response to binding of specific metabolites. Two evolutionarily and mechanistically divergent riboswitches that recognize the universal methyl donor S-adenosylmethionine are shown to undergo dynamic conformational sampling before ligand binding.

STIM proteins are ubiquitous endoplasmic reticulum Ca²⁺ sensors that rapidly translocate to couple with 'store-operated' Orai Ca²⁺ channels when luminal Ca²⁺ levels are low. STIM1 also senses heat changes, which trigger a similar translocation and prime STIM1 to activate Orai, suggesting that STIM1 functions as a sensor of multiple stress signals.

Bacteria oscillate between the planktonic and biofilm states through many hierarchically organized networks that respond to environmental cues. Recent research describes how a bacterial toxin-antitoxin system mediates this transition by controlling bacterial motility in response to extracellular stress.

The systematic exploration of off-patent drugs in combination with the antibiotic minocycline uncovers unexpected synergies in antibiotic-nonantibiotic pairs. These interactions are exemplified by the nonantibiotic loperamide, which finds a new function in facilitating tetracycline uptake.

Heat causes oligomerization and targeting of the ER-based calcium sensor STIM1 to ER–plasma membrane junctions but prevents the functional coupling between STIM1 and the calcium-permeable Orai1 ion channel, resulting in a unique heat off-response of calcium entry.

The toxin-antitoxin pair MqsR and MqsA are linked to biofilm formation, quorum sensing and motility, but their specific role in these and other cellular processes is unclear. The demonstration that MqsA directly represses transcription of rpoS, encoding the master regulator of the stress response, provides a unifying explanation.

Single-molecule fluorescence resonance energy transfer allows visualization of three distinct phases of DNA digestion mediated by λ exonuclease and identifies base melting as a rate-limiting step in the reaction pathway.

A target-identification strategy based on the yeast three-hybrid system and the SNAP-tag labeling technique identifies new targets for three small-molecule drugs and helps identify a new mechanism for the activity of the anti-inflammatory drug sulfasalazine involving inhibition of sepiapterin reductase.

SAM riboswitches are RNA elements that regulate bacterial gene expression in response to binding of the small-molecule metabolite S-adenosylmethionine. Assembly of a functional SAM-I riboswitch occurs hierarchically and involves magnesium-induced preorganization of the SAM binding site.

SAM riboswitches are RNA elements that regulate bacterial gene expression in response to binding of the small-molecule metabolite, S-adenosylmethionine. The SAM-II riboswitch binds its ligand through a conformational capture mechanism that is dependent on formation of a transient pseudoknot.

Big science' initiatives and investigator-driven 'small science' research in chemical biology will both contribute to a more integrated view of biological systems.