Commentary

The capability to generate multi-omic data sets raises the issue of resource allocation for data generation versus data curation and integration. The initial experience of researchers shows that the effort required for the latter can be much greater than that for the former.

Biological messiness relates to infidelity, heterogeneity, stochastic noise and variation—both genetic and phenotypic—at all levels, from single proteins to organisms. Messiness comes from the complexity and evolutionary history of biological systems and from the high cost of accuracy. For better or for worse, messiness is inherent to biology. It also provides the raw material for physiological and evolutionary adaptations to new challenges.

Excitatory synapses are located in confined chemical spaces called the dendritic spines. These are atypical femtoliter-order microdomains where the behavior of even single molecules may have important biological consequences. Powerful chemical biological techniques have now been developed to decipher the dynamic stability of the synapses and to further interrogate the complex properties of neuronal circuits.

Because of the large number of phospholipids, their highly active metabolism and our lack of understanding of protein-lipid specificity, lipid signaling is a particularly challenging subject to study. Help might come from new tools that will allow us to follow and manipulate lipids and lipid-binding proteins in living cells.

Bioactive lipid signaling allows individual cells within the body to 'see' the surrounding environment and to respond in ways that will benefit the whole organism. Successful drug development for bioactive lipid targets requires a deep knowledge of the biology and pathobiology of each specific lipid signaling pathway.

Artificial biosynthetic pathways are typically assembled and optimized progressively, from earlier to later steps. This commentary highlights the potential of an alternate regressive method for biochemical pathway design and generation, inspired by the retro-evolution hypothesis and the concept of retrosynthesis. In addition to being a pathway design tool, 'bioretrosynthesis' has potential as a construction and optimization methodology.

Chemical biologists frequently aim to create small-molecule probes that interact with a specific protein in vitro in order to explore the role of the protein in a broader biological context (cells or organisms), but a common understanding of what makes a high-quality probe is lacking. Here I propose a set of principles to guide probe qualification.

The complexity of cancer signaling and the resulting difficulties in target selection have strongly biased kinase drug discovery towards clinically validated targets. Recently, novel kinase targets that are uncharacterized have emerged from genome sequencing and RNAi studies. Chemical probes are urgently needed to functionally annotate these kinases and to stimulate new drug discovery efforts.

Bioactive compounds are most frequently identified via high-throughput screening campaigns. This article discusses the strengths and weaknesses of the most popular screening approaches and the utility of compounds derived from them.

Intrinsically disordered proteins (IDPs) are subject to ubiquitin-independent degradation, a default and passive process. We describe here a model wherein a group of 'nanny' proteins function to protect newly synthesized IDPs from degradation by default, thereby insuring their maturation into important regulatory molecules.

In their native environments, proteins perform their biological roles in highly concentrated viscous solutions and in complex networks with numerous partners. Yet for many years, the normal practice has been to purify a protein of interest in order to characterize its structural and functional properties. In this Commentary, we discuss how protein scientists are now tackling the theoretical and methodological challenges of studying proteins in their physiological context.

Phenotypic diversity exists even within isogenic populations of cells. Such nongenetic individuality may have wide implications for our understanding of many biological processes. The field of study concerned with the investigation of nongenetic individuality, also known as the 'biology of noise', is ripe with exciting scientific opportunities and challenges.

Annotations of enzyme function provide critical starting points for generating and testing biological hypotheses, but the quality of functional annotations is hindered by uncertain assignments for uncharacterized sequences and by the relative sparseness of validated experimental data. Given the relentless increase in genomic data, new thinking and validation methods are urgently needed to provide high confidence in enzyme functional assignments.

The scope of enzymology has expanded rapidly over the last century, from an early focus on the chemical and catalytic mechanisms of individual enzymes to more recent efforts to understand enzyme action in the context of dynamic, functional biological systems consisting of many interacting enzymes and proteins. Continuing progress in probing the link between molecular structure and function now promises to pave the way for a deeper understanding of the evolution and behavior of the complex biological systems that govern cellular behavior.

Protein improvement strategies today involve widely varying combinations of rational design with random mutagenesis and screening. To make further progress—defined as making subsequent protein engineering problems easier to solve—protein engineers must critically compare these strategies and eliminate less effective ones.

Understanding the structure and function of carbohydrates remains a key challenge for chemical biologists. Developments in carbohydrate synthesis and analysis together with the advent of high-throughput methods such as carbohydrate microarrays have helped shed light on the function of glycoconjugates. Similarly, consortia have provided technology platforms and focus to a burgeoning field. Now, recruitment of scientists from related fields and further integration of chemistry and biology to achieve technical goals are needed for rapid advancements.

Chemical biology is beginning to enhance our understanding of diverse cellular processes in plants, including endomembrane trafficking, hormone transport and cell wall biosynthesis. To reach its potential requires the development of a community-wide infrastructure of technology and expertise. We present some of the opportunities and challenges in this emerging branch of plant biology and offer some suggestions for enhancing the approach to the benefit of the community at large.