What is Chemical Biology?

We live in an "omic" era. Remarkable advances in both analytical methodology and computer algorithms pave the way for the discovery of the molecular basis of biology, both normal human biology and the aberrant processes and elaborate networks of gene, behavior and environment that lead to human disease. From the study of the genome to the proteome to the metabolome our ability to correlate the function of genes as components of a complex inter-related network of organism and environment promises to unlock the secrets of human organism, in sickness and in health. That disease is a complex interaction of genetic makeup, gene expression, protein action, and the environment mandates a holistic study of the complex organism at the level of the common language - chemistry.

The discipline of chemical biology begins with the chemical nature of life. For decades the traditional disciplines of chemistry - synthetic, physical and theoretical chemistry - have been mapped onto the task of understanding discrete biological entities, from proteins to nucleic acids to lipids. Although important challenges remain at the most fundamental levels of molecular structure and activity, today an important area of research involves the behavior of intact systems, from multidomain proteins to whole organisms. The inherent complexity of studying biological systems requires new methodological paradigms, approaches that allow the systematic alteration of specific components of a system and evaluating the effect of that modification on the behavior and activity of the system. But what aspects are we to alter, and how?

An astonishing discovery that came with the completion of the human genome was the remarkably small number of genes that our genome contains. The human genome was originally annotated at roughly 30,000 genes. This estimate is likely considerably overstated: human genes continue to be redacted and the final genome size may be as small as 20,000. Organisms considerably less evolved than humans contain a similar or even larger number of genes. The inescapable conclusion of this observation is that complexity in biology cannot derive from diversity - there are simply too few permutations of known genes to account for the incredible differences between simple plants and man. Rather, the complexity of biology arises from control, control of the spatial and temporal expression of genes and control of the modifications of their protein products.

A time-tested approach to assessing the biological function of a gene is the loss-of-function approach. In such studies, a gene encoding a putative protein target is deleted or disrupted and the phenotype considered. The logical counterpart to this "loss of function" experiment is a "gain of function" experiment, in which a gene product is either introduced or amplified. But to the extent that biological complexity is contained in control, rather than in gene expression, such experiments are crude tools with which to examine the subtle complexities of biology. Many "knock-outs" are embryonic lethal; many more produce either no discernable phenotype or phenotypes that are difficult or impossible to interpret.

The contemporary study and therapeutic manipulation of biology requires "switches" of protein function that act locally, specifically, immediately, and reversibly. From a practical perspective, these switches must have sufficient solubility and stability in a biological milieu to reach the target site intact. They must penetrate biological barriers (membranes) to facilitate action in such privileged sites as nuclei and subcellular organelles. Only small molecules - species with molecular weights less than roughly 600 - possess all of these attributes.

Chemical Biology implies the use of small molecule probes to both interrogate and manipulate biology. Small molecule probes can be used to sense the existence, state and activity of macromolecules and macromolecular assemblies. Small molecules can be used to observe patterns of cellular trafficking and flux. Small molecules can be used as effectors - agonists and antagonists - to regulate biological activity, by the suppression and activation of specific components of a system. Because chemical biology uses small molecules to probe and manipulate biology, the pharmacological treatment of human disease is a natural outgrowth of the discipline.

The goal of the Chemical Biology group is to enable small molecule approaches to biological discovery. The Group provides a suite of resources and capabilities that provide access to small molecules, enable small molecule approaches to biological discovery, and facilitate the discovery of novel biologically active species. We hope to provide educational opportunities at both the undergraduate and graduate level that help prepare students for research careers that make use of small molecule approaches. Finally, because the use of small molecules to manipulate biological activity is the definition of pharmacological intervention, the Group provides support for drug discovery and development, from screening and hit identification, to computational approaches for data compilation and analysis and in silico screening, to medicinal chemistry and lead optimization. At this site you will find descriptions of and links to the resources offered by the Group, as well as links to other researchers at Duke with specific expertise in various aspects of Chemical Biology.