Chemical genetics: Reshaping biology through chemistry

Abstract

To understand biological processes, biologists typically study how perturbations of protein functions affect the phenotype. Protein activity in living cells can be influenced in many different ways: by manipulation of the genomic information, by injecting inhibitory antibodies, or, more recently, by the use of ribonucleic acid‐medicated interference (RNAi). All these methods have proven to be extremely helpful, as they possess a high degree of specificity. However, they are less suitable for experiments requiring precise timing and fast reversibility of the perturbation. The advantage of small molecules is that they specifically interact with their target on a fast time scale and often in a reversible manner. In the last 15 years, this approach, termed “chemical genetics,” has received a lot of attention. The term genetics pays tribute to the analogy between chemical genetics and the classic genetic approach, where manipulations at the gene level are used to draw conclusions about the function of the corresponding protein. Chemical genetics has only recently been used as a systematic approach in biology. The term was coined in the 1990's, when combinatorial chemistry was developed as a fast method to synthesize large compound libraries [Mitchison (1994) “Towards a pharmacological genetics,” Chem. Biol. 1, 3–6; Schreiber (1998)"Chemical genetics resulting from a passion for synthetic organic chemistry,” Bioorg. Med. Chem. 6, 1127–1152].