Chemical genetics,  which relies on selecting small molecules for their ability to induce a biological phenotype or to interact with a particular gene product, is one of the best examples of a methodological development in lead generation. Forward (screening for phenotype) and reverse (screening for activity against a selected protein) chemical genetics, by combining medicinal chemistry, biological screening and combinatorial synthesis techniques, has enabled us to address previously intractable problems. Since developments in synthetic methodology tend to be incorporated into new library development, and improvements in analytical and biological methodology are applied to screening systems, chemical genetics research often encapsulates the best of both chemistry and biology.
One of the most elegant examples of the extension of biological processes to ligand discovery is that of in vitro evolution. One of the reasons why antibodies have such good binding parameters is that in vivo they are subjected to rounds of expansion, selection and mutation which allow them to evolve with repeated exposure to the challenging agent. This process of evolution of activity by selection and mutation was first utilised ex vivo in phage display technology  and later using yeast or bacteria as vectors. This has been extended to in vitro techniques such as ribosome display , a wholly cell-free system for the directed evolution of peptides. Methods for the in vitro generation and evolution of aptamers (RNA and DNA sequences which bind specific targets) are also now well established . Stability and cell permeability remain a problem, although such systems have been improved by incorporating synthetic residues, or by undertaking post selection modification. One particularly striking example of the integration of aptamer evolution with chemical modifications, utilised combinatorial chemistry techniques during the selection process to generate a new moiety which tightly binds the transactivational responsive (TAR) element of HIV-1 .
Design, induction and adaptation of new catalysts
Chemical approaches to biological systems have not only generated target-binding entities, but also novel catalysts. Stable analogues of transition-states are routinely used to generate antibodies which catalyse reactions of interest, and these have been applied to drug activation, drug detoxification, and synthetic chemistry . Naturally occurring enzymes have also been engineered to alter their activities and specificities for use in synthetic, environmental and medical applications . Conversely, wholly synthetic inorganic complexes have been used successfully as artificial mimics of enzymes such as catalase and superoxide dismutase [8, 9].
There is a vast armament of traditional chemical analytical techniques (both classical and instrumental) which may be applied to the products of living systems. Experimental design, engineering and computer processing developments have allowed us to examine complexes and structures of ever increasing molecular weight and complexity with ever greater accuracy and resolution. Previously unobservable non-covalent interactions have been mapped, and the cross-talk between cellular (and extracellular) components investigated. New phenomena in quaternary structure and binding site topology are also being reported.
However, we do still have some really challenging analytical problems that only just beginning to be addressed. The phenotypic heterogeneity of supposedly identical individual cells has proved a confounding problem for molecular biologists. Standard biological techniques such as western blotting and microarraying require large numbers of cells, and can only produce an average result for a culture or tissue sample masking the intrinsic heterogeneity of populations of cells. Developments in miniaturisation and quantitative amplification methods are starting to generate more quantitative and qualitative data from single cells. Equally, new non-destructive methods, particularly those which can be used in vivo, are opening up whole new areas of research .
Control of cell division
Some of the most notable breakthroughs have been made in elucidating and intervening in the processes involved in cell division. There has been intense activity in this area not just because it is such a fundamental part of living systems, but also because of the potential for anti-cancer applications. One of the first, and perhaps best known, successes in this aspect of Chemical Biology is that of Monastrol . Monastrol was selected as a result of a phenotype-based screen to identify compounds which disrupt the mitotic spindle during cell division. It was found to act by specifically inhibiting the activity of the kinesin Eg5, and has opened up a whole new aspect to cell cycle research and enabled completely new modes of inhibiting cell growth.
It should not be forgotten that the converse of uncontrolled cell division, cellular senescence, also represents an important biological target. With every division there is an increasing chance of cells entering cellular senescence, and never dividing again. This is not only a problem in terms of our ability to replace damaged tissues. In addition, cells which have entered senescence persist in tissue, and take on an altered, deleterious phenotype which is thought to contribute to ageing. Work which elucidates replicative control pathways thus also has a high likelihood of generating important information relating to the ageing process, an area in which I have a particular interest. The Chemical Biology of Ageing is really in its infancy, but the current demographic shift towards an aged population means that it is likely that this will represent one of the most important areas for progress in the future.
Cellular activity modulation
Whilst there are many modes of cellular regulation, membrane bound receptors represent an attractive target for small molecule-mediated control of cellular activity because of their accessibility. Small molecules which act as receptor ligands or inhibitors have been used successfully for neurological problems such as bladder control  and epilepsy , and for controlling smooth muscle activity  although work continues on improving the activity and selectivity over the drugs currently in use. Other receptor targets, such as those controlling the immune system and the induction of apoptosis have really only been exploited using antibody and peptide ligands, and successful synthetic modulators have yet to appear. Alternative possibilities for the chemical regulation of cellular processes including selective ion-channel modulators  and sequence specific DNA binding molecules (which promote or inhibit the transcription of specific genes),  are also being investigated.
Another type of approach is to study the chemical interactions between biological systems in their natural environment. Electrochemical methods have been used to characterise the effects of naturally produced algal exudates on the behaviour of other algae,  leading to the discovery of some interesting new ligands which affect growth rate and trace metal uptake.
Small biological molecule targets
Although natural products are popular as lead compounds, there has been rather less research devoted to small biological molecules as targets, and this remains a relatively undeveloped area. One such example, the group of compounds known as reactive oxygen and nitrogen species (RONS), has been successfully targeted, with a body of work devoted to antioxidants designed to prevent damage by soaking up the radical by-products of respiration. This approach has even been extended to inorganic complexes which mimic the actions of the antioxidant enzymes catalase and superoxide dismutase [8, 9].