Ilya Shestopalov and James Chen of Stanford University, US, look at how chemistry can be used to probe the earliest processes of life

How does the human newborn-composed of approximately one trillion cells and over 200 cell types-arise from a single, fertilised egg? Since the time of Aristotle, scientists have strived to explain this fascinating transformation, using a perturb-and-observe approach to study model organisms. These pioneering developmental biologists examined embryos from sea urchins, chickens, frogs, and other animals, using dyes to follow cell lineages and surgical procedures to study interactions between tissues. Their investigations revealed conserved embryological processes among evolutionarily diverse organisms and introduced concepts such as morphogen gradients - gradients of cell signalling molecules that influence tissue growth patterns.

Chemical technologies can be used to perturb-and-observe the molecular mechanisms that regulate embryo development

Modern developmental biology has focused on deciphering the molecular mechanisms that regulate tissue patterning. For example, computational models of cell signalling networks have been used to simulate how a developing fruit fly wing orients hundreds of tiny hairs in the same direction. But while many discoveries have arisen from advances in molecular biology, transgenic organisms, and genome sequencing, chemistry has also made important contributions. 

Since embryonic patterning arises from spatially and temporally controlled gene function, chemical technologies, which allow scientists to perturb-and-observe molecular events with spatiotemporal precision, have been used to target multiple steps in the process. These include DNA transcription into RNA, RNA translation into proteins, and protein function. For example, several approaches for regulating gene transcription with small molecules have been developed. Engineered transcriptional activators and repressors can be used to regulate gene expression with respect to time and activity level, simply by controlling the timing and dosage of small molecule administration. 

The chemical regulation of RNA function has been achieved largely through artificial oligonucleotides rather than small molecules. The oligomers can target specific genes so that RNA processing, translation, or stability can be perturbed. Unlike small molecules, synthetic oligonucleotides are not membrane permeable and typically must be introduced into embryos by microinjection. Yet this 'limitation' also allows the reagents to be used to perturb gene function in selected cell populations within an embryo. 

Rapid kinetic control of embryonic patterning can also be achieved with small molecules. Accordingly, several compounds that inhibit or activate developmental signalling proteins have been discovered through studies of natural teratogens and high-throughput screens of synthetic chemical libraries. The plant-derived alkaloid cyclopamine is one of the best known small molecule modulators of embryonic development, and was discovered to be the cause of an outbreak of cyclopic lambs during the 1950s. It is now used routinely in the laboratory to block Hedgehog signalling, a key pathway in animal development, and compounds targeting other developmental pathways have also been identified. 

While these and other chemical strategies have provided key insights into the molecular processes that regulate embryonic patterning, technology development for the 'observe' half of the perturb-and-observe approach is a relatively unexplored frontier. Photoactivatable markers have replaced the dyes used in the 1920s for visualising cell lineages, and synthetic sensors have enabled real-time calcium imaging during embryo development. Chemists have an opportunity to make unique and significant contributions to developmental biology that are unlikely to be fulfilled by scientists trained in other disciplines. New synthetic probes of gene expression, protein function and other biological processes would revolutionise how we interrogate fundamental questions in embryology. Thus, chemical technologies could be the key to merging the molecular discoveries of the post-genomic era with the scientific tradition of embryological observation.

Read more in the tutorial review 'Chemical technologies for probing embryonic development' in issue 7, 2008,  of Chemical Society Reviews, a thematic issue examining the chemical biology interface.