Chemical biology

Chemical biology is a scientific discipline spanning the fields of chemistry and biology that involves the application of chemical techniques and tools, often compounds produced through synthetic chemistry, to the study and manipulation of biological systems.

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Introduction

Some forms of chemical biology attempt to answer biological questions by directly probing living systems at the chemical level. In contrast to research using biochemistry, genetics, or molecular biology, where mutagenesis can provide a new version of the organism or cell of interest, chemical biology studies sometime probe systems in vitro and in vivo with small molecules that have been designed for a specific purpose or identified on the basis of biochemical or cell-based screening.

Chemical biology is one of many interfacial sciences that are characteristic of a general trend away from older, reductionist fields toward those whose goals are to achieve a description of scientific holism. In this sense, it is related to other fields such as proteomics. Chemical biology has historical and philosophical roots in medicinal chemistry, supramolecular chemistry (particularly host-guest chemistry), bioorganic chemistry, pharmacology, genetics, biochemistry, and metabolic engineering.

Systems of interest

Proteomics

After the completion of the human genome project, many scientists realized the next big target would be the human proteome. As genes ultimately encode cellular proteins, the purpose and ultimate destination of proteins in cells is technically encoded as well. However, in practice, the ability to determine the structure, let alone function, of a protein just from its genetic sequence is impossible. Chemical biology is attempting to answer many questions about the function, structure, affinity and location of all the proteins within a living cell.

The global analysis of the proteome is called proteomics. The major challenge in proteomics is that in any given tissue, there are approximately 10,000 different proteins being expressed at levels that vary by as much as six orders of magnitude. Chemical biologist Stuart Schreiber advocates building a “perturbogen” library of small molecules that could specifically activate or deactivate every protein in the human body. Schreiber estimates such a project would require at least a decade. A purpose of the library would be to enable biomedical engineers to develop therapies more efficiently. A number of scientists have developed ways to break the proteome down into meaningful pieces that can be studied more easily. Notably, activity based proteomics developed by Benjamin Cravatt III uses specially designed chemical probes to analyze classes of active enzymes in within a tissue.

Another challenge of chemical biology is to decipher the myriad signal transduction pathways involving kinase and phosphatase signaling. In this regard, Kevan Shokat at UCSF has developed a method for selectively inhibiting a given kinase upon the addition of an otherwise biologically orthogonal competitive inhibitor (1-napthylmethyl-PP1). Shokat's technique involves altering a protein kinase (by mutating the so-called "gatekeeper" residue in the kinase catalytic domain) to contain an unnatural hydrophobic binding pocket which distinguishes it from the other highly homologous cellular kinases, allowing it to be selectively inhibited. A related method has been developed in his lab which uses these so-called "analog-sensitive" kinases to label their substrates using an unnatural ATP (adenosine triphosphate) analog, facilitating their visualization and identification. Identification of enzyme substrates (of which there may be hundreds or thousands, many of which are unknown) is a problem of significant difficulty in proteomics and is vital to the understanding of signal transduction pathways in cells; techniques for labelling cellular substrates of enzymes are a typical approach used by chemical biologists to address this problem.

Many researchers are working on ways to manipulate the way that proteins are assembled by cellular systems. In this regard, Peter Schultz at the Scripps Research Institute has evolved bacteria to install synthetic, non-natural amino acids into proteins.

Glycobiology

While DNA, RNA and proteins are all encoded at the genetic level, there exists a separate system of trafficked molecules in the cell that are not encoded directly at any direct level: sugars. Thus, glycobiology is an area of dense research for chemical biologists. For instance, live cells can be supplied with synthetic variants of natural sugars in order to probe the function of the sugars in vivo. Carolyn Bertozzi at University of California, Berkeley has developed a method for site-specifically reacting molecules the surface of cells that have been labeled with synthetic sugars.

Combinatorial chemistry

Some chemical biologists use automated synthesis of many diverse compounds in order to experiment with effects of small molecules on biological processes. More specifically, they observe changes in the behaviors of proteins when small molecules bind to them. Such experiments may supposedly lead to discovery of small molecules with antibiotic or chemotherapeutic properties. Indeed, some scientists (such as Jon Clardy of the Harvard Medical School) hope chemical biology will lead to cures for malaria, tuberculosis, and AIDS.

Employing biology

Many research programs are also focused on employing natural biomolecules to perform a task or act as support for a new chemical method or material. In this regard, researchers have shown that DNA can serve as a template for synthetic chemistry, self-assembling proteins can serve as a structural scaffold for new materials, and RNA can be evolved in vivo to produce new catalytic function.

Publications

• ACS Chemical Biology - The new Chemical Biology journal from the American Chemical Society.
• Bioorganic & Medicinal Chemistry - The Tetrahedron Journal for Research at the Interface of Chemistry and Biology
• ChemBioChem – A European Journal of Chemical Biology
• Chemical Biology - A point of access to chemical biology news and research from across RSC Publishing
• Chemistry & Biology - An interdisciplinary journal that publishes papers of exceptional interest in all areas at the interface between chemistry and biology.
• Journal of the Royal Society Interface - A cross-disciplinary publication promoting research at the interface between the physical and life sciences
• Molecular BioSystems - A new high quality chemical biology journal with a particular focus on the interface between chemistry and the -omic sciences and systems biology.
• Nature Chemical Biology - A monthly multidisciplinary journal providing an international forum for the timely publication of significant new research at the interface between chemistry and biology.