What is chemical genetics?

Chemical genetics is a research method that uses small molecules to change the way proteins work—directly in real time rather than indirectly by manipulating their genes. It is used to identify which proteins regulate different biological processes, to understand in molecular detail how proteins perform their biological functions, and to identify small molecules that may be of medical value.

The term chemical genetics indicates that the approach uses chemistry to generate the small molecules and that it is based on principles that are similar to classical genetic screens. Scientists use two kinds of genetic approaches—forward and reverse—depending on the starting point of the investigation. As the table illustrates, a classical forward genetic analysis starts with an outward physical characteristic (called a phenotype) of interest and ends with the identification of the gene or genes that are responsible for it. In classical reverse genetics, scientists start with a gene of interest and try to find what it does by looking at the phenotype when the gene is mutated.

Comparing Classical Genetic and Chemical-Genetic Approaches

Chemical genetics applies these same principles, but the analyses focus on proteins rather than genes. In a forward chemical-genetic screen, scientists start with a phenotype to find the protein or proteins responsible for it, and in a reverse chemical-genetic screen, the starting point is a protein of interest.

In a classical forward genetic screen, genes are mutated at random. The resulting changes in phenotype of a cell or organism are then attributed to the mutated genes and, by inference, to their protein products. For example, scientists can create random mutations in different genes of the fruit fly Drosophila melanogaster by irradiating the eggs. If they are interested in understanding wing development, scientists can select flies born from the irradiated eggs with specific wing defects, such as small wings. Next, they find a mutation in a specific gene by scanning the genome of these flies. Once a gene is identified and isolated, further experiments can be done to show that it is important for proper growth of wings. In the early 1970s, Seymour Benzer's lab at the California Institute of Technology used a forward genetic strategy to identify the first gene known to affect the fly's biological clock (see lecture two at http://www.hhmi.org/biointeractive/genomics/lectures.html).

The discovery that a small molecule called FK506 blocks the production of several substances produced in an immune response was one of the first successful applications of this chemical-genetic process. Subsequent studies found that FK506 targets the protein calcineurin, indicating that calcineurin is important for inducing the immune response. This study, therefore, revealed to scientists a previously unknown biological function of calcineurin, and it identified a small molecule, FK506, with possible medical use as an immunosuppressant drug (Kino, T., et al. 1987. Journal of Antibiotics 40(9): 1249–55; Kino, T., et al. 1987 Journal of Antibiotics 40(9): 1256–65).

In a sense, the small molecules that bind to proteins and affect their activities mimic the random mutations used in classical genetic screens. However, there are important differences. In a genetic screen the activity of a protein is altered indirectly—by mutating its gene—but in chemical genetics this change is direct and occurs in real time (when the molecule is added). Another difference between the two approaches is that the effect of the "mutation" caused by a small molecule is reversed when the small molecule is removed. In contrast, the effect of mutating a gene is, in most cases, permanent. Therefore, chemical-genetic approaches may be more useful when scientists want to study genes that are essential to an organism's survival, since altering their function in eggs or embryos might cause the organism to die before or shortly after birth. A small molecule can be administered to a cell or an animal for a very short time to study the function of the target protein.

Thousands of small molecules can also be tested systematically against known protein targets to identify molecules that change the proteins' functions. This process is analogous to reverse-genetic approaches, such as creating mice deficient in a particular gene to understand the biological function of the gene of interest. In a reverse chemical-genetic screen, a protein is purified and then tested against a large number of small molecules. Typically, between 10,000 and 1 million small molecules can be tested in a large screen, yielding 10 to 1,000 candidate small molecules that bind to the protein. The candidates are retested several times under different conditions, and only those that "pass" subsequent tests are used to determine the biological consequences of altering the target protein's function in a cell or an animal.

This approach was used to find a small molecule that binds to and inactivates the protein MEK1, an enzyme whose activity is needed for cell division. Subsequent studies showed that when mice with cancer were treated with this small molecule, the sizes of their cancers started to shrink, indicating that MEK1 also functions in tumor growth. Again, this study alerted scientists to a new function of MEK1 and identified a small molecule that might be used as an anti-cancer drug (Sebolt-Leopold, J.S., et al. 1999. Nature Medicine 5(7): 810–16).

An important tool for chemical genetics is a collection, or "library," of small compounds. Stuart Schreiber's laboratory was one of the first to use various chemical-synthesis techniques to obtain compounds of many different chemical structures—a process often called diversity-oriented synthesis. Schreiber has generated libraries of compounds that bind to many different proteins and that produce different effects when added to cells. This has led to his concept of ChemBank, a giant database that links small molecules to their known specific effects on particular proteins and to their effects on specific cell types or even organisms. These matrices of small-molecule activities will help tie protein functions to particular cellular activities and may also help identify small molecules that could become useful drugs.

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