This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
What is chemical genetics?
Chemical genetics is an approach that can be used to study protein function and signal transduction pathways by using small molecules to disrupt protein function and studying the resultant phenotypic changes. The goal of chemical genetics screens can either be to create a phenotype of interest or to find a small molecule that binds to a specific protein of interest [1]. Chemical genetics is similar to classical genetics in that both forward and reverse genetics, usually done with mutations, can be done using small molecules (see image to the right). An advantage of chemical genetics for disrupting a protein's function is that disruption with small molecules can be reversible, whereas knocking out the gene is not [1].
How are small molecules identified?
To identify small molecules that bind to the protein of interest, a high-throughput chemical genetics screen using a small molecule library can be used. Screens can look for small molecules that bind a specific protein or that inhibit a biological function in cells. A small molecule is considered a hit if it elicits the desired phenotype [2] or if it binds to the protein of interest [3]. One high-throughput option for identifying which small molecules interact with proteins is to immobilize many small molecules on a surface and incubate this surface with the labeled protein. After incubation, the areas of the surface with the protein label indicate the small molecules that bind the protein of interest [3]. The opposite approach can also be used, where the protein is immobilized and the small molecule is labeled.
Once relevant small molecules are identified, they can be tested further to verify that they interact with the protein of interest. Alternatively, if the screen identified small molecules that bring about a desired phenotype, further testing must be done to determine the targets of the small molecule hits [2].
Once relevant small molecules are identified, they can be tested further to verify that they interact with the protein of interest. Alternatively, if the screen identified small molecules that bring about a desired phenotype, further testing must be done to determine the targets of the small molecule hits [2].
How can chemical genetics be used to study disease?
There are two major ways that chemical genetics can contribute to our understanding of a disease:
- Chemical genetics can identify compounds that disrupt proteins involved in diseases. These molecules can then be used to study the disease by conditionally inducing the phenotype either in cell lines or organisms. The advantage to using chemical genetics to study a disease is it is reversible (and can also be induced at a later age instead of from birth in model organisms), the dose can be controlled, and knockout state can be studied in cells even if a full genetic knockout is not viable [4].
- Chemical genetics is also important for drug discovery. Once biologically active small molecules are identified using the high-throughput screen, their protein targets can be identified using techniques such as liquid chromatography–tandem mass spectrometry [5]. Once the target protein is identified, the phenotypic effects of the small molecule can be assessed in cells and disease models study its toxicity and effectiveness.
References
[1] Kawasumi and Nghiem. 2007. Chemical genetics: elucidating biological systems with small-molecule compounds. http://www.ncbi.nlm.nih.gov/pubmed/17568801
[2] Jay Yang. Chemical Genetics and Drug Target Discovery. http://www.singerinstruments.com/application/chemical-genetics-and-drug-target-discovery/
[3] Brent Stockwell. 2004. Exploring biology with small organic molecules. http://www.nature.com.ezproxy.library.wisc.edu/nature/journal/v432/n7019/full/nature03196.html
[4] David R. Spring. 2005. Chemical genetics to chemical genomics: small molecules offer big insights
http://pubs.rsc.org/en/content/articlehtml/2005/cs/b312875j
[5] Cong et al. 2012. Chemical Genetics–Based Target Identification in Drug Discovery. https://www.ncbi.nlm.nih.gov/pubmed/21819237
[1] Kawasumi and Nghiem. 2007. Chemical genetics: elucidating biological systems with small-molecule compounds. http://www.ncbi.nlm.nih.gov/pubmed/17568801
[2] Jay Yang. Chemical Genetics and Drug Target Discovery. http://www.singerinstruments.com/application/chemical-genetics-and-drug-target-discovery/
[3] Brent Stockwell. 2004. Exploring biology with small organic molecules. http://www.nature.com.ezproxy.library.wisc.edu/nature/journal/v432/n7019/full/nature03196.html
[4] David R. Spring. 2005. Chemical genetics to chemical genomics: small molecules offer big insights
http://pubs.rsc.org/en/content/articlehtml/2005/cs/b312875j
[5] Cong et al. 2012. Chemical Genetics–Based Target Identification in Drug Discovery. https://www.ncbi.nlm.nih.gov/pubmed/21819237