Tools of the trade

CAMBRIDGE, Mass. — In the film “It’s a Wonderful Life,” an angel shows a suicidal George Bailey how his small town would have fared had he never been born. For years, scientists have conducted countless George Bailey experiments on genes, identifying their function by knocking them out with specially designed complex molecules, then observing what happens to the cell.

In the past, such complex molecules took months to engineer. But since 2001, more scientists are adopting a new method that shuts down a single gene within days using small segments of RNA called short interfering RNA, or siRNA. Now, Whitehead Institute’s Bioinformatics and Research Computing group has developed a Web-based tool that increases the accuracy and speed of this widely used technique.

When placed in a cell, these short strands of RNA interfere with a gene’s ability to produce protein. Several academic labs and drug companies have pursued siRNA’s ability to immobilize key genes involved in viral and immunological diseases, cancers and other illnesses. But sorting out which siRNA sequences block which genes is cumbersome; scientists must randomly select siRNA segments from thousands of possibilities in the hopes of hitting the bull’s-eye.

The siRNA Selection Program, completed in February 2003 by Whitehead’s Bioinformatics group, could make the process less cumbersome—and faster. Last September, the group received a grant from the National Science Foundation to improve its accuracy. Developed by Bingbing Yuan, the siRNA Selection Program enables scientists to quickly pinpoint a small number of specific siRNAs that likely will knock out a specific gene. Users enter the DNA sequence for the human or mouse genes they’re studying, and the program returns potential siRNA sequences that can be used to target the gene.

A recent survey in Genome Technology magazine ranked Whitehead’s program as one of the top three most used siRNA design tools. “The advantage of our tool over other available software is that we identify sequences that exclusively target the gene of interest, and provide information as to why the resulting siRNA candidates got selected,” says Fran Lewitter, director of the Bioinformatics group.

In collaboration with Thomas Tuschl, former Whitehead postdoc and a pioneer in siRNA research, and other leading siRNA researchers, the Bioinformatics group is now developing a public database that will help the team further refine its program. Lewitter’s team also has launched a new project to produce additional experimental data that could yield an even more sophisticated program.