Jan. 14, 2014: RNA Interference for All: Transformative Technology to Speed Translation

The Human Genome Project revolutionized science, not only because it identified all 3 billion letters of the human genome sequence, but also because all data from the project were made freely available to the public — a revolutionary idea at the time. The availability of these data has enabled scientists to develop better ways of understanding, diagnosing, treating and preventing disease, and it led to the development of entirely new areas of science. The Project’s success encouraged the public release of other large data sets, including from the International HapMap Project, an effort to create a map of variations in genome sequences among different people, and ENCODE, a project to catalog of all the functional elements in the human genome sequence.

One of the first steps of scientific translation is called “target validation,” when investigators try to determine whether a particular molecule will be a good “target” on which a drug can act. Choosing a good target out of the thousands of possibilities is difficult, and the lack of available data for comparison makes this step even more challenging. However, on Dec. 11, 2013, NCATS and Life Technologies Corp. announced that, for the first time, large-scale data on the biochemical makeup of small interfering RNA (siRNA) molecules are available to the public. siRNAs are small pieces of ribonucleic acid (RNA) that block the activity of genes through a natural process called RNA interference (RNAi). Discovered only a decade ago, RNAi has rapidly become a key tool for target validation. Because each siRNA molecule can block a different gene, RNAi can tell us about the role of any gene in maintaining health or causing disease.

Until now, a major limitation for RNAi researchers has been the lack of publicly available data on the chemical sequences for siRNAs. Historically, the companies that own these molecules have not published this information. To address this obstacle, NCATS and Life Technologies are providing all researchers with access to siRNA data from Life Technologies’ Silencer Select siRNA library, which includes 65,000 siRNA sequences targeting more than 21,000 human genes. At the same time, NCATS is releasing complementary data about the effects of each siRNA molecule on biological functions. Scientists from the NIH-wide RNAi initiative, part of NCATS’ Division of Preclinical Innovation, use high-tech robots to introduce siRNAs into human cells to block the activity of each gene, one at a time. This process, called a genome-wide siRNA screen, can produce a complete list of all genes involved in a particular biological function or disease process — an invaluable step in target validation. Life Technologies’ siRNA sequence library and data from the RNAi initiative are available to the public free-of-charge through the National Library of Medicine’s public database PubChem.

Consistent with NCATS’ mission, the RNAi initiative is designed to improve the technology and efficiency of genome-wide RNAi for target validation. Before the initiative, screens produced unreliable results for reasons that were poorly understood. During the past two years, the RNAi team has published findings describing the source of unreliability and new approaches to overcome it. These advances, now combined with the public release of siRNA screening data, promise to turbocharge the identification of new targets for drug development.

A great example of how the RNAi initiative is producing new insights about genes involved in disease as well as new targets for therapies was announced in November. RNAi experts at NCATS, collaborating with a team from the National Institute of Neurological Disorders and Stroke, performed a genome-wide siRNA screen that revealed dozens of genes that may represent new targets for treating Parkinson’s disease. The network of genes appears to regulate the disposal of defective mitochondria, the structures that produce energy for cells. The findings, which were published online in Nature, also may be relevant to other neurological diseases caused by damage to mitochondria.

The development of new genome-wide RNAi technologies and the production and public release of genome-wide RNAi data are increasing our understanding of the role of individual genes in basic cell functions and aiding discovery of new therapeutic targets. In the “3Ds” vernacular we use at NCATS, we have developed new technologies for genome-wide RNAi, demonstrated their effectiveness in Parkinson’s disease, and now are publicly disseminating our results to the scientific community. I look forward to sharing more about the RNAi initiative’s successes as NCATS and our collaborators continue to make target validation, and translational research as a whole, more efficient and effective.

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences