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siRNAs: Small Molecules that Pack a Big Punch

Posted on by Dr. Francis Collins

Photo of parkin protein (green) that tags damaged mitochondria (red)
Caption: NIH scientists used RNA interference to find genes that interact with the parkin protein (green), which tags damaged mitochondria (red). Mutations in the parkin gene are linked to Parkinson’s disease and other mitochondrial disorders.
Credit: Richard J. Youle Laboratory, NINDS, NIH

It would be terrific if we could turn off human genes in the laboratory, one at a time, to figure out their exact functions and learn more about how our health is affected when those functions are disrupted. Today, I’m excited to announce the availability of new data that will empower researchers to do just that on a genome-wide scale. As part of a public-private collaboration between the NIH’s National Center for Advancing Translational Sciences (NCATS) and Life Technologies Corporation, researchers now have access to a wealth of information about small interfering RNAs (siRNAs), which are snippets of ribonucleic acid (RNA) with the power to turn off a gene, or reduce its activity—in much the same way that we use a dimmer switch to modulate a light.

To enhance this resource, Life Technologies has now contributed the chemical sequences of 65,000 siRNAs to NIH’s PubChem database. Previously, investigators using this commercial siRNA library have known what gene target each siRNA is aimed for, but have not had access to the precise nucleotide sequence of these molecules.  Public revelation of those critical details will now empower many research programs that aim to silence nearly all of the protein-coding genes in the human genome and properly interpret siRNA screening data.

Let me share some background to give you a better sense of the tremendous value of this new tool. The human genetic blueprint, or genome, contains about 21,000 genes [1]. These genes, which are made of deoxyribonucleic acid (DNA), produce an intermediate molecule called messenger RNA (mRNA) that is then translated into a protein. To regulate this system, DNA also encodes short RNA molecules that interfere with gene activity by targeting matching mRNAs, inhibiting their translation, and even destroying them. This prevents an mRNA from being translated into a protein and dials down or even silences the gene. This is a natural process the body uses to regulate the activity of genes. But that’s not all—small RNAs, such as siRNAs, have turned out to be amazing research tools for probing biological mechanisms in the lab. By using siRNAs to silence genes one by one in individual cells, researchers can observe what happens to a cell when a specific gene is turned off.

Besides helping to expand our understanding of basic biological mechanisms, siRNA research may also uncover new targets for therapeutic development.  Indeed, researchers have already used siRNAs to identify genes linked, albeit indirectly, to Parkinson’s disease, a movement disorder that causes tremors, shakes, and a debilitating loss of motor control [2]. There is mounting evidence that some forms of the disease result from a glitch in the garbage disposal system in the cell. A protein called parkin typically tags for disposal any of the cell’s power generators, called mitochondria, that are damaged or malfunctioning. Some mutations in PARK2, the gene that codes for parkin, disrupt this tagging activity, causing an accumulation of damaged mitochondria that sickens cells.

Recently, a team led by a researcher at NIH’s National Institute of Neurological Disorders and Stroke teamed up with experts at NCATS who used siRNAs and some very high tech robots to turn off each of the 21,000 human genes. Once the genes were silenced, the group then used a microscope to peer into cells and observe the impact on damaged mitochondria and parkin activity. This impressive effort yielded four genes that may be particularly useful therapeutic targets. Specifically, researchers discovered that when two genes called TOMM7 and HSPAI1L were silenced, the parkin protein was unable to tag the trash for collection. On the other hand, silencing the BAG4 and SIAH3 genes boosted parkin activity and trash labeling.

The siRNA saga certainly doesn’t begin or end with Parkinson’s disease, and I expect we’ll soon be hearing many more stories of success. Hats off to LifeTech and NCATS!  Thanks to the creativity and generosity of all who contributed to the new siRNA data, researchers around the globe now have what they need to begin applying similar approaches to their work aimed at helping people affected by many other diseases and conditions.


[1] An integrated encyclopedia of DNA elements in the human genome. ENCODE Project Consortium, Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M. Nature. 2012 Sep 6;489(7414):57-74.

[2] High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Hasson SA, Kane LA, Yamano K, Huang CH, Sliter DA, Buehler E, Wang C, Heman-Ackah SM, Hessa T, Guha R, Martin SE, Youle RJ. Nature. 2013 Nov 24.


Learn more about RNAi. (NCATS website)

Gene-silencing data now publicly available to help scientists better understand disease.” (NCATS press release)

PubChem Database

For assistance with submitting to PubChem, researchers may contact:

NIH support: National Center for Advancing Translational Sciences; National Institute of Neurological Disorders and Stroke; National Institute of General Medical Sciences; Office of Intramural Research; Trans-NIH RNAi Initiative


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