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It has been three years since F1000 Faculty Member Roger Tsien shared the Nobel Prize in Chemistry with Osamu Shimomura and Martin Chalfie for their discovery and development of green fluorescent protein (GFP). Widely considered one of the most important tools in bioscience, GFP is a guiding light that illuminates protein function. Tagging proteins with fluorescence enables the tracking of genes as they are expressed in cells or in whole organisms and is integral to the study of protein folding, protein transport, and RNA-protein dynamics. Tsien’s contributions to the Nobel Prize included expanding the color choices beyond green to facilitate the tracking of several biological processes at once.

This summer, research published by scientists at Cornell University’s Weill Medical College reported a new tagging tool for RNAs that could quickly bring about significant advances in the understanding of RNA dynamics. The paper, “RNA mimics of Green Fluorescent Protein,” (Science, July 29, 2011) has become one of Faculty of 1000’s most highly ranked papers of all time.

Co-authors Jeremy Paige, Karen Wu, and Samie Jaffrey noted that “RNA has complex roles in cellular function and is increasingly used for various applications, but a comparable approach for fluorescently tagging RNA is lacking.” Or, at least, it was lacking.

The team hunted for a small molecule whose fluorescence could be activated by a specific RNA sequence, but not other cellular constituents. The first of these was an RNA sequence-fluorophore complex that they call “Spinach” for its bright green glow. Then they went beyond Spinach to identify a palette of aptamer-fluorophore complexes in colors from cyan to yellow to orange-red.

Two characteristics that make this tool perhaps even more useful than GFP (leading one evaluator to call it an “enhanced” or “eGFP-like” RNA aptamer) are that it is resistant to photobleaching, and the fluorescence appears shortly after transcription in cells, rather than after fluorophene maturation. The researchers suggested that genetically encoded RNA-fluorophore complexes could be used in RNA-RNA and RNA-protein fluorescence resonance energy transfer, and in simultaneous imaging of multiple RNAs.

Fourteen Faculty Members from eight different biology faculties have evaluated this paper, demonstrating its broad utility. The paper now holds the fifth highest article ranking (FFa), and it is the only one published since 2009 to make it into the FFa All Time Top 10. Eight of the evaluators gave it an “exceptional” rating, and while evaluators from different sections were in wide agreement that the work has the potential to dramatically advance RNA science, the most provocative evaluation is the most recent one, posted November 7, by Etienne Joly:

For me, the reason why this paper is really interesting is because it shows that, under the right conditions of selection, one can get RNA to carry out the function of a protein. This is not only a promising development for biotechnology but it also strongly reinforces the idea that, at the origin of life, the first enzymes were almost certainly just folded up RNA molecules.

Coincidentally, an evaluation of this paper was our 110,000th published F1000 evaluation in August this year. It turns out that it wasn’t just a landmark for F1000, but a breakthrough for genetics research and a potential revolution for our understanding of RNA.