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Crowdsourcing RNA Design Beats Doing It by Computer

An "Internet-scale citizen science game" is helping scientists at Carnegie Mellon University, Stanford University and Seoul National University better understand the design rules for creating RNA structures. As a recently published paper on the project explained, "an online community can carry out large-scale experiments, generate hypotheses and design better algorithms to advance science."

"RNA design rules from a massive open laboratory," published in January by the National Academy of Sciences, described EteRNA, which lets people create RNA designs. RNA, as the game explains, are tiny molecules in every cell that play "critical roles" in the processes of biology, from genetic regulation to viral replication.

To understand how RNA molecules work, some of the same researchers behind Foldit, a massively popular protein folding game, developed EteRNA and invited people to manipulate the building blocks of RNA. The game has drawn 37,000 "enthusiasts" to the design puzzles. The best design results as voted by the players themselves have been synthesized in labs at Stanford.

The process of creating those designs have taught both the players and the scientists new rules about what works and what doesn't work when it comes to the engineering of RNA. Those rules, in turn, have led to the development of an automated algorithm, EteRNABot, which outperforms previous RNA manipulation algorithms in a dozen tests.

Ultimately, the researchers have found that the community and the EteRNABot have "significantly outperformed" previous approaches to the problem of reengineering RNA molecules.

"The quality of the designs produced by the online EteRNA community is just amazing and far beyond what any of us anticipated when we began this project three years ago," said Adrien Treiulle, an assistant professor of computer science and robotics at Carnegie Mellon.

Treiulle leads the project with Rhiju Das, an assistant professor of biochemistry at Stanford, and Jeehyung Lee, a Ph.D. student in computer science at Carnegie Mellon.

"This wouldn't be possible if EteRNA members were just spitting out designs using online simulation tools," he said. "By actually synthesizing the most promising designs in Das's lab at Stanford, we're giving our community feedback about what works and doesn't work in the physical world. And, as a result, these non-experts are providing us insight into RNA design that is significantly advancing the science."

The report stated that computers could generate designs in less than a minute, while most people would take one or two days; synthesizing the molecules to determine the success and quality took a month for each design, so the entire experiment lasted about a year.

The designs produced by humans had a 99 percent likelihood of being superior to those of the prior computer algorithms, while EteRNABot produced designs with a 95 percent likelihood of besting the prior algorithms.

"The quality of the community's designs is so good that even if you generated thousands of designs with computer algorithms, you'd never find one as good as the community's," Lee said. "Most players didn't have tactical insights on RNA designs," he added. "They would just recognize patterns — visual patterns."

Now the research project is looking to expand its "game" to include three-dimensional designs. The scientists are also developing a template for other researchers to use to turn their own scientific projects into online challenges.

EteRNA is supported by funding from the National Science Foundation, the National Research Foundation of Korea, Google, and the W.M. Keck Foundation.

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