| Carnegie Mellon University
Te (Ford) Hu
Game with a purpose, Puzzle
Foldit, Phylo, Eyewire, Quantum Moves
EteRNA is a browser-based "game with a purpose", developed by scientists at Carnegie Mellon University and Stanford University, that engages users to solve puzzles related to the folding of RNA molecules. The project is funded by the National Science Foundation.
Similar to Foldit—created by some of the same researchers that developed EteRNA—the puzzles take advantage of human problem-solving capabilities to solve puzzles that are computationally laborious for current computer models. The researchers hope to capitalize on "crowdsourcing" and the collective intelligence of EteRNA players to answer fundamental questions about RNA folding mechanics. The top voted designs are synthesized in a Stanford biochemistry lab to evaluate the folding patterns of the RNA molecules to compare directly with the computer predictions, ultimately improving the computer models.
Ultimately, EteRNA researchers hope to determine a "complete and repeatable set of rules" to allow the synthesis of RNAs that consistently fold in expected shapes. EteRNA project leaders hope that determining these basic principles may facilitate the design of RNA-based nanomachines and switches. EteRNA creators have been pleasantly surprised by the solutions of EteRNA players, particularly those of non-researchers whose "creativity isn't constrained by what they think a correct answer should look like".
As of 2016, EteRNA has about 100,000 registered players.
Players are presented with a given target shape into which an RNA strand must fold. The player can change the sequence by placing any of the four RNA nucleotides (adenine, cytosine, guanosine and uracil) at various positions; this can alter the free energy of the system and dramatically affect the RNA strand's folding dynamics. In EteRNA, different restrictions, such as those on the number of certain bases and the number of the three base pair types, as well as locked bases, are sometimes imposed. A molecule is occasionally also included, which binds with the RNA and has critical effects on the free energy of the system. In some more advanced puzzles, players may be presented with two or three different target shapes at the same time; the single sequence the player produces must fold in the respective shapes under different conditions (presence or absence of a binding molecule).
EteRNA puzzles are roughly classified into three types: Challenges, Player Puzzles, and Cloud Lab. Challenges are the puzzles prepared by the game-makers to introduce players to the workings of EteRNA as well as to provide series of pre-set puzzles for players to attempt. Player puzzles are generated by players, and Cloud Lab is where the active, proposed and archived laboratory projects are presented for players to review, vote or attempt.
Once players have completed a sufficient number of RNA puzzles, they unlock the chance to generate puzzles for other players. These puzzles can be selected as future synthesis candidates if they fit certain rules and prove interesting. Other more complex puzzles are not currently lab synthesis candidates.As of August 2011, approximately 26,000 players have contributed RNA sequence designs and over 306 designs have been synthesized for in vitro testing.
In January 2014, the results from EteRNA have been published in the PNAS journal, with "EteRNA participants" listed as co-authors in the paper.
The EteRNA gamers beat the supercomputer-powered algorithms in solving all the 100 RNA secondary structure design challenges while the best score of the six algorithms used is 54. By manipulating the chemical sequences of RNA the gamers created stable forms of desired shapes. The strategies designed by the players identified specific structural features that make inverse RNA folding difficult. The EteRNA researchers hope that by integrating their strategies into algorithms, improvement in automated RNA secondary structure design can be achieved. The results of the challenges were published in the Journal of Molecular Biology on February 2016.