New videogame lets amateur researchers mess with RNA

The line between computer-game player and scientist is about to disappear
June 26, 2012 | Source: Wired Science

(Credit: EteRNA)

EteRNA, an online game with more than 38,000 registered users, allows players to design molecules of ribonucleic acid — RNA — that have the power to build proteins or regulate genes.

EteRNA players manipulate nucleotides, the fundamental building blocks of RNA, to coax molecules into shapes specified by the game.

Those shapes represent how RNA appears in nature while it goes about its work as one of life’s most essential ingredients.

EteRNA was developed by scientists at Stanford and Carnegie Mellon universities, who use the designs created by players to decipher how real RNA works. The game is a direct descendant of Foldit — another science crowdsourcing tool disguised as entertainment — which gets players to help figure out the folding structures of proteins.

The game’s elite players compete for a unique and wondrous prize: the chance to have RNA designs of their own making brought to life. Every two weeks, four to 16 player-designed molecules are picked to be synthesized in an RNA lab at Stanford.

The chance to win this reward has proven highly motivating for EteRNA‘s players. They carefully study the data that the lab provides on how the synthesized molecules behave when ushered into existence, then use their observations to refine their next designs. In doing so, they — like their Foldit-playing peers — have helped scientists take advantage of the human brain’s unparalleled talent for recognizing patterns and solving puzzles.

But EteRNA players have also done something much more profound: By scrutinizing their creations, learning from their triumphs and mistakes, and using their accumulated wisdom to develop new hypotheses, they aren’t just building better RNA molecules; they’re discovering fundamental aspects of biochemistry that no one — not even the world’s top RNA researchers — knew before. And in doing so, they are blurring the line that separates gamer from scientist.

EteRNA has two tiers. The first is a series of “challenge puzzles,” in which players earn points by creating known RNA molecules. When the puzzle starts out, the RNA model is just a string of yellow disks that represent adenine — one of the four nucleotides that comprise RNA. A player must flip a certain number of those A disks to uracil (or U, colored blue), guanine (G, red), or cytosine (C, green) so that the structure morphs into the target shape — a two-dimensional form full of circular loops connected by straight “stem” sections, made from pairs of nucleotides. The task requires a working knowledge of how nucleotides attract and repel one another. The more nucleotides a puzzle has, or the more labyrinthine the shape the player is trying to mimic, the higher its point value.

Once players exceed 10,000 points — a milestone reached by about 7 percent of the game’s users — they are granted access to the lab section of the game. Here players are asked to mimic an all-new RNA shape — one that researchers would very much like to learn to make. Each player’s attempt has a shot at being synthesized at Stanford. The selection process is democratic, and each lab-qualified player is able to cast eight votes per week. Designers jockey for support by giving their creations snappy names (Strange Bird, Crimes Scene, Ends Justify Means) and writing descriptions of their trademark moves (“Added guanine boost to the tetraloop,” “This design includes a GU closing pair at 55-79″). Ultimately though, the voting players try to judge whether a given sequence is likely to form properly in the real world.

After the winners are synthesized, Das analyzes how well their structures mirror the game’s target shape. Then he grades each one on a scale from zero to 100. The highest-scoring molecules are posted in EteRNA‘s equivalent of the Hall of Fame, where they are scrutinized by scores of jealous also-rans. This is how the game’s newbies learn the secrets of RNA design and how its veterans reach epiphanies so profound they stun even EteRNA‘s creators.

The only question, then, is how long it will take EteRNA to produce  “the Terminator algorithm” — a program better than any human. The answer depends on how quickly the game can amass data from synthesized designs. If EteRNA were to maintain its current pace, with Das making about 32 molecules a month, it would likely take decades to compile the requisite intelligence. But the game’s experimental tempo is about to pick up.

In the earliest days of EteRNA, after growing frustrated at missing out on Stanford a few too many times, several players began to discuss the possibility of synthesizing designs themselves. One of this group’s more technically inclined members even priced the necessary equipment, such as a thermocycler to carry out polymerase chain reactions. The cost proved prohibitive, but home-brewing molecules is quickly becoming a realistic option.

Sequencing a genome costs less than 1 percent of what it did in 2002, a plunge that reflects the astonishing affordability of tools and technologies that barely existed a decade ago. Sooner or later, industrious EteRNA players are bound to invest the time and money to make Das superfluous, by building improvised labs where they can make molecules as they please. Instead of competing for slots at Stanford, they will use the game as a simulator to determine which of their designs are promising enough to synthesize in the garage.

Far from dreading his impending marginalization, Das is invigorated by the prospect of EteRNA players running their own experiments. “Any way we can get them more resources to test their hypotheses is going to be really revolutionary for this field and for science in general,” he says.

In the meantime, Das is trying to provide some of those experimental resources himself. He is planning to scale up the number of player molecules he can synthesize at a time, from eight to 20,000. Using part of the $1.7 million in funding that EteRNA recently received from Google and the W. M. Keck Foundation, Das plans to purchase DNA printed onto glass slides, which will let him analyze tens of thousands of RNA molecules at a time in parallel.

But Das also points out that garage labs aren’t the only way for players to make molecules — he envisions them eventually enlisting the services of satellite labs. “You could give EteRNA users remote access to a workstation. It doesn’t have to be at Stanford — it could be in Siberia,” Das says. “And they press a button that’s like, ‘I want to make this piece of RNA,’ and it gets uploaded to the biochemical cloud and synthesized.”

By synthesizing molecules of their own design, EteRNA players will be doing work that was once the sole domain of scientists. With all this coming together, Treuille and Das figure, why not also implement the final piece of the scientific process: publishing. Das is in talks with the Public Library of Science to create a way for players to contribute papers to the online journal PLoS Currents using the data generated by the RNA synthesis.

“Imagine on the website you start typing in the intro paragraph, and then the other paragraphs, and then you hit Create and Submit Paper,” says Treuille, who is now in the midst of a yearlong sabbatical at Google’s advanced-projects lab, Google X. “And it assembles the whole thing — puts in your data collected from EteRNA. And then it goes to the journal, and they know the data is true because they know that EteRNA is true.”

Once that happens, biochemistry will face a dilemma that other, far less technically demanding fields have been grappling with for years: Who exactly are the professionals? The line between computer-game player and scientist will be nearly gone. If someone can form a hypothesis, test it herself, and then publish her groundbreaking results in a respected journal, she is a scientist — even if she makes her living stocking shoes.