Citizen scientists are usually asked to perform mundane tasks: supplying surplus computing power or exercising pattern-recognition skills. But now citizen scientists can do something more exciting. Within a video game–like environment called Foldit, they can help design novel synthetic proteins.

While playing Foldit may not improve gamers’ hand-eye coordination, it will engage them in creative work. Even better, gamers who excel in Foldit may score points that count for something in the real world. For example, gamers may design structures that lead to novel applications in medicine, such as vaccines and biologic drugs, as well as in other fields.

Work on Foldit commenced in 2008 under the leadership of scientists at the University of Washington’s (UW) Institute for Protein Design. Now—after many iterations of player design, analysis of the top-scoring solutions, and subsequent game improvement—the UW scientists and colleagues from Rutgers University, the University of Massachusetts Dartmouth, Northeastern University, and other institutions report that players have indeed designed potentially useful proteins.

“The diversity of molecules that these gamers came up with is astonishing,” said Brian Koepnick, PhD, a postdoctoral researcher at the Institute for Protein Design. “These new proteins are by no means inferior to the stuff a PhD-level scientist might make.”

Through gameplay, Foldit players have helped determine the structure of an HIV-related protein and improved the activity of useful enzymes. Until now, however, Foldit players could interact only with proteins that already existed. There was no way to design new ones.

“Designing completely new proteins that didn’t exist in nature has been our goal with Foldit for a long time,” said Seth Cooper, PhD, assistant professor in the Khoury College of Computer Sciences at Northeastern University. “This new set of results shows that it’s possible.”

These new results appeared June 5 in the journal Nature, in an article titled, “De novo protein design by citizen scientists.” It describes how researchers turned Foldit into a platform for protein design by encoding biochemical knowledge into the game. In the revised game, designer molecules that score well are more likely to fold up as intended in the real world.

“One hundred forty-six Foldit player designs with sequences unrelated to naturally occurring proteins were encoded in synthetic genes,” the article’s authors wrote. “[Of these designs,] 56 were found to be expressed and soluble in Escherichia coli, and to adopt stable monomeric folded structures in solution.”

The diversity of these structures, the authors noted, is unprecedented in de novo protein design, representing 20 different folds—including a new fold not observed in natural proteins. “High-resolution structures,” they added, “were determined for four of the designs, and are nearly identical to the player models.”

These results suggest that Foldit can put the implicit knowledge of biochemical experts into the hands of game players, who are then able to supply their own creativity and intuition to problems of protein design.

“There are more possible proteins than there are atoms in the universe. It’s exciting to think that now anyone can help explore this vast space of possibilities,” said David Baker, PhD, the Nature article’s senior co-author, professor of biochemistry at the UW School of Medicine, and director of the Institute for Protein Design.

Full computer enumeration of design elements such as protein backbones is not possible; consequently, Foldit tries to harness the human element, letting players experiment with the conformations available to a polypeptide chain, which is huge even for a modestly sized protein.

“We didn’t give [Foldit players] any lectures or tell them to read anything,” recalled Firas Khatib, PhD, assistant professor of computer science at the University of Massachusetts Dartmouth. “Instead, we tweaked the code that has run the game over many years.”

“I never would have believed they would get that good,” he continued, “but Foldit players never cease to amaze us.”

Crafting new proteins is a bit like trying to tie never-before-seen knots using rope that is a million times thinner than a human hair. To date, only a small group of experts with intimate knowledge of the way biomolecules twist and turn bothered with this exceedingly complex task. Most use automated molecular design algorithms, and most design algorithms fail far more often than they succeed.

“We are always trying to make the algorithms better, but the human element is key,” Khatib emphasized. “In fact, through Foldit design, players have even discovered flaws in the Rosetta energy function—our state-of-the-art method for protein design.”

Protein design is an emerging scientific discipline. In the past five years, experts at the Institute for Protein Design and their colleagues have created proteins that stimulate the immune system to fight cancer and others that act as potent vaccine candidates.

Could gamers contribute such efforts? Before they reach “game over,” Foldit players could even create the next blockbuster drug.

“Foldit players are a new addition to the research arsenal,” Khatib asserted. “They’re not a silver bullet, but they are an amazing resource.”

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