Games with a scientific purpose

Genome Biology Games with a scientific purpose Benjamin M Good 0 Andrew I Su 0 0 Department of Molecular and Experimental Medicine, The Scripps Research Institute , La Jolla, CA 92037 , USA The protein folding game Foldit shows that games are an effective way to recruit, engage and organize ordinary citizens to help solve difficult scientific problems. Modern science is filled with challenges of massive scale. From classifying terabytes of astronomical images to annotating gigabases of genome sequence, many of these challenges require enormous amounts of human effort. To address these kinds of labor-intensive problems, scientists have increasingly sought to harness the voluntary contributions of large communities of individuals from outside the traditional scientific community. These crowdsourcing initiatives work by distributing the required cognitive labor across the minds of thousands and sometimes millions of volunteers, mirroring how the Search for Extraterrestrial Intelligence (SETI) project first distributed computational tasks across many of the world's personal computers. This general strategy has been used successfully, for example, to classify the morphologies of uncharted galaxies [1], to conduct comprehensive ecological censuses [2], and to organize knowledge around human gene function [3]. The key challenge for these efforts to succeed is to inspire the required numbers of volunteers. The motivations for individuals to voluntarily contribute to crowdsourcing initiatives have been widely debated, but they range from altruism, to ego, to a shared sense of purpose. One emerging trend expands that list of motivations to include the pursuit of fun and enjoyment through games. In particular, David Baker and colleagues [4] have described several success stories behind their game for protein folding, called Foldit. Among these successes, the most recent and perhaps the most groundbreaking was the development of a novel algorithm for protein folding by game players. - In many of the most successful video games, the players basic mission is the same: to save the world. Whether it is alien invaders or zombie-creating viruses, the imminent peril of the human race is at hand and you are the only one who can stop it. Foldit harnesses this same instinct to motivate players in a similarly epic mission, specifically to unlock the secrets of protein folding. In its implementation, Foldit is a visual puzzle game. The player is presented with a primary protein sequence or partially folded structure, and then challenged to find its lowest-energy three-dimensional structure [6]. Players interactively manipulate the protein structure by pulling, twisting and tugging the protein backbone and side chains into various conformations. Foldit also provides players with a panel of tools that automate common operations, such as wiggle, which performs a local gradientbased energy minimization. Foldit gives continuous feedback to the player about the quality of their folding attempts through a real-time score derived from the Rosetta free energy function. As more hydrophobic residues are buried and more hydrogen bonds established, the players point total increases. In addition, the interface provides visual cues that highlight, for example, steric clashes that need to be resolved. The process of manually folding the protein provides players with the visual satisfaction of solving a puzzle, which, in addition to improving their numeric score, provides some of the psychological rewards of gameplay. Foldit is also a social game. Using the website and provided software, players can share their partially solved puzzles and folding strategies, chat live with other players and contribute to a wiki for the Foldit community. Players can also join teams, participate in contests and track their progress on leaderboards. From structure solution to algorithm discovery The scientific value of the Foldit system was first demonstrated by showing that game players could solve specific structure prediction problems. In the first major publication to discuss Foldit, Baker and colleagues [6] showed that game players could, in many cases, generate better structure predictions than the state-of-the-art Rosetta structure prediction program. Foldit then unleashed their army of folders on the task of solving the structure of the Mason-Pfizer monkey virus retroviral protease, a problem that was previously intractable to both computational and experimental methods [7]. After 3 weeks of game play, the best solutions were screened and, remarkably, a solution to this previously unsolved structure was identified and subsequently validated. This achievement established Foldit as a legitimate resource for the structural biology community. Although solving individual structures is valuable, an even greater challenge is to develop the ability to solve any structure automatically. Accordingly, Baker and colleagues [4] recently tested the gamer communitys proficiency at actually designing protein folding algorithms. Foldit provides players with a script-building interface that they can use to design and execute their own folding recipes. Recipes can be constructed using either a scripting language or a graphical interface that allows players to drag and drop different folding actions together into a workflow. These recipes can be shared with and extended by other players in much the same manner that code from open source software projects can be mixed and matched by developers. During a 3.5month study period, 568 Foldit players wrote 5,202 folding recipes, which were collectively executed more than 150,000 times. Sharing between players resulted in the social evolution of the best strategies. In particular, a single strategy named Blue Fuse ultimately came to dominate the recipe landscape, being used more than three times as often as any other strategy. On detailed examination, Blue Fuse bore a strong resemblance to an unpublished algorithm called Fast Relax, which was concurrently being developed by members of the Baker laboratory. Applying both algorithms within the computational constraints of the Foldit environment, Blue Fuse showed superior performance to the algorithm developed by professional structural biologists. Although the final author of the Blue Fuse recipe provided the crucial adaptations that made it successful, these would not have been possible without the work of other members of the community. Effectively, the gamer community collaboratively wrote the Blue Fuse algorithm using Foldit as a distributed software development environment. Baker and colleagues [4] noted that Blue Fuse was an adaptation of another players algorithm, Acid Tweaker v0.5, and that Blue Fuse itself has subsequently been adapted into many different forms by many different players. Although the early successes of the Foldit initiative highlighted the games ability to tap into human spatial reasoning skills, the task of dev (...truncated)