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WASHINGTON -- In 2008, University of Washington researchers had a flash of brilliance. They would develop a medical “for purpose game” that someday would be used to solve some of medical science's greatest mysteries.
The plan was to allow gamers and students to use their game called Foldit. The students and gamers signed up for two different groups, the Contenders and the Void Crushers. Participants were given online access to the game and a toolbox of online realistic tools to solve the chosen mysteries. This time, their target was a monomeric protease enzyme, a cutting agent in the complex molecular tailoring of retroviruses, a family that includes HIV.
The research paper titled “Crystal structure of a monomeric retroviral protease solved by protein folding game players” was co-authored by both scientists and gamers who together took kudos for cutting-edge research and methodology. The paper was published in the September issue of Nature Structural & Molecular Biology.
This is the first case in which researchers and gamers have teamed up to solve a problem.
Dr. Firas Khatib, a professor of biochemistry, who has been working with the university Centre for Game Science in partnership with the Baker Lab at the University of Washington, said, “We wanted to see if human intuition could succeed where automated methods had failed. … These features provide exciting opportunities for the design of retroviral drugs, including AIDS drugs."
In the laboratory, a microscope gives only a flat image of what, to an outsider, looks like a plate of scrunched-up spaghetti. Pharmacologists need a 3-D picture that literally “unfolds" the molecule and rotates, revealing potential targets for drugs. Cracking the enzyme "provides new insights for the design of antiretroviral drugs," say the researchers in the study, referring to the lifeline medication against the human immunodeficiency virus (HIV).
The unusual strategy allowed gamers and researcher to work together to achieve a breakthrough and have fun at the same time. Sometimes research grinds to a halt because computers lack the human element of intuition in solving problems.
Foldit enables players to pool resources and compete in predicting the structure of protein molecules. It was a breakthrough that online game players pieced together something so complex and was a great surprise to researchers and scientists who had been baffled for more than a decade. The gamers did it in a mere three weeks.
This is the first case in which researchers and gamers have teamed up to solve a problem. The online protein-folding game has engaged thousands of players all over the world and has spread far beyond the university.
The gamers discovered a viable structure by playing Foldit, following repeated failure in discovering the structure. "We wanted to see if human intuition could succeed where automated methods had failed," said Khatib.
"These features provide exciting opportunities for the design of retroviral drugs, including AIDS drugs," wrote the authors.
The focus of the UW Centre for Game Sciences," said director Zoran Popovic, associate professor of computer science and engineering, "is to solve hard problems in science and education that currently cannot be solved by either people or computers alone."
The class of enzymes, called retroviral proteases, is essential in understanding how the AIDS virus matures and proliferates. The knowledge on the molecular structure has long been a topic of research. Scientists have sought to try and design anti-AIDS drugs that can block those enzymes. Most studies on the structure of those proteases were hampered because scientists were not able to identify the molecular configuration of the enzymes.
"People have spatial reasoning skills, something computers are not yet good at," said Seth Cooper of the UW Department of Computing Science and Engineering and co-creator, lead designer and developer of Foldit.
"Games provide a framework for bringing together the strengths of computers and humans. The results in this week's paper show that gaming, science and computation can be combined to make advances that were not possible before,” according to the authors of the study.
To piece together the retrovirus enzyme structure, Cooper said, gamers used a new alignment tool for the first time to copy parts of known molecules and test their fit in an incomplete model.
Scientists know that that the bonds between the atoms in the enzyme's molecules can be twisted and turned in a million possible combinations. The challenge lies in developing the right chemical keys so that the design is the most efficient, lowest-energy variant of the molecule.
Gamers scored points by creating a more elegant structure of the molecule with a lower energy state. If the structure required more energy to maintain, or if it did not comply with real-life chemistry, their score correspondingly dropped. Gamers used their 3-D spatial abilities to rotate the chains of amino acids in cyberspace. New players started at the basic level, according to the authors.
Researchers at the University of Washington and other institutions are beginning to focus on how crowd-sourcing and game playing can be used in scientific discovery and the potential for integrating online video games into real-world science.
Allowing direct manipulation tools, and the assistance from a computer program called Rosetta, participants configure graphics into a workable protein model. Teams send in their answers, and UW researchers constantly improve the design of the game and its puzzles by analyzing the players' problem-solving strategies. The Foldit software has been described as using molecular multicolored structures that can be literally folded-up like a flexible Tinker Toy set. The virtual molecules must conform to the same chemical rules as those exhibited by their real molecular counterparts.
Games provide a framework for bringing together the strengths of computers and humans. The results in this week's paper show that gaming, science and computation can be combined to make advances that were not possible before.
–- Authors of the study
Determining the shape and misshape of proteins contributes to research on the causes of various medical conundrums, including cures for cancer, Alzheimer's, immune deficiencies and a host of other disorders. Figuring out the structure of proteins is vital for understanding the causes of many diseases.
Gamers will be able to assist scientists in developing drugs to block enzymes and will eventually even assist in the completion of environmental work on biofuels. "The ingenuity of game players," Khatib said, "is a formidable force that, if properly directed, can be used to solve a wide range of scientific problems.”
According to Popovic, "Foldit shows that a game can turn novices into domain experts capable of producing first-class scientific discoveries. We are currently applying the same approach to change the way math and sciences are taught in school."
Online gamers may now contribute to a cause that far exceeds achieving a Second Life or Dungeons and Dragons (both online games). Now they are deciphering the structure of an enzyme of an AIDS-like virus that had thwarted scientists.
The name of the article is "Crystal structure of a monomeric retroviral protease solved by protein folding game players," and it can be accessed by going to the journal article.
Gamers who want to sign up to work on various projects can go to the game portal by clicking http://fold.it/.
Mel Borup Chandler lives in Southern California and frequently reports on similar stories. His email address is mbccomentator@roadrunner.com
