Seattle, WA, USA. With enough hindsight, the greatest scientific achievement of this century may well be our decoding of the human genome. However, this knowledge has limited utility unless scientists take the next step and understand how our DNA is used to build the proteins that make up the machinery of living cells. The human body has over 100,000 different kinds of proteins. They form every cell, make up the immune system, and establish the speed of chemical reactions.

 

Protein Folding & Structure

 

Proteins are workhorses, biological nanomachines that carry out functions essential to life. However, proteins must assemble themselves, or fold, before they can carry out their important functions. If proteins do not fold correctly (i.e. if they "misfold"), there can be serious consequences for human health. [cf. Sidebar]

 

A preeminent challenge in biology is the predicting the shapes of natural proteins, a necessary step in finding treatment solutions. Following the Human Genome Project, scientists had a flat, or 2-dimensional (2D), view of the molecular structures of proteins. Their primary structure, the amino acid sequence, makes up the working parts of living cells and the human organism. Scientists must know the 3-dimensional (3D) structure of the protein, known as the tertiary structure, to understand what a protein does. From this knowledge, scientists can infer the role of proteins in cell processes and create new effective therapeutics to treat disease and other, mainly neurological, birth conditions.

 

Protein folding is critical and fundamental to virtually all of biology, but despite the progress to date, process details remain an enduring mystery. We know many of the genetic sequences, but don't know how proteins fold up into complex shapes whose nooks and crannies play such crucial roles in biology. Scientists could run computer simulations to calculate all possible protein shapes, but all the computers in the world would take centuries to solve such a huge mathematical problem.

 

Rosetta At Home

 

David Baker is a professor of biochemistry at the University of Washington (UW) and a Howard Hughes Medical Institute (HHMI) investigator [1]. Baker and his colleagues have made steady progress over the past decade in developing computer algorithms that predict how a linear string of amino acids will fold into a given protein's characteristic shape. Detailing a protein's structure can provide ontricate information about a protein's biological function and suggest new therapeutic designs.

 

In 2005, Baker developed a distributed networking project named RosettaAtHome that harnesses excess and available computer capability from volunteers around the world [3]. The computing logic is an algorithm called Rosetta that implements the Monte Carlo method to find the best “fit” for all of the parts of a given protein. It depends on repetitive random samplings to obtain the results. But even 200,000 volunteers aren't enough. To model even a small protein requires trillions of calculations.

 

"There are too many possibilities for the computer to go through every possible one," Baker said. "An approach like RosettaAtHome does well on small proteins, but as the protein gets bigger and bigger it gets harder and harder, and the computers often fail." The Baker team thought that a little human intervention might speed things up.

 

Baker didn't know how to incorporate human creativity until he went hiking on Mt. Rainier with his neighbor David Salesin, a UW computer scientist who also runs a research laboratory at nearby Adobe Systems Inc. [1] Baker and Salesin began by discussing different ways RosettaAtHome could be more interactive. Given the inherent fun of competition, Salesin thought a multiplayer online game could fulfill their goals. By the time they returned to their car, the researchers had settled on the basic approach. Salesin provided Baker with the names of three colleagues who could help Baker create the game, led by Zoran Popović — a  UW associate professor of Computer Science & Engineering (CSE).

 

Baker figured that "People, using their intuition, might be able to home in on the right answer much more quickly." The basic idea is to direct the capabilities of gamers at home toward the process of medical discovery, a process that potentially could accelerate research and the discoveriy of cures for our most puzzling medical problems.

 

They had a talent pool available, albeit one not normally used by academic research teams (except as objects of study). Computer gamers often have higher powered computers and — in the aggregate anyway — devote many years of collective brainpower to solving involved simulations and puzzles for entertainment. By 2008, UW researchers extended their approach by coupling the considerable desktop computer power of gamers with their finely honed game play skills.

 

The result was a new game, called Foldit, that accelerates protein folding and turns it into a competitive computer gaming experience [2, 3]. Over the next few months, doctoral student Seth Cooper and postdoctoral researcher Adrien Treuille worked with Popović and Baker to create the new program. The team tested it in small venues. Baker notes one memorable match between teams representing the University of California (UC) and the University of Illinois that aroused unexpected fervor and cheering among spectators. “30 or 40 people participated,” says Baker. “The competition was very intense.”

 

The Foldit Game

 

Gamers learn the Foldit rules by navigating through introductory levels of play, structured by the same laws of physics protein strands use to curl and twist into three-dimensional shapes. This is fundamental for biological mysteries ranging from Alzheimer's to vaccines. After about 20 minutes of training, people are mouse-clicking in the name of medical science, but feel like they're playing a video game. 

 

“Our main goal was to make sure that anyone could do it, even if they didn't know what biochemistry or protein folding was,” says Popović. At the moment, the game only uses proteins whose three-dimensional structures have been solved by researchers. But, says Popović, “soon we'll be introducing puzzles for which we don't know the solution.”

 

Zoran Popovic said "We're hopefully going to change the way science is done, and who it's done by," said Popovic, who presented the project at a Games for Health meeting in Baltimore. "Our ultimate goal is to have ordinary people play the game and eventually be candidates for winning the Nobel Prize."

 

Both RosettaAtHome and Foldit use the Rosetta protein-folding software. Foldit is the first protein-folding project that asks volunteers for something other than unused processor cycles on their computers or Playstation machines. Foldit also differs from recent human-computer interactive games that use humans' ability to recognize images or interpret text. Instead, Foldit capitalizes on the natural 3-D problem-solving skills exhibited by humans.

 

The intuitive skills that make someone good at playing Foldit are not necessarily the ones that make a top biologist. Baker says his 13-year-old son is faster at folding proteins than he is. Others may be even faster. "I imagine that there's a 12-year-old in Indonesia who can see all this in their head," Baker says.

 

Eventually, the researchers hope to advance science by discovering protein-folding prodigies who have natural abilities to see proteins in 3-D. "Some people are just able to look at the game and in less than two minutes, get to the top score," said Popovic. "They can't even explain what they're doing, but somehow they're able to do it."

 

Foldit Game Play

 

The game looks like a 21st-century version of Tetris, with multicolored geometric snakes filling the screen. [cf. Sidebar] A team that includes a half-dozen UW graduate and undergraduate students spent more than a year figuring out how to make the game both accurate and engaging. They faced some special challenges that commercial game developers don't encounter.

 

"We don't know what the best result is, so we can't help people or hint people toward that goal," Popovic explained. The team also couldn't arbitrarily decide to make one move worth 1,000 bonus points, since the score corresponds to the energy needed to hold the protein in that shape.

 

Almost 1,000 players have tested the system in recent weeks, playing informal challenges using proteins with known shapes. However, the developers have opened the game to the public and offer proteins of unknown shapes. Foldit gamers can face off against research groups around the world in a major protein-structure competition held every two years.

 

Foldit includes elements of multiplayer games in which people can team up, chat with other players and create online profiles. Over time the researchers will analyze people's moves to see how the top players solve puzzles. This information will be fed back into the game's design so the game's tools and format can evolve.

 

The Next Level

 

Baker hopes the game will speed up the sometimes tedious business of structure prediction.

 

Beginning in the fall of 2008, gamers will be able to design all-new proteins. proteins that we might wish existed — enzymes that could break up toxic waste, for example, or that would absorb carbon dioxide from the air. Novel proteins could find use in any number of applications, from pharmaceuticals to industrial chemicals, to pollution clean up.

 

Computers alone cannot design a protein from scratch. The game lets the computer help out when it's a simple optimization problem — the same way that computer solitaire sometimes moves the cards to clean up the table — letting the player concentrate on interesting moves. With the ability for any person with a computer and an internet hookup to start building proteins, Baker thinks the pace of discovery could skyrocket. “My dream is that a 12-year-old in Indonesia will turn out to be a prodigy, and build a cure for HIV,” he says.

 

Eventually, the researchers hope to present a medical nemesis, such as HIV or malaria, and challenge players to devise a protein with just the right shape to lock into the virus and deactivate it. Winning protein designs will be synthesized in Baker's lab and tested in petri dishes. The researchers will credit high-scoring players in scientific publications the way that the current top RosettaAtHome contributors already are credited for their computer time.

 

"Long-term, I'm hoping that we can get a significant fraction of the world's population engaged in solving critical problems in world health, and doing it collaboratively and successfully through the game," Baker said. "We're trying to use the brain power of people all around the world to advance biomedical research."

 

[1] The research is funded by the Defense Advanced Resarch Projects Agency (DARPA), the Howard Hughes Medical Institute (HHMI), Microsoft Corp. and Adobe Systems Inc., and through fellowships at Nvidia Corp. and Intel Corp.

[2] The Foldit game was developed by University of Washington (UW) doctoral student Seth Cooper and UW postdoctoral researcher Adrien Treuille, both in computer science and engineering, working with Zoran Popovic, a UW associate professor of computer science and engineering; David Baker, a UW professor of biochemistry and Howard Hughes Medical Institute (HHMI) investigator; and David Salesin, a UW professor of computer science and engineering.

Professional game designers provided advice during the game's creation.

[3]The Berkeley Open Infrastructure for Network Computing (BOINC) platform is currently the most popular volunteer-based distributed computing platform. Wikipedia maintains a list of distributed computing projects (BOINC and others). Two of immediate interest include the following.

Seti Home is a well-known and pioneering distributed computing project. In 1995, David Gedye proposed doing a radio Search for Extraterrestial Intelligence (SETI) using a virtual supercomputer composed of large numbers of Internet-connected computers, and he organized the project to explore this idea. Seti Home was originally launched in May 1999 to exploit data analysis on home computing platforms. Some of the advances in the BOINC platform are traceable to Seti Home.

FoldingAtHome, a project of Stanford University, comparable in many ways to Rosetti in scope and scale. It is a distributed computing project which studies protein folding, misfolding, aggregation, and related diseases.

 

 

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