Gamers Help Researchers Tackle The Problem Of Protein Folding

By Benjamin Ross

December 13, 2017 | “You don’t have to be a scientist to do science better than a computer whose job it is to do science,” was a statement made by YouTube vlogger Hank Green in a video discussing Foldit, an online puzzle video game designed to fold the structures of selected proteins as perfectly as possible, using tools provided in the game.

Researchers at the University of Washington and Northeastern University developed the game in 2008 with the idea that human eyes, particularly those used to detecting patterns like those in video games, were better at recognizing spatial relationships than computers were.

The game is built on top of a piece of biochemistry software called Rosetta, Seth Cooper, Assistant Professor in the College of Computer and Information Science at Northeastern University and a co-creator of Foldit, told Bio-IT World.

Cooper described a screensaver application for Rosetta called Rosetta@home, which would try to compute how proteins folded while users were away from their computers. “One of the things people noticed was you could see a visualization of the protein and how the computer was trying to fold it up. They could see that the computer was making kind of random moves that wouldn’t really work.”

“Foldit attempts to predict the structure of a protein by taking advantage of humans' puzzle-solving intuitions and having people play competitively to fold the best proteins,” according to Foldit’s website.

The game provides players with a 3D structure of a protein that they must then fold into a stable representation. The rules of the game are simple: Pack the protein, avoiding empty spaces in the structure of the protein where water molecules can get inside; hide the hydrophobics, surrounding them with as many atoms as possible so the water won't get to them; and clear the clashes, represented by a red spiky ball where the two sidechains are intersecting.

Foldit is specifically looking at the proteins in diseases that cause viruses and bacterium to grow, because in order to stop a protein you need to know how it works, Green says in his video.

The game is intended to be played by people without a deep understanding of biochemistry, Cooper said. However, that doesn’t mean the players don’t understand the importance of what they’re working on when playing the game. “A lot of the players who have been playing for awhile have in common an interest in contributing to science.”

The developers of Foldit are currently working on the game’s interface, integrating touch screen, and multi-touch capabilities. “We want to see if this will make this change more enjoyable for the players, makes it easier to use, or even if it helps them find structures quicker,” Cooper said.  

So far Foldit has run around 1,500 games with more than 500,000 people taking part in successfully folding proteins linked to diseases such as Mason-Pfizer Monkey virus retroviral protease.

“The interesting thing is that these protein structures that the players design in the game get tested by scientists in the lab, synthesized, and evaluated,” Cooper said. “The ability to go from the theoretical within the game to being taken out into the real world and seeing if it works is very exciting.”

Taking This To Mars

The company behind M&M’s, Skittles, and Pedigree dog food is also turning to the Foldit platform to help target the issue of carcinogens in food. Mars Incorporated (Mars) has teamed up with Thermo Fisher Scientific (Thermo Fisher), and the University of California, Davis (UC Davis) to create and host a game-a-thon in hopes of finding solutions to aflatoxins, which are compounds produced by certain fungi that can grow in or on almost all grains and groundnuts.

Mars is providing support in the form of personnel and supplies to test the player designs, as well as media and general translational support. Thermo Fisher is providing synthetic DNA, converting the players’ digital designs into a physical reality. UC Davis helped identify the protein scaffold to build the aflatoxin game around, and will be analyzing the data and testing the player-designed enzymes.

This series of Foldit puzzles attempts to restructure an enzyme that can be used to destroy aflatoxin. Once the enzyme structures have been designed, the best designs will be synthesized to assess their real-world potential to eradicate aflatoxin.

According to Helge Bastian, vice president and general manager of synthetic biology at Thermo Fisher, 4 billion people worldwide are affected by aflatoxins. “People have known for years [about these aflatoxins], but they haven’t found a solution to address this,” Bastian told Bio-IT World.

On October 16, 2017, Thermo Fisher and Mars hosted a game-a-thon in which 11 gamers, ranging from high school students to players with a scientific or technological background, attended the event in San Francisco, along with key partners and selected guests, for the first round of puzzles, and more are expected to roll over the next few weeks.

“It was amazing to see how differently each of the expert players tackled this problem,” Justin Siegel, Assistant Professor in the Department of Biochemistry, Chemistry, and the Genome Center at UC Davis, told Bio-IT World in an email interview. “Some were playing by instinctively trying to design structures, some were building algorithms to direct the computer to design structures, and some simply looked at it as a form of art! All provided exciting and creative potential solutions to the problem.”

While results from the game-a-thon are still being processed, Howard-Yana Shapiro, Chief Agricultural Officer of Mars, told Bio-IT World in an email interview that, if all goes smoothly, the first round of data should be coming back in early 2018. Bastian is enthusiastic about the Foldit’s approach to synthetic biology and the potential discoveries it presents.

“Synthetic biology can be very powerful technology if people understand the logic of it and that it’s all built on the fact that biology is run on a digital code,” he said. “Outside of the scientific field this seems to be new for many people that you can apply these technologies. And that’s where I think bringing science closer to the consumer by doing things like [the game-a-thon] have the opportunity to take these problems to many different areas.”