New video game makes game players Stanford professor's virtual lab assistants

- By Bruce Goldman

Norbert von der Groeben Jackie Gu

Teenager Jackie Gu helped scientists at Stanford and Carnegie Mellon develop the rules for a video game that allows players to design RNA molecules.

Jackie Gu’s mom thought her daughter was just goofing off, and told her to knock it off already with the online video game she spent so much time playing last summer. Little did she know that her 14-year old was actually advancing the progress of science.

The video game, called EteRNA, was designed by scientists at the Stanford University School of Medicine and Carnegie Mellon University. EteRNA taps gamers’ skills to accelerate biochemists’ understanding of DNA’s once-unsung chemical cousin, RNA. Gamers — no experience is necessary — design molecules composed of RNA, which is now “the emerging superstar in the field of biochemistry,” according to Rhiju Das, PhD, assistant professor of biochemistry at Stanford.

Then comes EteRNA’s unique kicker: Das’s laboratory actually synthesizes the “winning” RNA sequences on a weekly basis, and figures out if they fold up as designed. The lab then feeds the experimental findings back to the players. “This way, there’s a chance that thousands of non-expert enthusiasts will be able to collectively solve biochemical challenges that experts can’t,” said Das. “If the molecule folds as the players think, they win — and so do we.”

Many thousands of different RNA molecules are being created within a cell at any given time. While some RNAs carry information for making proteins, what many of these molecules are doing is still a mystery. Scientists agree that knowledge of an RNA molecule’s shape is a big step toward understanding how it works. And such understanding of shapes is important for designing antibiotics, antivirals and tumor-killing strategies based on RNA biology. “But we have only the scarcest knowledge regarding what shapes RNA molecules fold into,” said Das.

The game makes its public debut today at Registration is free and open to all comers. Players get points for designing RNA molecules that algorithms embedded in the game predict will best resemble the shapes specified by a team of scientist/programmers.

Das conceived the notion of EteRNA along with Adrien Treuille, PhD, an assistant professor of computer science at Carnegie Mellon, and Treuille’s graduate student, Jeehyung Lee. Das and Treuille met while the two were postdoctoral fellows in the same laboratory at the University of Washington. They continued their collaboration when both became assistant professors. Treuille estimated that about 14,000 developer-hours have gone into spawning EteRNA’s interface and infrastructure. He particularly credited Lee, who he said has been “living and breathing EteRNA for over a year now.”

Das and Treuille think nonscientists have much to offer biological and computer scientists. “To solve complex scientific puzzles typically requires having a huge reservoir of technical knowledge.” Treuille said. “But we’ve tried to pare our problems down to a few simple rules that everybody can master.”

At least one smart 14-year-old proved to be extremely good at that. Jackie Gu played her part in EteRNA’s development by playing the game, hands-on, in its early, larval stage. In May 2010 Gu, then finishing her first year of high school in the San Jose suburb of Saratoga, wrote a letter to Das asking if he had any openings for summer interns. The next thing she knew she was spending 40 hours a week in his laboratory helping to shape the rules that would shape the EteRNA interface. For starters, Das provided the teenager with an online link to the game and encouraged her to try it at home, which she did, to her mother’s initial chagrin.

Norbert von der Groeben Rhiju Das

Biochemist Rhiju Das stands next to a high-throughput RNA map in his office. He is working with video game players to help better understand how different RNA molecules fold.

But it ended well. “Jackie designed an RNA species that completely shifts its shape if you make one single, tiny change in its composition,” said Das. More than 100 beta-testers have since played the game to the benefit of science.

Gu is an excellent student at Saratoga High, where she’s a reporter for the school newspaper, plays cello in the orchestra and is a member of the math club. But she didn’t sign on for her summer internship in the Das lab as a black belt in RNA biochemistry. “From what I’d learned in my first-year biology course, I assumed RNA was like just some temporary worker that came to do its job and then died,” she said.

Until not long ago, so did a lot of people, including scientists. RNA used to be thought of as a more or less inert messenger molecule serving as a mobile, short-lived copy of its more durable lookalike, DNA, the stuff genes are made of. RNA, biologists figured, simply ferried information from the genes to the cell’s protein-manufacturing machinery. But scientists now realize that RNA molecules do much more. Far beyond mere messenger status, they are involved in virtually every intracellular process, helping to determine which proteins are made in a cell, as well as when and how much.

Like DNA, RNA molecules are strings of four different chemical units that act like letters in a truncated alphabet. But DNA is famously double-stranded. That’s because, of its four component “letters,” two in particular are highly attracted to each other, biophysically speaking. Happily, the other two letters have a chemical crush on one another as well. Thus, when the letters composing one DNA strand are complementary to those on a closely opposed strand, the two strands lock in a lasting embrace to form a stable double helix.

In contrast, an RNA molecule typically travels without its exact partner, like a single-stranded soloist. It is thus a rather playful, floppy molecule. Nonetheless, the same alphabetical affinities that produce DNA’s double helix are at work in an RNA molecule, albeit in a more fleeting form: Small sequences of chemical letters along the molecule find themselves attracted to complementary sequences elsewhere on the same molecule, causing it to fold into structures featuring pinched double-stranded sections alternating with bulges and loops, hairpins and hinges.

Biochemists today are keen to understand how the folds that individual RNA molecules form bear on the myriad regulatory roles these molecules play within cells. They also want to know how such molecules’ structures vary when they interact with other molecules like drugs or proteins. In addition, replacing even a single chemical letter with another one can radically alter an RNA molecule’s folding tendencies. Because RNA is a copy of the DNA from which it was generated, a tiny genetic mutation at the DNA level can result in an RNA molecule that functions differently, fails to function at all or malfunctions.

RNA folding is what Das’s lab is all about. “In my lab, we’ve figured out how put together long RNA sequences, cheaply and quickly,” he said. “We can synthesize a customized RNA molecule within 24 hours.” Das and associates can then determine the shape that RNA molecule is most likely to assume.

EteRNA players, who need no gaming experience or biochemistry background, walk through a few introductory tutorials. Then they’re presented with on-screen depictions of RNA molecules: sequences of chemical letters strung together like beads on a string. At the press of a button, a player can see what shape the molecule being presented would be expected to take in its current form. The challenge is to find an appropriate set of chemical-letter substitutions that will cause the RNA molecule to instead take on another, desired shape.

Then, in an unprecedented liaison of game and experiment, the Das lab takes the most-promising player-provided molecular sequences, actually conjures up the physical molecules themselves and tests them to see whether they, indeed, stably fold into the predicted structures. The lab is cranking out about eight different ones weekly and expects to greatly increase this rate over the coming months.

Now 15, Gu is back in school, with all the work that implies. But she still gets some time — maybe a half-hour a week or so — to play EteRNA.  “It’s really easy,” she said. “The rules are definitely not as complicated as other games’. But it’s fun to make these RNAs fold the way you want them to.”

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