ACADEMIA

Researchers expect to test thousands of player-designed molecules each month

Researchers at Carnegie Mellon University and Stanford University are expanding EteRNA — a unique research project that taps online game play to create RNA designs that are then tested in a laboratory — thanks to new support from the W.M. Keck Foundation.

Among the additions already implemented is a new puzzle in which players design RNA switches — RNA molecules that change shape in the presence of other molecules.

A $1 million grant through the Keck Foundation's Medical Research Program will provide ongoing support for the year-old EteRNA project, which has already engaged more than 30,000 citizen-scientists in the study of RNA design. Researchers say the online game has identified a number of people, some without formal science training, who display a strong aptitude for RNA design and are generating important scientific insights.

Biologists believe RNA molecules may be a key regulator of living cells. But they have struggled to understand the complex principles that dictate the three-dimensional shape of RNA, which is critical to deciphering the molecules' functions and to designing new RNA devices.

"EteRNA was designed to test the interplay between high-throughput experimental science and crowdsourcing," said Adrien Treuille, an assistant professor of computer science at Carnegie Mellon who leads the project with Rhiju Das, an assistant professor of biochemistry at Stanford, and Jeehyung Lee, a Carnegie Mellon Ph.D. student in computer science. "What we've seen emerge from a group of talented players is a dedicated community of researchers who have out-performed the best existing computer models for RNA design."

EteRNA was the first online game to harness wet-lab experimentation to the wisdom of crowds. Players are given design challenges and then use the latest computer modeling programs to create possible solutions. Players vote on the best of their virtual designs, which are then synthesized in the Das lab and evaluated to see if they work in real life.

The Keck Foundation support will help the researchers leverage advances in biotechnology that, Das said, "are leading to a radical re-imagining of the game." Until now, only about 32 of the designs could be evaluated in the lab each month. But Keck Foundation support, as well as rapid advances in the technology for synthesizing molecules, should now make it possible to synthesize thousands each month. Players can still respond to weekly challenges, but the expanded capability to synthesize molecules also will enable them to pursue and test their own design hypotheses, much as an academic researcher might.

"You couldn't have done this a year ago," Das said. "It's an exciting time."

Players have responded enthusiastically to the new puzzles implemented this month that challenge them to design shape-shifting RNAs that sense other molecules. These designs could lead to RNA molecules that have a number of applications — as sensors for RNAs such as those expressed by viruses or cancer cells, as logic gates in RNA-based computer circuits, and as switches for rapidly turning genes on and off as scientists explore functions in model cells.

Das said the project also is creating a pipeline that will help non-expert players turn their own discoveries into published research papers, rewarding them with recognition of their work.

As part of the Keck initiative, EteRNA is creating an advisory board of noted scientists, including Paul Berg, a Stanford biochemist and Nobel laureate in chemistry; Dr. Patrick O. Brown, also a Stanford biochemist; and David Baker, a biochemist at the University of Washington, to provide guidance as EteRNA explores this new way of conducting scientific research.