In the new Eterna challenge, called OpenCRISPR, players will design a guide RNA molecule that leads CRISPR to the right sequence of DNA for editing or binding. “The RNA is the part that confers gene specificity. It’s the thing that says, ‘Go after gene A, not gene B,’” said Chang.

The difficulty for Eterna players is to come up with an RNA molecule that does several things, said Greenleaf. The guide RNA has to be recognized by the CRISPR-associated enzyme. The CRISPR-enzyme system has to be able to recruit biochemical activity to the targeted gene. And lastly, the activity of the CRISPR-enzyme system has to be controlled by a small-molecule drug, so there needs to be a “binding pocket” for that small molecule. The RNA molecule has to function so that the CRISPR system is active when the small-molecule drug is present and inactive when it’s not. So far, experts have not been able to create such a drug-activated CRISPR, which is why Chang and Greenleaf are calling on the community of Eterna gamers for help.

The new puzzle will be quite different from the recent challenge in which Eterna players had to design a molecule that could do a mathematical calculation for a tuberculosis diagnostic test. “The CRISPR puzzle actually should be pretty easy to solve in silico, even for new players who get to the switch design levels,” said Rhiju Das, PhD, associate professor of biochemistry and principal investigator for Eterna.

From in silico to in vitro: an iterative process

How those Eterna-designed switches will behave in living cells is a big question. Das said the team will be asking players for different possible solutions to the same problem. “We’re not sure yet if there will be unforeseen problems with the Cas9 protein experimentally. That’s partially why we want as many diverse solutions as possible for the Greenleaf and Chang labs to test, even in this pilot round,” Das said.

It will be an iterative process, said Greenleaf. His Stanford lab will test the first round of solutions and then return these data to the players with refinements that will guide their design work.

“We’re hoping for 10,000 to 100,000 players to contribute 10 solutions each. If we get that many, we’ll indeed work to get that many synthesized and tested,” Das said.

Out of the ivory tower

One of the goals of Stanford’s Center for Personal Dynamic Regulomes is to get people interested in science, said Chang. “The Eterna game is a powerful way to engage lots and lots of people,” he said. “They’re not just passive users of information but actually involved in the process.”

Like other computer games, Eterna allows players to accumulate points, build expertise and advance to higher levels. The best players have a chance of having their designs implemented in the lab.

One thing that makes the project exciting, said Chang, is that it is an experiment in the sociology of science. “There is a misconception of science as something that happens in an ivory tower by someone in a white coat with a long beard. And they are saying things and drawing things that nobody understands. But it’s not like that! It’s really like a puzzle that anybody can get engaged with,” he said.

Anyone interested in playing Eterna can sign up here.

In addition to the funding from NIGMS and Stanford’s Center for Personal Dynamic Regulomes, the new Eterna challenge is being launched with collaborative support from the Innovative Genomics Institute at the University of California-Berkeley. Stanford’s departments of Biochemistry and of Genetics also supported the work.