In February, Matthew Zada, a 39-year-old Australian with no formal academic or scientific credentials, co-authored a paper in the Journal of Molecular Biology. He earned that byline, though: The paper is part of an effort by Professor Rhiju Das, a computational biochemist at the School of Medicine, to leverage the intelligence and expertise of tens of thousands of citizen-scientists. It’s done through Eterna, an online video game that challenges players to design RNA molecules and connects their results to a wet lab that can synthesize their designs.
The recent paper outlines the “Eterna 100,” benchmark challenges to fold RNA into desired, stable shapes representing a wide range of design difficulty. It follows a 2014 paper in the Proceedings of the National Academy of Sciences that had 35,000 co-authors, only 11 of them professional scientists.
“There are so many smart people that I knew in middle school, or high school, but they couldn’t be bothered to do well on the SAT or to jump through hoops,” Das explains. “Some of our best players are college dropouts. The current academic system is great, but having another track is great too. It’s not a zero-sum game. The players get this interaction with the physical model that traditional researchers just don’t.”
Das chose to focus the game on RNA because, he believes, it is becoming the hot new subject in biochemistry.
“RNA is a really fascinating molecule,” Das explains. “There’s a hypothesis that life began in an all-RNA world. Unlike DNA, which forms a stable double helix, RNA folds into crazy-looking structures; it’s like the unstable cousin of DNA, or the crazy grandpa. Some think RNA created DNA, a stable version of itself. Some of the core machines in our cells are made of RNA. Many diseases can be linked to RNA malfunctions in our cells—folds or misfolds.”
Much of the work in Das’s lab is related to finding RNA structures that can be useful—by forming molecular computers to do simple computations, or shapes that can become drug targets or structures that might aid in diagnostics.
If you log on to the Eterna website, a 10-level tutorial teaches a few basics: the four bases that make up RNA, which base bonds are strong and which ones are weak, and how these bases and bonds result in various simple shapes.
The game is fun and encouraging. I got a ridiculous thrill moving from rank 83,890 to 75,762. (I know that’s not that great, but I took nary a biochem class at Stanford.) For players more sophisticated at logic and spatial relationships, the concepts and shapes can become fantastically complex.
“The players began to create puzzles by players for players,” Das says. “Some of the concepts that they were using could be considered advanced, or even not known.” Zada says the puzzles are compelling “to the point of addiction.”
Jeffrey J. Anderson-Lee, an IT manager at UC-Berkeley and another co-author of the recent paper, explains, “The initial appeal was the quick ‘success’ of solving an RNA design puzzle. Later it was the challenge of designing RNA to be folded and tested in vitro—which is harder than simply solving a design challenge or player puzzle in many ways.
“Still later it was the challenge of understanding how the energy model works with sufficient detail to write scripts that can solve puzzles. Most recently it is the challenge of designing RNA sequences that ‘switch’ in shape in specific ways in response to the presence of other molecules in the mix. In short, there is an ever-
deepening range of challenges to be met and surpassed.”
Eterna grows out of a robust history of distributed computing and research that began more than two decades ago and includes SETI@home, which uses home computer downtime to analyze interstellar radio waves in a search for alien life. Since then there’s been Einstein@home, searching for gravitational waves. Those applications led to “games” that could aid research, such as FoldIt, which seeks to predict protein structures.
The innovation of Eterna is the linkage of this computational, abstract work in a digital universe to real-world experiments in the Eterna Massive Open Laboratory at the School of Medicine.
“Working with RNA is just so much faster than working with proteins,” Das says. “If you want to make a protein [the basis of many medicines], you have to make it in another living organism. You have to culture it. It’s like growing a vaccine; it takes a long time. To make an RNA structure, you just have some DNA overnighted to you. You feed the DNA to this enzyme, and in half an hour, you’ve got RNA. If you get an idea in the morning, by the evening of the next day you can know whether it works.”
Das says that his lab has recently expanded its ability to synthesize RNA and hopes to test molecules as quickly as players can devise them, as many as a million new ones per month.
The next step: testing on patients.
Working with a team at MIT that designs modular lab and diagnostic devices, this spring Das launched the OpenTB challenge, a quest for a quick test for tuberculosis, a huge problem in the developing world. The most common TB test takes several days to yield results. Part of the problem is that it’s not as simple as looking for one antibody or one hormone, but the ratio of three concentrations of different RNAs. The hope is that Das and his army of Eterna players can come up with an RNA calculator to crunch those numbers and give an instant result. The MIT team is working to embed that RNA calculator in a device design as simple as a “pee-on-a-stick” pregnancy test.
“It’s an attempt to make a medical device that’s public and open through all the process. RNA players are doing this; we’re crowdsourcing the design. It’s a Lego-like diagnostic kit,” Das says.
“If it works, it won’t just be for tuberculosis. We could create RNA calculators to detect sepsis, viral infections. Citizens can invent their own medicine. It sounds like science fiction. But I can’t wait to try it.”
Heather Millar, ’85, writes on health, science and environmental issues.