Game on

The hundred thousand or so players of the online videogame Eterna have not done battle with digital terrorists or built synthetic worlds from imaginary resources. Instead, the players have been competing to design a molecule that would be able to perform specific functions — among them, acting like tiny computers.

The molecule those players tinker with is RNA, which carries out many roles in the body, most famously, translating DNA’s genetic code into proteins.

Molecular computation could reshape modern medicine, said Rhiju Das, PhD, a Stanford Medicine professor of biochemistry and creator of the crowdsourcing Eterna gaming platform, which has the tagline “Solve Puzzles. Invent Medicine.”

Das and his colleagues recently used insights from gamers to craft a molecule that could solve a serious public health challenge: identifying cases of active tuberculosis quickly and affordably.

“Molecules that compute can recognize infectious disease states and might also be able to distinguish cancer from healthy tissue. If put into therapies, molecular computers could deliver life-saving drugs directly to a tumor or autonomously edit faulty genes inside cells,” Das said.

A quarter of the world’s population is infected with the bacterium that causes tuberculosis, one of the leading causes of death from infectious disease. The microbe can lie dormant for years, causing no symptoms and resulting in no spread. But when the immune system can no longer contain the infection, the disease wakes up.

Unfortunately, there’s no rapid, inexpensive diagnostic method that can indicate that TB has transitioned to this dangerous active state: Current strategies rely on costly tools to measure ratios of specific gene transcripts in the blood that signal the switch between dormant and active modes. The ratio is far more accurate than simply measuring any single gene, but it is difficult to compute.

So Das and his collaborators set a challenge to identify, via the gaming platform, a molecule that can calculate the gene transcripts’ ratios. Their thinking: Such a molecule could serve as the basis for a speedy, low-cost blood test.

“Now we have a working, inexpensive proof-of-concept test,” Das said. “It even creates a little pink line on a piece of paper, just like those antigen tests people use during COVID.”

“Humans are just good at finding shortcuts. The players can see things in the molecules and the experiments that our algorithms can’t.”

Rhiju Das, PhD, a professor of biochemistry

Stanford Medicine is filing a patent on a technology for nucleic acid amplification developed by Das’ lab that is necessary to bring the test to market, and Das is looking for an industry partner to help develop a viable point-of-care test.

“TB kills more than 1 million people each year, yet it is still in need of better and cheaper diagnostics that are adapted to low-resource settings where TB is most prevalent,” said Stijn Deborggraeve, PhD, an advocacy adviser for pediatric tuberculosis at Doctors Without Borders.

“I encourage the researchers to translate their research into accurate, affordable and user-friendly diagnostic products. We need more innovative strategies to diagnose TB — especially in children.”

Molecular logic

The story of Das’ research, however, is not only about the introduction of a groundbreaking test for tuberculosis but also how Das and his team arrived at the solution. They invited an army of citizen-scientists to play the Eterna videogame where the objective is to solve molecular puzzles by designing new RNA molecules. Those solutions, in the form of molecular diagrams, are then synthesized and tested for efficacy.

“Humans are key to this work. We can’t just ask AI to churn through all the possibilities. Computationally, it’s too hard, and we don’t have any prior solutions that could be training data for an AI,” Das said. “Humans are just good at finding shortcuts. The players can see things in the molecules and the experiments that our algorithms can’t. We rely on this community of humans to figure out where the simulations are going wrong and to correct for it in future designs.”

The key scientific principle behind Das’ work is RNA’s role as a sort of switch, changing its structure when binding to specific molecules — for example, a drug, a gene or a hormone. These folding patterns are a form of true-false computational logic, like 1s and 0s in an electronic computer. Fold one direction for true; another for false. “The molecules are computers,” Das said.

“These molecules are computationally aware of their surroundings and can autonomously calculate next steps. You can imagine all sorts of possibilities from there.”

Das, creator of the crowdsourcing Eterna gaming platform

“The idea is that when the computation reaches a certain threshold, a chemical signal would change the color of a line on a piece of paper,” explained William Greenleaf, PhD, a professor of genetics and co-creator of the tuberculosis test.

Eterna’s players, for their part, suggest novel molecular designs and predict how they will fold. Sometimes, they succeed; often they do not. Regardless, the results are fed back into the game for refinement until a solution is found.

The players are then tasked with more difficult challenges. With the tuberculosis test, they designed a single RNA molecule that acts as a sensor able to detect whether concentrations of three particular RNA molecules are present in the ratio indicative of active TB.

“Humans are able to look at a problem and ask, ‘Could this work?’ in a way that a computer can’t yet,” said one of Eterna’s top players, Andrew Kaechele, a key contributor to the molecular computation behind the tuberculosis test.

“What I find most enjoyable is not just the challenge of complex RNA puzzles but also knowing that my contributions are helping science,” he said, noting the game has had a positive influence on his neurodivergence. “Being part of this supportive community has helped me connect with others and feel less isolated, which is incredibly rewarding.”

Deeper implications

Beyond tuberculosis, the results offer a pathway to a virtually unlimited array of RNA sensors for other conditions ranging from septic shock and cardiovascular disease to cancers.

“The authors chose a difficult problem to solve — TB ratio sensing encoded in a short RNA sequence — and successfully crowdsourced solutions and molecular designs,” said Angela Yu, PhD, a professor of biochemistry and molecular pharmacology at Baylor College of Medicine, a peer reviewer of the paper who did not participate in the research. “This study is a great example of the game’s ability to approach many challenges at once to expand our understandings of RNA. I think it will have deep implications for future medical applications.”

Das said he can imagine molecular computers that go inside cells and weigh the collective signals as a neural network would to distinguish a malignancy from healthy tissue, for instance. A computationally enhanced cancer-killing drug might then turn itself on when in a tumor or off when in a healthy organ, like the liver, where it would otherwise prove toxic. Similar gene-editing molecular computers might one day seek out and repair faulty genes, while leaving healthy genes alone.

“These molecules are computationally aware of their surroundings and can autonomously calculate next steps,” Das said. “You can imagine all sorts of possibilities from there.”

Spotlight on William Greenleaf
Professor of genetics

William Greenleaf links molecular biology, computer science, bioengineering and genomics to understand how our DNA controls when genes turn on or off, and how that affects what’s happening in the body.

• Grew up in Rochester, Minnesota.
• His favorite book is The Making of the Atomic Bomb by Richard Rhodes.
• He breaks through research roadblocks by “obsessive thinking about said roadblock.”

In his words: “My long-term goal is to unlock an understanding of
the factors that control how the genetic information is read into biological instructions — to develop a quantitative understanding of how cells maintain, or fail to maintain, their state in health and disease.”

Spotlight on Rhiju Das
Professor of biochemistry

Rhiju Das first began to study computational protein folding as a postdoctoral scholar. He launched his Stanford Medicine lab in 2009, and in 2010, he co-founded Eterna, an open-science gaming platform that enlists amateur citizen-scientists to discover ways in which RNA molecules can bend into shapes that solve biological problems.

• Grew up in Bartlesville, Oklahoma.
• Enjoys solving word and jigsaw puzzles with his daughters.
• His motto is Eterna’s original tagline, “Played by humans, scored by Nature.” “It reminds us that scientific progress is not for people to evaluate, but for experiments. The whole thing, like life itself, is a cooperative game.”

In his words: “What really keeps Eterna players going is the community. They motivate each other. They teach each other. They geek out over the experimental data. That’s the coolest part about it all.”