Gaming a cure

Crowdsourced computer challenge tackles deadly toxin

Imagine this choice: You’re hungry, and there’s enough to eat, but the food increases your long-term risk for cancer. That’s the dilemma facing billions of people whose food supplies are infected by aflatoxins, the most prevalent carcinogen most people have never heard of.

“It doesn’t really exist here, so people don’t think about it, but this is a major problem worldwide, almost an epidemic,” says associate professor Justin Siegel, who directs the UC Davis Innovation Institute for Food and Health. “In certain parts of the world, it affects corn, sorghum, casaba, millet — essentially everything has aflatoxin in it.”

Aflatoxin is produced by the fungus Aspergillus flavus, which loves hot, humid climates. The poisonous molecule mutates DNA, has been linked to stunting and anemia, and is a major cause of liver cancer. Though it hasn’t been a problem in the United States since stringent regulations were imposed decades ago, climate change could alter that calculus. For people in India, Africa and parts of China, aflatoxin is a constant danger.

“There are fields of molding crops that people will eat,” says Siegel, “that are chockful of these toxins, because otherwise they have nothing.”

Siegel is helping lead a novel project to overcome aflatoxin. Working with the University of Washington, Northeastern University, Thermo Fisher Scientific, Mars Inc. and others, he is trying to reengineer promising enzymes to break down aflatoxin and create a much safer food supply. But there’s a problem: the number of potential enzyme shapes is virtually infinite.

“There are more potential structures than stars in the universe,” says Siegel.

What they needed was a way to distribute the workload and cover more ground. They found it in a crowdsourcing game called FoldIt.

Bring on the gamers

Developed by researchers at the University of Washington, FoldIt is not an ordinary computer game. Participants don’t look for treasure or conquer Wales, they experiment with different protein shapes to find the best structures. With proteins, form dictates function, so harnessing thousands of creative people to generate novel structures can really move the science.

“A human mind can come up with ideas for shapes and structures that look interesting,” says Siegel. “FoldIt takes this human intuition and applies a biophysical metric to ask: How realistic is it for this to happen? While you can imagine this structure, is it likely to occur or is it extremely unlikely? It couples the human imagination with physical reality.”

For the Aflatoxin Challenge, players are given enzymes that could potentially break down the molecule and make it nontoxic — they only have to redesign it in just the right way.

“We thought it would be a good way to get people engaged in this problem, which a lot of FoldIt players have never heard of,” says Siegel. “Around 4.5 billion people are eating this toxin on a daily basis, and we’re trying to eliminate it without destroying their food.”

There have been a number of design cycles, each one lasting several months, giving thousands the opportunity to play. Patrick Camarador was a pharmaceutical chemistry major at UC Davis when he joined in.

Camarador had tried playing FoldIt in high school, but it didn’t resonate with him. But after taking a biochemistry class, he rediscovered the game and even started livestreaming his play on Twitch.

He had never heard of aflatoxin before the challenge, but embraced the opportunity to take on a deadly poison. He liked that it was contributing to good science, and it didn’t hurt his studies either.

“FoldIt helps me memorize the 20 amino acids just by visual shape alone,” says Camarador. “The more I played the game and designed my own proteins, the more I got familiar with which amino acid is which.”

Camarador is now a PharmD candidate at California Northstate University. He still plays FoldIt, as his studies allow.

“It’s cool for me,” he says, “because I get to apply concepts I’ve learned in pharmaceutical chemistry and design classes.”

The continuing journey

The Aflatoxin Challenge is a unique partnership between universities, an international consumer company and life sciences giant Thermo Fisher, and each group brings important talents to the project.

“Thermo is providing DNA at a scale that normally wouldn’t be possible to let us really explore what these players are making,” says Siegel. “Mars is providing social, financial and translational support. It took this uncommon collaboration to really drive this project forward.”

Once they solve this enzymatic puzzle, Siegel envisions spraying the enzyme on crops or even engineering it into the plants themselves. The group has been testing some of the better designs in the lab to see how they work against aflatoxin, but it’s a trial and error process and could take a while.

“No hits yet, but it’s early days,” says Siegel. “We’ve learned a lot about how much you can change these enzymes before they break. We haven’t had a breakthrough, but we’re making progress.”