Firas Khatib is a professor of computer and information science at the University of Massachusetts Dartmouth. In 2008, Khatib helped develop a computer game, called “Foldit,” that offers players the opportunity to search for cures of various diseases through protein building.
Since then, more than 50 protein structures designed by the gamers were found to be stable, suggesting the gamers produced proteins that were possibilities. Khatib spoke with PBN about the genesis of the game and how vital it is for the medical community.
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PBN: What was the initial driving force behind designing the game?
KHATIB: The project began with the Rosetta@home distributed computing project: boinc.bakerlab.org, where people donate their free CPU cycles to help us fold proteins. The idea with Rosetta@home was that rather than running these computationally expensive calculations solely on our supercomputers, we could harness even more power by extending the computations to as many home computers as possible.
While this was a game-changer in terms of the vast search space we were suddenly able to sample, all calculations were still driven by the Rosetta energy function, and simply adding more computers was not enough. Even if we could take all the supercomputers on the planet, we still wouldn’t be able to sample all the different possible conformations that a single protein can take! There are just too many different possible ways that proteins can fold.
Our new approach was: What if we can guide these automated computations in an intelligent manner? That is how Foldit was born.
PBN: Can you offer readers how the game is played?
KHATIB: The goal of Foldit is not to compete with or replace computers, but rather to augment the computational power that computers have – which humans cannot compete with – with the visual and pattern recognition skills that humans have. Humans are very good at visual and spatial reasoning tasks – this is why we often have to solve captchas to prove that we are not computers.
The Foldit game provides the powerful computational tools that the Rosetta algorithm uses, but the players are able to decide when and how to use them.
In addition to the automated protocols that the players can use – renamed to sound more fun, such as “Shake” and “Wiggle” – players can manually manipulate the protein by pulling on parts of the polypeptide chain and dragging it however they want, in order to increase their Foldit score.
Every Foldit player’s score is on a leader board at the top of the screen, so anyone can see how they are doing compared to the rest of the Foldit community. Foldit players can also form teams and share their solutions with one another, as well as their strategies, which are called “recipes.”
PBN: Why is the game important to the medical community?
KHATIB: Knowing the correct structures of proteins is essential for the medical community. Proteins are molecules that carry out many different functions that are fundamental to life; they are the workhorses in every cell of every living thing. Unfortunately, despite all the different things proteins do to keep our bodies functioning and healthy, they can also be involved in diseases, such as HIV, cancer, Alzheimer’s, Ebola, hepatitis, measles, influenza, the Zika virus and many more. The more we know about how certain proteins fold, the better new proteins we can design to combat the disease-related proteins and cure those diseases.
PBN: Have there been instances where proteins designed by gamers were proven to be beneficial to medical research?
KHATIB: In 2011, Foldit players were able to solve the structure of a protein that no one else had been able to solve. For over 10 years scientists tried to determine the structure of a retroviral protease – that causes simian-AIDS in rhesus monkeys – in its monomeric form. Until this player discovery, crystal structures of all retroviral proteases, including all human ones, had only been solved as dimers – where two copies of a protein bind to one another. Foldit players were able to generate models of sufficient quality for scientists to successfully solve the monomeric Monkey Virus protein, providing new insights for the design of antiretroviral drugs.
More recently, undergraduate students used the Foldit interface to create and experimentally test an enzyme to break down gluten, with potential as a therapeutic for celiac disease. They have started clinical trials for it this year!
PBN: Do you hope this technology can help find a cure for cancer and other life-threatening illnesses in the near future?
KHATIB: Of course, this has always been our goal. The Foldit players proved early on that they could compete with state-of-the-art protein-folding methods, but we want to take this one step further: I want Foldit to become part of the pipeline for solving new protein structures, not just predicting how they will fold but actually solving them. Ideally, if scientists have been unable to solve a protein using every traditional method that currently exists, I want them to ask the Foldit players for help. Foldit can be another tool in the arsenal of different methods that scientists use to solve proteins!
The other important result that I believe Foldit has demonstrated is that anyone can help contribute to science. This doesn’t mean that citizen scientists or gamers will replace anybody, but they are another important resource that should no longer be ignored. There are many challenging problems that the world will need to face, and we need as many minds tackling those problems as possible.
James Bessette is a PBN staff writer. Email him at Research@PBN.com.
