An online puzzle game where players solve protein-folding problems, contributing to research through collective problem-solving and shared experimentation.

The origin: Rosetta@home

Foldit's origins trace back to Rosetta@home, a protein structure prediction program created by molecular biologist David Baker. Distributing calculations across thousands of volunteer home computers, Rosetta@home was capable of performing 100 trillion calculations per second (Bohannon, 2010). Rosetta attempted to identify the most stable and energy-efficient protein states using a slow but effective system. Eventually, some Rosetta users reported occasionally seeing potential solutions but were frustrated when they could not make direct modifications. Recognising this limitation, Baker then approached computer science professors David Salesin and Zoran Popović to develop an interactive solution, and they turned it into a video game instead (Technology Review, 2008).

Foldit, A Citizen Science Game (CSG)

In 2008, the University of Washington's Department of Biochemistry released Foldit, a crowdsourced protein-folding puzzle game. Players predict the 3D structures of proteins, uncovering the most stable, energy-efficient states. Foldit was among the first citizen science games designed for real-world scientific problem-solving, demonstrating that play could facilitate meaningful public participation in research. By the early 2010s, the term Games With a Purpose (GWAP) was often used to describe such efforts (Miller et al., 2023).

In 2019, a study compared the performance of Foldit players with Rosetta's automated strategies. The findings revealed that Foldit players significantly outperformed automated approaches such as Rosetta@home. Foldit reveals how play can operate as a distributed system of thinking. Rather than solving problems individually, players collectively explore possibilities, generating solutions that exceed traditional computational approaches.

As shown in Fig. 2a, Foldit players (red, blue, and green) explored new regions with significant increases in energy, whereas Rosetta's strategies remained limited and systemic. Red circles correspond to snapshots of the trajectory displayed in Fig. 2b. Finally, Fig. 2c illustrates the strategic trajectory of Foldit players; each colour represents different cooperating Foldit players, with the final structure (marked by a star) achieved after 17 branch points (Koepnick et al., 2019).

A decade-long problem

The protein shape defines its function and how it interacts with other molecules, scientists hoped that gamers manipulating protein structures might help uncover the enzyme M-PMV Retroviral protease, which is crucial for understanding how HIV multiplies. For over a decade, scientists and computer programmes failed to find the structure, so the M-PMV Foldit puzzle was created. In just three weeks, gamers produced a 3D model of the enzyme that was accurate enough for molecular replacement (Khatib et al., 2011; Zoran, 2011). This discovery paved the way for developing antiretroviral drugs, including treatments for HIV (Khatib et al., 2011).

Foldit has hundreds of thousands of registered players who contribute to cancer and Alzheimer's research, among other causes. Gameplay has since evolved to allow players to design never-before-seen synthetic proteins, which led David Baker to experiment with protein design.

Foldit Legacy

Simultaneously, Demis Hassabis, co-founder of DeepMind, started experimenting with game systems and AI. After experimenting with an automated game system based on old arcade classics, he took on a more complex one and created AlphaGo, which plays the ancient strategy board game Go. AlphaGo eventually defeated the Go (board game) world champion, Lee Sedol. Seeking a new challenge, Hassabis looked at Foldit's success, which led him to "think that AI could maybe try to mimic that intuitive capability that those gamers were demonstrating" (BBC, 2020). Hassabis and scientist John M. Jumper started testing with protein folding, and in 2020, DeepMind released AlphaFold2. The programme's success led experts to claim that the half-century-old protein folding problem has been broadly solved. In 2024, the Nobel Prize in Chemistry was awarded to David Baker for computational protein design and Demis Hassabis and John M. Jumper for protein structure prediction.

Tiz Creel of Living Things Studio ©2024

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