Recreation of Borderlands video game advances microbiome research and algorithms

19 Apr 2024 --- An experiment involving 4.5 million gamers of Borderlands Science (BLS), a mini spin-off of Borderlands 3, a looter-shooter video game, has helped scientists trace the evolutionary relationships of more than a million kinds of bacteria in the human gut. The findings have also allowed the researchers to improve algorithms for future biomedical research.

“We didn’t know whether the players of a popular game like Borderlands 3 would be interested or whether the results would be good enough to improve on what was already known about microbial evolution,” says Jérôme Waldispühl, associate professor in McGill’s School of Computer Science and senior author of the study.

“But we’ve been amazed by the results. In half a day, the Borderlands Science players collected five times more data about microbial DNA sequences than our earlier game, Phylo, had collected over a 10-year period.”

McGill University researchers led the project in collaboration with interactive entertainment company Gearbox and Massively Multiplayer Online Science (MMOS), a Swiss IT company connecting scientists to video games. Genomic material from the Microsetta Initiative, the world’s largest microbiome project, was used for the experiment.

Global citizen science project
The idea to integrate DNA analysis into a commercial video game with a mass market was hatched by Attila Szantner, CEO and co-founder of MMOS and adjunct professor at McGill’s School of Computer Science.

“As almost half of the world population is playing with videogames, it is of utmost importance that we find new creative ways to extract value from all this time and brainpower that we spend gaming. Borderlands Science shows how far we can get by teaming up with the game industry and its communities to tackle the big challenges of our times,” says Szantner.

Leveraging gamers and video game technology can significantly boost research, according to the Borderlands experiment researchers whose study has been published in Nature Biotechnology. The scientists show that their multiple sequence alignment improves microbial phylogeny estimations and UniFrac effect sizes better than other state-of-the-art computational methods.

The gamers have helped refine the estimate of relationships of microbes in the human gut and helped construct microbial evolutionary histories. The collaboration findings will advance microbiome knowledge and improve AI programs for this kind of research.The scientists are inspired by using the gaming community to further scientific study (Credit: Gearbox). 

The BLS integration uses a novel game-first design where the design aspect has the highest priority and a suitable task is mapped to it. BLS crowdsources a multiple alignment task of one million 16S ribosomal RNA sequences obtained from human microbiome studies.   

“We expect to be able to use this information to relate specific kinds of microbes to what we eat, to how we age and to the many diseases ranging from inflammatory bowel disease to Alzheimer’s that we now know microbes to be involved in,” says Rob Knight, lead on the Microsetta Initiative.

“Because evolution is a great guide to function, having a better tree relating our microbes to one another gives us a more precise view of what they are doing within and around us.”

The Microsetta Initiative (TMI) is a highly collaborative microbiome research study conducted at the Knight Lab and the Center for Microbiome Innovation at the University of California San Diego. The American Gut Project initiated the project in 2012, followed by the British Gut Projects in 2014. The name “Microsetta” mirrors a conceptual relationship to the Rosetta Stone, which in the 19th century helped scholars decipher the code of hieroglyphics. 

Evolutionary relationships of bacteria
The gaming escapades improved on results produced by existing genomic programs used to analyze data sequences and laid the groundwork for the improvement of AI research programs to come. The data has been taken from a set of 953,000 rRNA fragments sequenced from stool samples submitted by the participants in the classical arabinogalactan protein 25 (AGP25), powered by TMI.  

The fragments are 150 nucleotides long and come from the V4 region of the 16S rRNA gene. In the BLS mini-game, the player sees 7–20 sequences of 4–10 nucleotides. Each sequence is displayed as a vertical pile of bricks. Each color represents a nucleotide via random mapping between colors and nucleotides. 

The researchers aligned rows of tiles representing the genetic building blocks of different microbes in a manner superior to the way existing algorithms have been solving it thus far. The data has exponentially increased the level of information about the microbiome to date. 

“Borderlands Science created an incredible opportunity to engage with citizen scientists on a novel and important problem, using data generated by a separate massive citizen science project. These results demonstrate the remarkable value of open access data and the scale of what is possible with inclusive practices in scientific endeavors,” adds Daniel McDonald, scientific director of TMI. 

The scientists believe synthetic data should be integrated into the future design of the game to complement the current proxy for the “ground truth.” The present study relied on the Greengenes phylogeny as a proxy for ground truth. The research was funded in part by Genome Canada and Génome Québec.

By Inga de Jong