A pioneer of synthetic biology at the University of California, San Diego, Jeff Hasty has spent his 20-year career designing strategies to make genetic circuits in engineered bacteria work together. But several years ago, Hasty had to admit that even he couldn’t outfox the humble bacterium Escherichia coli.

Hasty didn’t have a problem engineering useful, tightly regulated new genetic traits or getting them to work in cells. That was the easy part. What’s harder, he discovered, is maintaining those traits. If a cell needs to divert some of its resources to make a desired protein, it becomes marginally less fit than cells that don’t synthesize it. Inevitably, cells acquire mutations deactivating the introduced genetic circuitry, and the mutants quickly replace the original cells. As a result, the desired characteristic disappears, often within 36 hours.

“It’s not a matter of if, it’s a matter of when,” Hasty said.

For years, Hasty watched mutant E. coli disable even his elegantly engineered systems. But last September in Science, Hasty, his doctoral student Michael Liao and their colleagues designed a strategy to thwart even the most mutation-happy bacterium through a kind of “microbial peer pressure,” as an accompanying commentary called it. The UCSD team used three engineered strains of E. coli that worked in tandem. Each strain produced a toxin, a corresponding antitoxin to protect itself, and a second antitoxin for protection against one of the other strains. The first strain could kill the second but not the third; the second could kill the third but not the first; the third could kill the first but not the second.

This round robin of antagonism meant that, by sequentially adding the strains of bacteria, the researchers could keep the numbers of engineered E. coli high while ensuring that unhelpful mutants were snuffed out by the newcomers’ toxins. The ecological interaction of the cells stabilized the system.

The project was nearing completion when Liao stumbled across the fact that other scientists were already paying attention to this strategy. Researchers in ecology and evolution had wrestled with it for decades as one possible answer to a major question in their field: How does so much biodiversity survive in nature? But even aside from its scientific history, the strategy is better known as a game used by children around the world to settle playground squabbles.

The game is rock-paper-scissors, “a classic game in game theory and evolutionary theory,” said the mathematical biologist Barry Sinervo of the University of California, Santa Cruz, whose field studies on side-blotched lizards helped to establish its relevance to ecosystems.

The rules of the game are easy: Rock beats scissors, scissors beat paper, and paper beats rock. No player has an advantage, and the chances of winning are equal regardless of what item they pick. When two people play, there’s always a clear victor. Add in more players, however, and the game becomes more complex, with the success of different strategies often cyclically rising and falling.

Biologists studying rock-paper-scissors have modeled how the game plays out with scores or even hundreds of species. They have also investigated how it changes when the species interact in various landscapes, and when the species differ in their mobility and competitiveness. What they have found is that over time, rock-paper-scissors may enable many species to coexist in the same area by cycling in and out of dominance.

Scientists are still determining the true importance of the game to living systems, but their discoveries have implications that could affect evolutionary theory, our understanding of ecological dynamics, biotechnology, and conservation policy. “It’s a universal game, which is pretty darn neat,” Sinervo said. “Rock-paper-scissors covers the entire biological universe.”

Equations of Abundance

When Charles Darwin published his theory of natural selection in 1859, he and his contemporaries hypothesized that competition between individuals provided the force behind evolution. More than 150 years of experiments following Darwin’s initial work confirmed that competition is indeed a major evolutionary force. There is just one problem.

If simplistic competition were the only evolutionary force, then after billions of years, only a handful of highly competitive species should be left. Instead, the planet is home to a staggering array of life. The number of species for which Earth is home is almost impossible to estimate; one recent attempt pegged it at about 2 billion, but earlier efforts ranged from under 10 million to 1 trillion. The lowland Amazon rainforests alone are home to more than 6,700 tree species and 7,300 other seed plant species — numbers that don’t begin to account for the accompanying insects, mammals, fungi and microbes.

“We look around and there are thousands, even millions, of microbes living in one hectare of forest,” said Daniel Maynard, an ecologist at the Swiss Federal Institute of Technology Zurich. “And no matter what you do, they all survive. It’s not like one tears through the community and beats out everything else.”

One of the first breakthroughs in explaining biodiversity came not from ecology but from mathematics. In 1910, the American biophysicist and statistician Alfred Lotka developed a series of equations to describe certain chemical reactions. By 1925, he had realized that the same equations could be adapted to describe the cyclic rise and fall of predator and prey populations. A year later, the Italian mathematician and physicist Vito Volterra independently developed the same set of equations.

Their work showed how the number of predators depends on the number of prey. That insight might seem obvious, says Margaret Mayfield, an ecologist at the University of Queensland in Australia, but the equations of Lotka and Volterra were groundbreaking in their time because they gave ecologists a way to start measuring and modeling the natural world.

Still, the equations weren’t perfect. They rested on useful but simplistic assumptions, and they couldn’t represent relationships between species that weren’t predator and prey but competed for resources.

That began to change in 1975, however, when the mathematicians Robert May and Warren Leonard adapted the classic Lotka-Volterra equations for what ecologists call intransitive competition. When competition is transitive, it’s hierarchical: If A beats B and B beats C, then A also beats C, making A the winner in any contest. Intransitive competition lacks this hierarchy, because C can beat A. Instead of staying a clear winner, A will dominate for a while but then give way to C, which then gives way to B, followed once again by the rise of A.

What May and Leonard created was in effect the math to describe rock-paper-scissors in ecology. Later mathematicians extended their work to show that these intransitive relationships could involve a nearly infinite number of species.

Think of it like a gladiator death match, Maynard said. In single combat against a skilled fighter, he said, “I’m going to lose.” But if he were in a group of 100 fighters, he said, other defensive options might be available, such as forming an alliance with a stronger fighter. That strategy might help him outlast his competitors and come out on top.

Mating Games

In the 1970s and ’80s, scientists began to document real-life examples in papers that showed rock-paper-scissors relationships among organisms living on coral reefs and among strains of the common yeast Saccharomyces cerevisiae. Among the most famous studies, however, was Sinervo’s work on the common side-blotched lizard, published in Nature in 1996.