A single spoonful of soil might contain 10,000 or more species of bacteria. Many of these microbes are competing for the same limited resources available in that spoonful. They are constantly waging biological warfare on one another in an arms race of antibiotic production, sensitivity, and resistance. So how is it that such fierce competition does not lead to “survival of the fittest” but instead supports thousands of species in a shared environment?
Theoretical ecology uses mathematical models and simulations informed by lab and field experiments to understand a broad range of biological phenomena, including how such rich diversity can exist in communities like the one you might find in a spoonful of soil. Kalin Vetsigian of the Systems Biology theme at WID is on the forefront of research on the dynamics of microbial interactions, and his paper published with colleagues Eric Kelsic and Roy Kishony from Harvard Medical School today in Nature brings a fresh understanding to how microbes achieve such coexistence.
The traditional way of thinking about diversity in microbial communities relies on pairwise relationships — one species either helps or harms another. For example, an antibiotic-producing microbe can inhibit a neighboring sensitive microbe. Because there are so many different antibiotics, a third microbe might be resistant to the antibiotics produced by the first microbe, but sensitive to a different antibiotic produced by the second. This can result in relationships that look like rock-paper-scissors games in which every microbe can beat and be beaten by another.
Theoretical ecologists have found that such cyclical games allow for coexistence by having multiple species chase each other around; ‘scissors’ microbes can move into the territory of ‘paper’ microbes as ‘paper’ microbes displace ‘rock’ microbes and so on. But what happens when we mix things up?
In nature — or in a spoonful of soil, for that matter — microbes are rarely so neatly clustered. In fact, antibiotic producing, sensitive, and resistant species are often thoroughly intermixed and dispersed so that there are no patches dominated by individual species. This presents a problem for the standard rock-paper-scissors framework. “As you start increasing species dispersal, this mechanism stops working — diversity collapses,” says Vetsigian. The model based only on pairwise relationships results in some species spiraling into extinction while a select few dominate the niche. The rock-paper-scissors game is no longer capable of maintaining microbial diversity. “So maybe it’s not a very realistic explanation for what’s happening in nature.”
Finding a more realistic and satisfying explanation requires thinking about higher-order interactions between microbes. “We can ask, ‘how do the pairwise interactions change if we embed them in a community setting, if we have other bacteria around? … Does that change anything about our theoretical picture of coexistence?’” says Vetsigian. In particular, Vetsigian and his team examined antibiotic degradation among intermixed species.
“Both antibiotic production and degradation can be viewed as public goods.”
Many microbes, rather than being intrinsically resistant to a particular antibiotic, actively degrade the antibiotics produced by other microbes. The resulting protection, however, is not just limited to the degrader — other nearby antibiotic-sensitive “bystanders” benefit from the degradation. At the same time, antibiotic-resistant microbes benefit when their neighbors produce antibodies, curbing the competition. In this way, according to Vetsigian, “both antibiotic production and degradation can be viewed as public goods.” The counteraction of production and degradation results in a more complicated community where a single niche can support multiple microbes with different antibiotic production and resistance capabilities rather than a single winner.
One of the strengths of this new model for describing microbial diversity is that it works in many different situations and with different assumptions and parameter values. Unlike the simple rock-paper-scissors framework, it is robust not only to mixing and dispersal, but also to varying growth rates and, to a point, different initial species abundances. It even holds up as species evolve into “cheaters” — microbes that save resources by ceasing production or degradation of antibiotics but continue to benefit from the production and degradation of their neighbors.
There are, of course, a few prerequisites for the model to work. First, the model requires at least two different antibiotics for the system to work, with greater numbers allowing more complex communities capable of supporting more species. With millions of unique antibiotics in nature, this turns out not to be problematic at all. There is also a microbial diversity sweet spot for strength of antibiotic degradation. If degradation is too strong, it effectively cancels the antibiotic interaction; if it is too weak, it has no effect at all. So it is at the intermediate level of degradation that coexistence is supported.
Looking ahead, Vetsigian believes that exploration into the higher-order interactions among multiple species will facilitate further insights and discoveries about the assembly and stability of ecosystems. While the foundation laid by today’s Nature publication does not take into account all of the interactions that occur in the natural world, it does represent a big step forward in our understanding of the role of antibiotic production and degradation in development and maintenance of diversity. Says Vetsigian, “Now we have a viable way of thinking of how antibiotic interactions can contribute to diversity.”