Synthetic cooperation in engineered yeast populations

Abstract

Cooperative interactions are key to diverse biological phenomena ranging from multicellularity to mutualism. Such diversity makes the ability to create and control cooperation desirable for potential applications in areas as varied as agriculture, pollutant treatment, and medicine. Here we show that persistent cooperation can be engineered by introducing a small set of genetic modifications into previously noninteracting cell populations. Specifically, we report the construction of a synthetic obligatory cooperative system, termed CoSMO (cooperation that is synthetic and mutually obligatory), which consists of a pair of nonmating yeast strains, each supplying an essential metabolite to the other strain. The behavior of the two strains in isolation, however, revealed unintended constraints that restrict cooperation, such as asymmetry in starvation tolerance and delays in nutrient release until near cell death. However, the joint system is shown mathematically and experimentally to be viable over a wide range of initial conditions, with oscillating population ratio settling to a value predicted by nutrient supply and consumption. Unexpectedly, even in the absence of explicitly engineered mechanisms to stabilize cooperation, the cooperative system can consistently develop increased ability to survive reductions in population density. Extending synthetic biology from the design of genetic circuits to the engineering of ecological interactions, CoSMO provides a quantitative system for linking processes at the cellular level to the collective behavior at the system level, as well as a genetically tractable system for studying the evolution of cooperation. mathematical modeling ͉ mutualism ͉ obligate cooperation ͉ quantitative biology ͉ synthetic ecology

Microbial mutualism dynamics governed by dose-dependent toxicity of cross-fed nutrients

“…High cross-feeding levels can be detrimental to a mutualism Cross-feeding levels are inherently difficult to measure and yet are hypothesized to be a major determinant of mutualism dynamics and stability (Shou et al, 2007;Kim et al, 2008;Estrela et al, 2012;Hom and Murray, 2014). We therefore used our model to address the effect of NH 4 + -cross-feeding levels on mutualism dynamics.…”

“…As an alternative, synthetic microbial communities (cocultures) have been developed in which two or more species are cultivated together under laboratory conditions. Cocultures preserve core aspects of natural systems while offering greater practical experimental control (Shou et al, 2007;Hillesland and Stahl, 2010;Summers et al, 2010;Harcombe, 2010;Momeni et al, 2011;Hom and Murray, 2014;Mee et al, 2014). They are also more amenable to modeling than are natural systems and facilitate the development, experimental testing and refining of models for predicting community behavior (Zomorrodi and Segrè, 2015;Johns et al, 2016;Lindemann et al, 2016;Widder et al, 2016).…”

“…One factor that can promote cross-feeding in natural ecosystems is nutrient limitation, as crossfeeding can be a means by which to acquire scarce key nutrients (Shou et al, 2007;Klitgord and Segrè, 2010;Hom and Murray, 2014;Zelezniak et al, 2015). Limitation of bacterial growth is most commonly considered to result from nutrient deficiency; however, growth can also be influenced by diverse compounds that are inhibitory when abundant but serve as nutrients at lower concentrations (Abbott, 1973;Kunz et al, 1992;Alvarez et al, 2009;Barnhill et al, 2010).…”

Association between competition and obligate mutualism in a chemostat

“…Following this idea, a new class of synthetic cooperative system has recently been proposed. They are called CoSMO for cooperation that is synthetic and mutually obligatory [19]. In this paper, the yeast Saccharomyces cerevisiae was genetically modified to obtain two nonmating strains with different metabolic capabilities so that they behave essentially as two different species.…”

Experimental Modeling in Biology: In Vivo Representation and Stand-Ins as Modeling Strategies

“…For example, Shou, Ram, and Vilar (2007) engineered pairs of yeast strains so that one strain was deficient for the synthesis of an amino acid that the other was able to produce, and vice versa. This introduced a mutualistic interaction between the two strains where there was none before.…”