Grand Challenges is a family of initiatives fostering innovation to solve key global health and development problems. Each initiative is an experiment in the use of challenges to focus innovation on making an impact. Individual challenges address some of the same problems, but from differing perspectives.
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Ahmad Khalil of Boston University in the U.S. will develop a low-cost bioreactor platform to simultaneously optimize growth conditions of multiple bacterial species for large scale production of biotherapeutics. The human gut microbiome plays an essential role in health and development and living microbial biotherapeutics could be an effective treatment in the case of damage by illness or malnutrition. Commercial production is limited by the capacity of bioreactors, which are costly and challenging to scale and relatively inflexible. Using their eVOLVER continuous culture system, which is modular, inexpensive, and highly scalable, they will adapt the set-up and optimize protocols to allow for the management of unique growth conditions for individual species in parallel, and dynamic mixing of cultures from individual pools to precisely tune multi-species formulations. They will conduct full-scale tests to evaluate their approach for optimizing production of human gut microbiota.
Paul de Figueiredo and Daniel Alge of Texas A&M University in the U.S. will develop a portable, disposable bioreactor for the low-cost production of gut microbial biotherapeutics at an estimated $0.09 per dose in low-resource settings. Dysfunction of the human gut microbiome is a common consequence of malnutrition in poor countries. It may be effectively treated with live biotherapeutics, yet current production methods are complicated and expensive. Glucose oxidase consumes oxygen as a co-substrate in glucose oxidation and has been shown to create hypoxic microenvironments in vitro, similar to that in the human gastrointestinal tract. They will engineer an inexpensive bioreactor by immobilizing glucose oxidase in a hydrogel placed in dialysis tubing and incubated in liquid media; the glucose oxidation reaction will deplete the bioreactor of oxygen and create an oxygen gradient to mimic the intestinal lumen. This will enable growth of a consortium of anaerobic bacteria, after which the microparticles will be removed by filtration. They will optimize the system using an artificial consortium of at least ten strains of common gut bacteria.
Ricardo Valladares of Siolta Therapeutics in the U.S. will develop a low-cost method to manufacture large quantities of mixed populations of bacteria for use as biotherapeutics to restore a healthy population of gut microbes in infants. A diverse population of bacteria in the infant gut is essential for health, but malnourishment and antibiotics can destroy microbial diversity and cause metabolic and immune problems. Gut health may be restored by treatment with a consortium of bacterial strains. However, mass production of these strains is challenging as many have complex nutritional and environmental growth requirements. To date consortium microbes have been cultured individually, resulting in a costly, small-scale process. They will first study bacterial populations in healthy infant guts to determine what species are required and the combinations that co-exist naturally. To support their growth in vitro, they will optimize a vegetable-based culture media composed of low-cost, widely available food staples, and then apply bioreactor technology used by commercial breweries to manufacture large quantities of the microbial mixture at low cost. Together, these approaches could help make microbiota-based biotherapeutics accessible in low- and middle-income countries.
Christophe Lacroix of ETH Zürich in Switzerland will develop a new method to grow mixed strains of bacteria in bioreactors more efficiently and at lower cost for producing microbial-based biotherapeutics by immobilizing the bacteria on porous polysaccharide gel beads. Damage to the naturally-occurring bacterial populations in the human gut often occurs as a result of malnutrition and can cause serious illness. Healthy populations may be restored by gut microbial biotherapeutics – the ingestion of mixtures of naturally-occurring gut bacteria. Traditional processes to manufacture these mixtures is complex and expensive because many strains have strict growth requirements and do not grow well in mixed culture. They will immobilize bacteria on microbeads to allow multiple strains of bacteria to grow in the same culture: antagonistic strains will be spatially separated, less competitive strains will be maintained, and diversity will be preserved. Using inoculums from healthy human adults, they will optimize individual components of the system including the composition of the bacterial mixture, method of immobilization, and fermentation conditions within a continuous-culture stirred-tank reactor. The result will be the controlled, reproducible and efficient production of gut microbial biotherapeutics.
Ophelia Venturelli of the University of Wisconsin-Madison in the U.S. will study the growth kinetics and microbial interactions of a synthetic bacterial community in order to optimize bioreactor design and produce large quantities of mixed cultures at low cost. Mixed microbial populations are used to reconstitute the healthy gut microbiota in infants and children who have suffered malnutrition. However, affordable, large-scale production of microbial communities for biotherapeutics is challenging, in part because of poor understanding of how the growth and viability of individual strains are impacted by environmental factors and the presence of other microbes. To address this, they will build a dynamic model of a synthetic 12-member community that mimics the functional and phylogenetic diversity of the human gut microbiome and monitor its stability and growth over time and in response to variations in culturing parameters. This information will be used to predict community growth and stability in bioreactors, which will then be tested. Their approach is low cost, scalable to industrial-sized bioreactors, and can be generalized to other microbial communities relevant for human health.
Carol Sze Ki Lin of the City University of Hong Kong and Srinivas Mettu of the University of Melbourne in Australia will develop a new, low-cost bioreactor system to mimic the human gut and facilitate simultaneous growth of multiple bacterial strains with diverse growth requirements. A healthy mixture of bacteria in the human gut is essential to overall health, and live biotherapeutics could be used to restore this population in infants whose gut microbiota has been damaged by malnutrition. Manufacture of these therapeutics is difficult and expensive: the human gut contains multiple strains of bacteria with diverse environmental and nutritional growth requirements, and designing a bioreactor to accommodate such variation is difficult. They will create stratified growth zones within one reactor based on immobilization of the bacteria on a low-cost, biodegradable plant-based cellulose hydrogel. They will alter the porosity and surface chemistry of the hydrogel to create variations in pH and oxygen and nutrient levels within the reactor to simulate the human gut from stomach to rectum. This will facilitate the simultaneous growth of ten bacterial strains with diverse growth requirements, first in a lab setting and later on a commercial scale.
Gregory Medlock of the University of Virginia in the U.S. will develop a method to predict the optimal combinations of different strains of human gut microbes with health-promoting (probiotic) properties to maximize their yield by fermentation and minimize production costs. Microbes tend to grow better when they are in a mixed population (co-culture) because they can share resources and are more resistant to pathogens. Co-culturing can also lower production costs. However, identifying the right mix is challenging as it depends on the properties of each strain and how they interact with other strains. To simplify this, they will build an algorithm that can be applied to any strain of interest. Metabolic and growth profiles will be collected from 10 probiotic strains grown under different conditions to determine their nutrient preferences. These profiles will be used to model the metabolic space occupied by each strain for identifying the combinations that maximize the potential for cross-feeding and minimize resource competition when grown under specified culture conditions. They will test their predictions by comparing biomass produced using the predicted combinations with random combinations and with strains grown on their own.
David Mills of the University of California, Davis in the U.S. will determine whether specific plant-based oligosaccharide formulations can drive mixed-culture growth of selected strains of intestinal bacteria for the low-cost and efficient production of live biotherapeutics. Microbial colonization in the human gut is important for overall health. It has been shown that oligosaccharides can provide a food niche to specifically enrich key colonizing bacteria, even in the competitive environment of the human gut. They will exploit this to grow multiple strains simultaneously in a controllable, scalable manner. They have recently developed analytical tools to characterize over 1,000 plant polysaccharides. These will be screened using bioinformatics methods and then in vitro to identify optimal oligosaccharide-therapeutic bacteria combinations that can support mixed-culture growth. They will then progress to bioreactor screening of the top candidate combinations. Once established, the live biotherapeutics will be formulated with their paired oligosaccharides for synbiotic application that may enable them to more readily colonize the human gut.