With a Grand Challenges Explorations grant from the Bill & Melinda Gates Foundation, University of Wisconsin–Madison scientists Ophelia Venturelli and Brian Pfleger are working to further research on how to use human-associated intestinal microbes to combat malnutrition in developing countries.
Grand Challenges Explorations (GCE) supports innovative thinkers worldwide to explore ideas that can break the mold in how scientists solve persistent global health and development challenges. Venturelli and Pfleger’s project is one of approximately 50 Grand Challenges Explorations Round 22 grants announced by the Bill & Melinda Gates Foundation. Since the program’s launch in 2007, UW–Madison has been represented among nine of these projects, four of those being specifically from the Department of Biochemistry.
To receive funding, they and other Grand Challenges Explorations winners demonstrated in a two-page online application a bold idea in one of seven critical global heath and development topic areas. The title of their project is “Modeling of Microbial Community Dynamics to Enhance Ecological Stability and Growth.”
While the exact mechanisms have not yet been revealed, research shows there is a clear link between malnutrition and the composition, including the loss of diversity, of one’s gut microbiome, the communities of microbes that reside in the gut. This is where the Gates Foundation’s goals intersect with the expertise of Venturelli and Pfleger. A way to enhance the resilience of a person’s gut microbiome with a defined microbial community biotherapeutic — such as through a pill or food like yogurt — could help alleviate malnutrition.
The three aim's of the research team. They will utilize community dynamic
modeling, ecological principles, and bioreactor design to optimize community
stability and growth. Image courtesy of Ophelia Venturelli.
“A major challenge is how to manufacture defined communities with a desired composition and total yield at a large scale,” says Venturelli, a biochemistry professor and the project’s principle investigator. “Currently the biomanufacturing process for live biotherapeutic products (LBP) requires a separate culture for each organism in the consortium and then the strains are mixed together to produce the LBP. This procedure is not scalable to larger communities due to cost and complexity.”
It’s this manufacturing piece that is key. Bacteria are tricky to mass produce in diverse communities because they outcompete each other quickly. Traditionally they are grown up in large vats called bioreactors in big batches of just one species. However, this would be expensive to do for 50, 100, or especially 1000 species that might be necessary.
The scientists believe the secret lies in ecological principles and predictive modeling that exploit diversity-promoting microbial interactions and disparate environmental niches to enhance the growth and ecological stability of the community.
“We will manipulate temporal and spatial parameters to promote the growth and diversity of the community,” Venturelli says. “The challenge is how can we leverage kinetic modeling to inform the temporal and spatial inputs used to achieve a desired community composition.”
One aspect that complicates growing gut bacteria together is that they are anaerobic, meaning they can’t grow or do not grow well in the presence of oxygen. They also interact in other ways by competing for resources like space and nutrients and even, for example, by producing toxins that kill their neighbors.
Venturelli and Pfleger’s challenge is keeping the peace in this complex bacterial soup. They believe that by introducing heterogeneity into the culture could accomplish this. For example, could different oxygen, temperature, or nutrient zones in the bioreactor facilitate the growth of bacteria occupying different and non-overlapping niches? During growth, the bioreactors are stirred and one avenue they are exploring is how strategic mixing or spatial gradients could help set up and maintain this heterogeneity.
Venturelli’s research focus is on microbial networks and modeling, while Pfleger’s lab in the Department of Chemical and Biological Engineering works with engineering and using bioreactors.
“We are using ecological principles and modeling to try to predict the conditions by which we can enhance the stability of the community,” she explains. “For example, the temporal feeding pattern and order of introduction of organisms in the culture are parameters that can be manipulated to maximize community diversity.”
Phase one of the grant gives the labs $100 thousand for 18 months to fund students and supplies that help gather preliminary data. They’ll then apply for significantly more funds in phase two. Venturelli says that their work will also allow a deeper understanding of microbial community stability that can inform the design of therapeutics for various diseases.
“We want to try to start tackling the malnutrition problem with the help of the Gates Foundation and have identified that defined and highly diverse consortia of human-intestinal bacteria could provide a novel therapeutic approach,” she says. “They are helping us explore new methods and technology that could allow a reproducible and robust pipeline for growing complex consortia.”
Read more about Venturelli's research in the UW–Madison Department of Biochemistry: