Professor of Ecology and Evolutionary Biology Nina Fefferman became a mathematician because she loves puzzles. She's just been awarded $18 million from the U.S. National Science Foundation to solve one puzzle that has the potential to change the world: how, when and why an infection in a population will spread, or cause an epidemic or pandemic, rather than dying out.

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Fefferman, director of the National Institute for Modeling Biological Systems and associate director of the UT One Health Initiative at the University of Tennessee, Knoxville, has secured the funding to launch the NSF Center for Analysis and Prediction of Pandemic Expansion (NSF APPEX) in the fall. The multidisciplinary center will focus on identifying the factors that constitute a "perfect storm" for the spread of infection across populations as well as ways humans can prevent or mitigate these threats.

"A lot of pandemic research is immunology and virology, work that happens in medical schools, but that's only two parts among the very many parts that come together to create a pandemic," said Fefferman, who has worked in pandemic preparedness for 20 years. "Think about it: A very small portion of an epidemic is what is happening inside one person. Public health is about changing the lives of an entire population."

The individual pieces of this puzzle could include the built environment, economic resources, media, safety systems engineering, social networks and surveillance along with other fields such as ecology, health care, immunology, pharmaceuticals and virology.

"That's the point of bringing together a multidisciplinary team of researchers - to gain a globally better understanding of how to interrupt the spread of infection so we help people before they ever get sick," Fefferman said. "Solving the puzzles you can't possibly solve by yourself - those are the most fun puzzles. This kind of work allows us to take each other's blindfolds off."

The seven-year $18 million grant builds on funding NSF awarded to Fefferman and her co-principal investigators in 2022. That Phase I award, Predicting Emergence in Multidisciplinary Pandemic Tipping-points, or NSF PREEMPT, brought together researchers from 17 different academic disciplines to collaborate on a common problem and see if they could accelerate scientific progress.

"It was a breakneck pace, but we proved it could be done, and the most valuable takeaway is that what came out of it was different than what would have happened if we all worked solely in our own disciplines," Fefferman said of the 18-month $1 million project. "There was a realization of 'Wow, this is not what I would have been doing at all.' It was great to work with people who were excited to do something outside their native areas."

This approach is not new to UT, which recognizes the inherent value of using creative collisions between disciplines for discovery and problem-solving. The university's commitment to perspectives and partnerships that stretch thinking in every direction is the foundation of UT's five innovation gateways, which convene experts, facilities and resources to tackle complex challenges.

Fefferman's proposal for the new center will expand the multidisciplinary group of researchers from NSF PREEMPT and add members from government, industry and nongovernmental organizations to those from academia. Their focal issue will be identifying the human-driven factors that constitute ideal conditions for pandemic expansion. They will restrict their considerations to the period after the emergence of a pathogen and the ways in which human activities shape and alter the environment in which the pathogen will either die out or spread and cause havoc.

Researchers at NSF APPEX will shift the way they think about pandemics, moving from the focus of traditional outbreak investigations on place- and context-dependent factors. They will instead use a case-control framework, widely employed in medical research, to test hypotheses about the conditions that could be associated with an outbreak. Researchers will be working to identify what they call minimally sufficient sets of conditions that lead to an outbreak. For a set to be considered minimally sufficient, the exclusion of any factor within the set must change the outcome from outbreak expansion to outbreak die-out.

Fefferman will stay on as both the principal investigator for NSF APPEX and director of the center. She is joined by co-principal investigators Lydia Bourouiba, a fluid and mathematical physicist at Massachusetts Institute of Technology; K. Selcuk Candan, a computer scientist at Arizona State University; Sadie Ryan, a medical geographer at the University of Florida; and Shelby Wilson, a mathematician at the Johns Hopkins University Applied Physics Laboratory. The project also involves Clinical Associate Professor Elizabeth Strand of UT's College of Veterinary Medicine, serving as consilience coordinator, and at least 80 other researchers in addition to postdoctoral staff and graduate students.

"I'm pinching myself that we get to do this unique and special work that will not just shape pandemic science but will shape the way we do multidisciplinary science," Fefferman said.

NSF APPEX will go beyond research to translate advances into accessible policy recommendations that will help inform decision-makers, train the next generation of researchers and practitioners as native multidisciplinarians, and engage the public in how STEM research helps us understand, prepare for and even prevent pandemics.

"That's the thing about public health: If you do it right, the public doesn't know you're there," Fefferman said. "If you do it right, it's easy to forget you ever needed it in the first place."

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