UChicago Team Secures $7.4 Million Grant to Study Cellular Adaptation

Cells use a variety of processes to adapt to changes and stressors in their environment, like increased temperature. When these processes go awry, causing proteins to misfold or clump together, it can contribute to a wide range of diseases and accelerate aging.

A team led by scientists at the University of Chicago recently received a $7.4 million, five-year grant from the National Institute of General Medical Sciences, a division of the National Institutes of Health, to study these fundamental, adaptive processes. The research team brings together expertise from the Biological Sciences Division (BSD), Pritzker School of Molecular Engineering (PME), and Department of Physics at UChicago, along with partners from Northwestern University.

This multidisciplinary group will launch the Cellular Adaptation Lab to study how cells respond at different time scales, from changing protein locations within milliseconds and adjusting gene activity over days to passing along adaptations to new generations years in the future. Through this collaborative, multiscale approach, they hope to build a unified framework that reshapes our understanding of cellular adaptation in aging, cancer, neurodegeneration, and stress responses driven by climate change.

If we better understand how adaptation works in healthy cells, we can also learn about the different ways it can break down in aging or be usurped in cancer. And to understand how climate change affects the global ecosystem, we must first understand how organisms are coping with changes in temperature, nutrient availability, or pH in their environment as the planet warms."

David Pincus, PhD, Assistant Professor of Molecular Genetics and Cell Biology and principal investigator (PI) on the new grant

A Launchpad for Team Science

Pincus studies these cellular processes in his own lab, including the "heat shock response," a classic model of biological survival that allows cells to shut down their normal machinery to ride out high temperatures. One of these adaptive processes involves aggregating proteins into liquid-like condensates to protect them from damage, and then dispersing them in an orderly manner when the temperature returns to normal. In 2023, he and his team used new imaging techniques to peer inside these condensates and see how they are formed and managed.

Pincus is joined by four others who will serve as PIs for the Cellular Adaptation Lab:

• Anindita "Oni" Basu, PhD, Associate Professor of Medicine at UChicago, specializes in single cell sequencing techniques that can measure gene expression one cell at a time, and works to understand mechanical forces that shape the structure and surfaces of microbial environments.
• Madhav Mani, PhD, Associate Professor of Engineering Sciences and Applied Mathematics at Northwestern, is a mathematician who will build machine learning models to interpret the enormous amounts of experimental data generated in the Lab to bridge cell biology and genomics.
• Scott Oakes, MD, Professor of Pathology at UChicago, focuses on how mammalian cells adapt or self-destruct in response to damage and what goes wrong with this process in cancer and neurodegenerative diseases, adding a translational perspective to the team.
• Allison Squires, PhD, the Neubauer Family Assistant Professor of Molecular Engineering at UChicago, is a leading expert in single molecular analysis of condensates that form under cellular stress, studying their biophysical properties and how they are regulated.

This group of five primary PIs is joined by three auxiliary researchers:

• Allan Drummond, PhD, Associate Professor of Biochemistry & Molecular Biology and Medicine at UChicago, who has pioneered work on the adaptive nature of cellular stress responses and condensates.
• Arvind Murugan, PhD, Associate Professor of Physics at UChicago, who studies the physics of evolution and what properties of systems help them become self-sustaining.
• Arjun Raman, MD, PhD, Assistant Professor of Pathology at UChicago, a systems biologist who will provide expertise on working with large genomic datasets.

The Lab will also have a three-member senior advisory board featuring Richard Morimoto, PhD, Professor of Molecular Biosciences at Northwestern; Rama Ranganathan, PhD, the Joseph Regenstein Professor in the Department of Biochemistry & Molecular Biology and the PME at UChicago; and Jack Szostak, PhD, Nobel Laureate and University Professor of Chemistry at UChicago.

Convening such a large and varied research team was no small feat. Many of the brainstorming sessions were convened by Ranganathan, who heads the Center for Physics of Evolving Systems at UChicago, a scientific launchpad for several members of the team. These early discussions prompted research questions and incubated ideas for the new Lab.

Applying for an RM1 grant with such a complex cast is also a Herculean feat, and the team received significant support in this process from the BSD's Research Development Team (RDT). Launched in 2023, the RDT provides support for faculty submitting large-scale, interdisciplinary and collaborative research proposals, meant to lower the administrative burden of these submissions so researchers can focus on the science in the proposals. Research Development Specialist Crystal Love, PhD, worked with Pincus and the team to refine their ideas, shape the proposal into a compelling narrative, and manage the sheer bureaucratic logistics and paperwork. The Cellular Adaptation Lab RM1 is the first successfully funded proposal supported by the RDT.

"This is a massive amount of work to put together a proposal like this. It's not easy to pull off," said Oakes, who is also the Vice Dean of Clinical Science Research in the BSD. "This kind of support is critical if you want to encourage more faculty to write these big team science applications. It tells you the institution is invested in helping us do this, and it speaks volumes for how important team science is at UChicago."

Expecting the Unexpected

In the near term, the Lab will focus on building technology to serve as platforms for later conceptual and experimental work. One new tool is a high-throughput sequencing technique called "cond-n-seq" (clustered or otherwise non-diffuse protein sequencing) that will allow the team to identify biomolecular condensates in cells and describe their protein composition across a variety of environmental conditions. Another cleverly named sequencing tool, "hide-n-seq" (high density Luria-Delbruck fluctuation assay sequencing), will help identify genes involved in tuning the variation in a group of cells that gives them the ability to adapt.

After using these tools and other techniques to begin building models and theories about adaptation in simple cellular systems like yeast, the team will be able to apply their learnings to more complex organisms and, eventually, human tissues and disease states.

"The most exciting thing is we can expect the unexpected. We know we're going to discover new stuff and we don't know everything right now," Pincus said. "This lab has legs to become a core expertise at the University of Chicago, so that in coming years, when people think about cellular stress response, adaptation, and the physics of evolution, they're going to think of us."