Scouring Nature for the Building Blocks of Biomedical Condensates
By Ken Kingery
Cross-campus collaboration seeks to discover naturally occurring biological condensates, like drops of oil forming in water, to engineer new therapeutics
Duke Engineering launched the Beyond the Horizon initiative to provide interdisciplinary teams with substantial investment to begin pursuing extremely high-risk, high-reward projects that have the potential for deep, transformative societal impact. Six proposals were selected for an initial round of funding that will play key roles in shaping Duke Engineering’s future research and teaching profile. Each plays to the school’s unique strengths and hold the promise of helping to define the future of their respective fields.
Biological condensates are small compartments that cells can build to either separate or trap together certain proteins and molecules, either hindering or promoting their activity. Rather than relying on physical boundaries like a cellular membrane, these compartments emerge due to differences in relative densities, like oil forming droplets in a vinegarette. These “oil droplets” form due to the properties of the “floppy” disordered proteins that group together.
Researchers are just beginning to understand how condensates work and what they could be used for, but one thing is clear: they’re important pieces of the biological puzzle. One of the major challenges to teasing out their various natural functions—and harnessing their abilities to suit our own purposes—is the field’s sheer newness.
“We’re focusing on exploring plants and fungi because they can’t walk from one place to another when times get tough. They have to adapt to their surroundings, so they’re more likely to have more tools in their evolutionary arsenal.”
Because they were only discovered in 2009, scientists have yet to explore the wide range of approaches life has found to create these compartments and evolve uses for their properties. This relative nativity also means that researchers have few examples to draw from when creating their own artificial versions for biomedical applications.
The Beyond the Horizon “Bioinspired design of thermoresponsive condensates” project seeks to change that.
“We want to build an entire library of biological condensates engineered from examples found in nature,” said Amy Gladfelter, professor of cell biology in Duke’s School of Medicine. “We’re focusing on exploring plants and fungi because they can’t walk from one place to another when times get tough. They have to adapt to their surroundings, so they’re more likely to have more tools in their evolutionary arsenal.”
Joining Gladfelter in this endeavor as a co-principal investigator is Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering, whose lab has experience developing bespoke, synthetic versions of biological condensates. Also working with the team is Lucia Strader, professor of biology, who has worked extensively with plant condensates.
“The design space is so limited now, we’re just beginning to understand what might be possible for the field.”
Together, the trio will begin a bioinformatics quest to find the genetic sequences that encode biological condensates in plants and fungi that live in extreme environments. They hope to find a wide range of examples that form and dissipate in response to different types of conditions such as temperature and pH, or that form out of RNA structures rather than protein structures. This will provide a large library of natural genetic sequences to inspire the engineering of simpler synthetic versions that feature these custom abilities.
The researchers plan to then begin applying these newfound tools to existing industrial processes that rely on microbes. For example, certain synthetic biological condensates could amplify or protect the activity of yeast used in biosynthesis processes. Or they could engineer yeast used in fermentation that could cope with saltwater surroundings.
Their findings could have biomedical implications as well. For example, Chilkoti’s group has already demonstrated that it can form artificial organelles to control cellular behavior using the same approach.
“This project will rely heavily on a lot of basic science work to start with, but the applications we predict it could extend to are almost limitless,” Chilkoti said. “The design space is so limited now, we’re just beginning to understand what might be possible for the field.”