While much is known about the parts of the cell that have membranes, such as the nucleus, more mysterious are the biomolecular condensates that collect and organize molecules without them. These condensates concentrate specific collections of proteins, RNAs and small molecules into discrete compartments to promote diverse processes; defective condensates play a role in neurodegeneration, cancer and viral infection.
A group of scientists at The University of Texas Southwestern Medical Center have been studying how these thousands of molecular processes in cells are organized in space and time, a central problem in biology, from their different research perspectives. Some four years ago, they started a monthly “condensate club” to compare notes. Now, thanks to the Welch Catalyst Grant, the group has created a broader multidisciplinary platform to advance this work, involving both experimental and computational approaches.
Principal investigator Mike Rosen explained, “Our goal is to explore how the 30 different types of condensates in a cell achieve specificity, which is needed for control of diverse functions such as transcription, cell division and DNA replication, among others. This is a complex challenge, and the best experimentation isn’t enough; we need computational analysis leveraging AI (artificial intelligence) and machine learning.”
Dr. Rosen is a founder of the field of biomolecular condensates and an expert in analyses of protein and small molecule partitioning into condensate. His lab is biochemically reconstituting condensates and developing high-throughput screens to see which proteins are enriched in them and learn whether patterns of small molecules partitioning can be used to characterize condensates. His findings provide information for the other Catalyst Grant team members’ research into the biology of the condensates.
On the computational front, Assistant Professor Qian Cong brings her expertise in machine learning-based prediction of protein-protein interactions and bioinformatics to the team. While condensates are a new area for her, Dr. Cong says the Welch grant has “catalyzed” her work. She is using an evolutionary lens to delve into how protein-protein interactions define condensate compositions.
Matthew Parker, assistant professor of biophysics, is applying both experimental and computational approaches to study what he calls “non-random conversations” taking place among many proteins. His goal is to determine if this “gibberish” is interpretable and, if so, to decode it to understand how it mediates the process of DNA replication.
Benjamin Sabari is an expert in mechanisms of gene activation and condensate-regulated transcription. The assistant professor is studying intrinsically disordered regions of proteins to learn how they assemble to regulate transcription. He is interested in how the different groups cooperate at the same time and in the same space, hypothesizing they must be able to communicate.
Rounding out the team is Assistant Professor Jeffrey Woodruff, an expert in chemical crosslinking and reconstitution of coiled-coil regions of proteins in the pericentriolar material (PCM), the outermost layer of centrosomes, which control DNA segregation in mitosis. While other team members are looking at how condensates are distinguished from one another, Dr. Woodruff’s focus is on how protein-protein interactions occur within condensates. He is using biochemical techniques to map how condensate proteins bind with each other to determine how they produce the PCM.
Condensate functions are defined by the specific collections of molecules within the condensates and the internal physicochemical environment the components produce. The team has two primary objectives: to crack the condensate specificity code and define how composition and physicochemical properties control reactions. Ultimately, their goal is to determine the sequence, chemical and physical features underlying condensate compositions and functions, and advance understanding of condensate-controlled chemistry across scales, from atoms to cells.
“The Welch Foundation has long been a terrific partner in UT Southwestern’s chemical research,” said Dr. Rosen. “The new Catalyst Grant is an amazing resource for cross-disciplinary investigations into important and complex issues. For our team, it is providing the glue to bring together outstanding scientists to address fundamental chemical questions in biochemistry through development of new experimental and computational tools, yielding a whole that is truly greater than the sum of its parts.”