The Center for Biomolecular Condensates launch kicked off with an inaugural symposium Oct. 14, highlighted by the Condensates Colloquium Series. Rohit Pappu, the Gene K. Beare Distinguished Professor of Engineering and director of the Center, said the Center, housed within the McKelvey School of Engineering at Washington University in St. Louis, is the first of its kind, with biomolecular condensates being crucial to future breakthroughs.
The molecules of life — DNA, RNA and proteins — are organized into distinct molecular communities known as biomolecular condensates. As the name implies, the organization arises from physical processes that involve the condensing of the right type of molecules at the right locations. This condensation reaction separates the key molecules into distinct condensates through a process known as phase separation. Biomolecular condensates are everywhere in cells, and they are distinct from one another. Appreciation of the importance of the physics of phase separation has transformed how we think about cellular organization, cellular mechanics, cellular responses and cell physiology. The dysregulation of condensates through aberrant phase separation underlies proliferative diseases such as cancers and degenerative illnesses such as ALS, Parkinson’s, Alzheimer's and Huntington's diseases.
“A key mission of the Center for Biomolecular Condensates is to develop technologies, uncover the relevant physical principles and apply these to study and understand how condensates function in live cells,” Pappu said. “This is one of the more important topics in cell biology today and one that is attracting attention across disciplines.”
At the symposium, Pappu defined what he said is the current thinking for biomolecular condensates.
“They’re viscoelastic materials and network fluids that have a terminal viscous behavior in some cases but could have terminal elastic behavior in some other cases,” he said. “They form through segregative transitions we refer to as phase separation and associative phase transitions we refer to as percolation.”
Aaron Bobick, the James M. McKelvey professor and dean of the McKelvey School of Engineering, was on hand to welcome the Center’s launch.
“Cells are the mechanism and model [units] by which biology achieves a lot of its life science construction,” he said. “The question becomes what is the machinery that cells leverage? I think today is that day where that focus is achieved,” Bobick said.
Pappu introduced the center’s four themes: the physics and physical chemistry of spontaneous and driven phase transitions; attempting bottom-up reverse engineering of condensates; technologies to measure condensates structure and material properties; and the fourth, which, he said, will basically focus on making synthetic condensates.
Clifford Brangwynne, a co-recipient of the 2023 Breakthrough Prize for Life Sciences and a 2018 MacArthur Fellow, was one of the speakers at the symposium. His talk focused on phase separation within the nucleus. The mechanics and organization of the cell is impacting phase separation, he said, and, in turn, phase separation, specifically through capillary forces that can be generated by condensates, can impact the mechanics and organization of the genome.
Anthony Hyman, a co-recipient with Brangwynne of the Breakthrough Prize, spoke about Condensates in Cell Physiology & Disease. He closed his presentation by singling out areas that will dominate the next decade and which he says underscore the appropriateness of launching the Center for Biomolecular Condensates: active matter, molecular grammar, fluctuations and precision.
Michael Rosen, a co-recipient of the Wiley prize in Biomedical Sciences along with Brangwynne and Hyman, spoke about the emergent properties of condensates. His presentation highlighted the unique internal environments that are likely to aid in developing small molecule therapeutics and the repurposing of natural compounds that can target condensates to elicit desired therapeutic responses.
Among the other symposium speakers were Amy Gladfelter, professor of biology at the University of North Carolina at Chapel Hill; Tuomas Knowles, professor of physical chemistry and biophysics at the University of Cambridge; Lucia Strader, associate professor of biology at Duke University; and Helen McNeill, the Larry J. Shapiro and Carol-Ann Uetake-Shapiro Professor of Developmental Biology in the School of Medicine and a BJC Investigator.
Gladfelter mentioned problems related to the RNA physical code, include understanding 3D structures for large RNAs and the emergent behavior from mixing different RNAs of different lengths and different structures. Knowles said it’s becoming clear that there are fundamental connections between the solid state and the liquid state, his research efforts heavily focused on the solid phase of proteins. He said the research he’s participated in has been transformed from interactions with the community of those focused on the liquid state.
Pappu said that the symposium’s roster of dedicated and talented speakers was a reflection of the importance of the center’s subject matter.
At launch, the Center for Biomolecular Condensates Center members include:
- Yuna Ayala, associate professor of biochemistry & molecular biology, Saint Louis University School of Medicine, who focuses her lab on neurodegenerative disorders and was also a speaker at the symposium.
- Abhinav Diwan, professor of medicine, of cell biology and physiology, and of obstetrics & gynecology at the School of Medicine whose interests in condensates focus on protein quality control mechanisms in cardiac myocytes.
- Alex Holehouse, assistant professor of biochemistry and molecular biophysics at the School of Medicine, whose research focuses on the evolution and physical interactions of intrinsically disordered regions and how they affect cellular information processing. Holehouse also spoke at the symposium.
- Nathaniel Huebsch, assistant professor of biomedical engineering, who focuses on stem cell mechanobiology.
- Meredith Jackrel, assistant professor of chemistry, whose lab focuses on the role of aberrant phase separation on the onset and progression of ALS. Jackrel also spoke at the symposium.
- Matthew Lew, associate professor of electrical & systems engineering, who also spoke at the symposium. Lew’s lab develops state-of-the-art single molecule imaging methods that are being brought to bear for characterizing the internal structures of condensates.
- Helen McNeill, the Larry J. Shapiro and Carol-Ann Uetake-Shapiro Professor of Developmental Biology in the School of Medicine and BJC Investigator, studies how cells are organized into tissues, and is exploring the role of condensates in determining fertility.
- Dmitri Nusinow, associate member of the Donald Danforth Plant Sciences Center, who studies the role of condensates known as photobodies in controlling circadian rhythms in plants.
- Amit Pathak, associate professor of mechanical engineering & materials science whose research focuses on mechanobiology and the influence of mechanotransduction on the biochemical functions of condensates.
- Srikanth Singamaneni, the Lilian & E. Lisle Hughes Professor in mechanical engineering & materials science, whose lab is advancing the development and deployment of novel plasmonic devices and technologies for the study and engineering of condensates.
- Andrea Soranno, assistant professor of biochemistry & molecular biophysics at the School of Medicine and one of the speakers at the symposium, whose research leverages single molecule spectroscopies for the study of intrinsically disordered proteins and their phase behaviors.
- Michael Vahey, assistant professor of biomedical engineering, whose research focuses on enveloped viruses and the engagement of viruses with nuclear condensates.
“We’re creating an environment for trainees from around the world to spend time with us in the center,” Pappu said. “We are also working to find enabling intersections among labs within the center to seek multi-investigator proposals and identify synergies with kindred spirits within WashU. It’s not just about a collaboration of center members but centers and bodies globally and setting up strategic alliances with biotech companies, pharma companies and more.”
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An excerpt from Rohit Pappu’s presentation at the Oct. 14 symposium:
Cells are messy, crowded places, chock full of molecules, small and large. And yet cells provide high fidelity responses to cues telling them when to eat, when to move, where to move to, when to be quiet, when to divide, and even when they should go through programmed death. The signals generated by molecular networks are central to the cellular responses.”
However, for the longest time, it was not clear how cells generate the right signals and responses at the right locations at the right times within cells and across cells. It turns that the molecules of life, DNA, RNA, and proteins are organized into distinct molecular communities known as biomolecular condensates. As the name implies, the organization arises from physical processes that involve the condensing of the right type of molecules at the right locations. This condensation reaction separates the key molecules into distinct condensates through a process known as phase separation.
Biomolecular condensates are everywhere in cells, and they are distinct from one another. The cumulative response of a cell to a stimulus is determined by the dynamical and integrated responses of condensates that form via phase separation. Appreciation of the importance of the physics of phase separation has transformed how we think about cellular organization, cellular mechanics, cellular responses, and cell physiology. The dysregulation of condensates through aberrant phase separation underlies proliferative diseases such as cancers and degenerative illnesses such as ALS, Parkinson’s, Alzheimer's and Huntington's diseases. They also underlie developmental disorders such as autism.
A key mission of the Center for Biomolecular Condensates is to develop technologies, uncover the relevant physical principles and apply these to study and understand how condensates function in live cells. In addition to having a direct impact on the biomedical sciences, the work being pursued in the CBC will also have a direct impact on the development of novel sustainable technologies based on novel biomaterials. Further, plants and their symbiotic fungal systems use condensates for communication, adaptation, and survival. Being able to engineer novel condensates will help us engineer adaptive responses in plants as they adapt to unpredictable changes in climate and strive to survive with diminishing resources.