UPDATE FROM KEYSTONE:

– RESCHEDULING IN PROGRESS –

Liquid-liquid phase separation (LLPS) has recently emerged as a fundamental strategy for organizing cellular contents and regulating biological processes. Indeed, LLPS has been revealed to regulate a staggering array of cellular activities, including aspects of DNA replication, transcription, DNA repair, RNA metabolism, receptor signaling, synapse formation, and more. In cells, LLPS leads to the assembly of biomolecular condensates that span a vast range of sizes and complexities, from nanometer-scale structures composed of a few peptide chains, such as the nucleosome core, to micron-scale structures composed of thousands of biomolecules, such as the pre- and post-synaptic compartments of neurons. Our understanding of the molecular basis for biological phase transitions and how this phenomenon regulates cell biology has deepened, but fundamental questions remain regarding the nature and function of these condensates, including how their molecular identities are established and maintained, how their material properties are controlled, how their assembly and disassembly relate to emergent biological functions, and how disturbances in their biophysical properties contribute to disease such as neurodegeneration and cancer. Here we propose a second meeting on this topic that brings together leading scientists from diverse areas impacted by phase separation to clarify the current state of knowledge in this exciting new field and identify a path forward to fully illuminate this new paradigm in cellular organization.

SIGNIFICANCE: It is increasingly appreciated that disturbance of biological phase transitions is a primary driver of disease. This is most notable in neurodegeneration (where ALS-causing missense mutations are located in intrinsically disordered protein segments and impair LLPS) and cancer (where translocations of intrinsically disordered protein segments to heterologous proteins drive aberrant LLPS to cause sarcomas). This meeting will prioritize fundamental unanswered questions regarding the nature and function of biomolecular condensates. Specifically, how are the molecular identities of distinct condensates established and maintained? How are their material properties controlled? How do these structures influence emergent biological functions? How do disturbances in their biophysical properties contribute to disease such as neurodegeneration and cancer? Understanding biomolecular condensates is a big problem that requires input from an unusually broad set of disciplines, including theorists in polymer chemistry, biophysicists, structural biologists, cell and molecular biologists, and disease biologists. The primary goals of this meeting are to: (1) address the most significant gaps in knowledge identified above, (2) assemble a cross-section of experts from different disciplines to think deeply together about a common problem, (3) introduce technological advances to the broad community studying biomolecular condensates, and (4) provide an entry point for investigators new to this field or interested in joining the field. This field is moving very, very quickly and we anticipate that the primary outcome of the meeting will be rapid dissemination of new scientific insights, conceptual advances, and technological breakthroughs to the community. Examples of recent technological breakthroughs include cryoEM tomography of condensates and optogenetic control of condensation.

INNOVATION: This meeting (held in odd years) will represent the single most important meeting on this topic in the United States, and will draw speakers and attendees not only from North America, but extensively from Asia, Europe, and to a lesser extent the Middle East and the other Americas. The only comparable meeting (held in even years) is an EMBO conference and is located in Heidelberg, Germany. These two meetings have been coordinated such that there is one major meeting per year on the biology of phase transitions, alternating each year between the United States and Europe. This is a new and rapidly moving field. Liquid-liquid phase separation (LLPS) has only recently become appreciated as a pervasive and fundamental strategy for organizing cellular contents and regulating biological processes. As stated above, LLPS has been revealed to regulate a staggering and rapidly expanding array of cellular activities, including aspects of DNA replication, transcription, DNA repair, RNA metabolism, receptor signaling, synapse formation, and more. Discoveries in this field are regularly generating paradigmatic shifts in how we think cells work, how certain diseases arise, and how one might intervene in these diseases. This field is also driving technological innovations, including novel imaging approaches, biophysical approaches, and optogenetic approaches. Among the most daunting but also exciting challenges in this field is the fact that understanding biomolecular condensates is such a big, complex problem that requires input from an unusually broad set of disciplines, including theorists in polymer chemistry, biophysicists, structural biologists, cell and molecular biologists, and disease biologists. A major goal of this meeting is convening this broad expertise in one place to discuss the common problem. This meeting could synergize with meetings from a number of complementary fields, for example RNA biology, where we have learned that phase separation plays a frequent and critical regulatory role. Provides the opportunity for consensus to emerge on key questions, such as the molecular basis for establishing identity of biomolecular condensates, the validity of the scaffold/client model, the mechanisms controlling material properties of condensates, and others.