“The real voyage of discovery consists, not in seeking new landscapes, but in having new eyes."
Recent advances in the study of biomolecular condensates may hold the key to explaining some of the biggest open questions in biology, paving the way for a revolution in our understanding of cellular physics. At Dewpoint, we believe condensates are also the key to creating medicines to treat some of the biggest unmet medical needs.
The Conventional View of Biology and its Limitations
For decades our understanding of cell biology has focused on two key aspects. The first is an obsession with membrane bound organelles (such as mitochondria, lysosomes, and the endoplasmic reticulum) and their role in the organization of the key cellular functions. For example, the energy source of the cell is compartmentalized inside a mitochondrion. But this classical view has always been hard to reconcile with images that show cells to have large numbers of condensates that lack membranes and perform diverse functions. It has become increasingly clear in the last decade that a significant proportion of proteins and RNAs in a cell are located in distinct condensates, where they perform diverse functions.
The second assumption is that proteins, the machines of the cell, have well-defined and stable structures that perform their functions through changes in their conformation. However, these approaches have downplayed the 40% of the coding sequence that encodes segments of proteins called “intrinsically disordered regions” (IDRs). IDRs have been largely ignored because their structures cannot be trapped by conventional techniques, such as crystallography, which have traditionally been used to characterize protein structure.
Human genetics studies are increasingly pointing to critical roles of these IDRs in disease, and parallel work coming from physical chemistry and cell biology has shown that IDRs are also essential for condensate formation. The fusion of these two fields is rewriting the rules of cell biology and disease.
Biomolecular Condensates: Paving the Way Towards a New Paradigm in Cellular Function
Starting with the study of P granules in C.elegans embryos in 2009, Tony Hyman, working with his collaborators like Frank Julicher, Cliff Brangwynne, Simon Alberti, Mike Rosen, and Rohit Pappu, began to unravel the mysteries of biomolecular condensates. These scientists realized that P granules behave like liquid droplets that form by phase separation (think of oil droplets in salad dressing) and called them condensates.
In subsequent studies, they found to their surprise that many compartments inside cells had the behavior of condensates: they are liquid-like and form by phase separation.
Inspired by the work of Tony and his colleagues, Richard Young, Phillip Sharp, and Arup Chakraborty at MIT applied these approaches to the study of gene expression, similarly shedding light on many important questions in gene control.
Foundational Papers in Biomolecular Condensates
Biology, Meet Physics, and Let’s Make Great Medicines Together
The concept that cellular compartments are liquid-like and form by phase separation reaches back over a century ago to seminal advances in physical chemistry by Gibbs, Van ’t Hoff, and Oswald, among others. Physical chemistry describes the macroscopic properties of materials that emerge from atomic structures. However, with the dominance of organic chemistry, protein sciences, and the subsequent sequencing of the human genome, the focus for the past half century has been on describing and characterizing individual molecules and proteins. Hence, the question of how collections of molecules operate together was never really resolved. The work over the last decade describing condensates as liquid-like that form through phase separation paves the way to a much better understanding of a range of biological phenomena.
The physics underlying condensate behavior differs from the classical approaches to condensed matter formation. This is because cellular processes are complex and non-linear, typically operating out of equilibrium (see, for example, Zwicker, Hyman and Julicher (2015) Phys Rev E).
This confluence of biology and physics will revolutionize both fields. Dewpoint has assembled a diverse group of scientists, spanning biology, chemistry, physics, physical chemistry, mathematics, chemical engineering and drug discovery. Together, this team of researchers is advancing the field of biomolecular condensates and the study of their role in biology and disease.