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. This 1903 drawing by Santiago Ramón y Cajal, for instance, depicts pyramidal neurons with visible Cajal bodies (a), nucleoli (b), and speckles (c). 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 percent of the coding sequence that encodes segments of proteins called “intrinsically disordered regions” (IDRs). IDRs have been understudied, largely because their structures cannot easily 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.
A new approach to biology
“The real voyage of discovery consists, not in seeking new landscapes, but in having new eyes.” Marcel Proust
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.
Condensates play a critical role in important, once-intractable diseases. Dewpoint develops drugs that exploit this biology.
Case Study: Neurodegeneration
Many of the proteins associated with neurodegenerative diseases are found in condensates called stress granules. Normally, stress granules are spherical and liquid, but disease-associated mutations can cause the granules to look and behave very differently, interfering with normal cell function. We have developed screening techniques that allowed us to identify small-molecule compounds that restore the normal behavior of stress granule condensates. Dewpoint is conducting high-throughput screens to identify more of these promising molecules.
Phase transition and ALS
Dewpoint is building proprietary tools for purposefully exploiting condensates to treat the most important diseases that patients face. If you would like to learn more about our platform please contact us.