Research

Our mission is to understand the molecular organizing principles of living cells, how these result in spatiotemporal organization of matter that manifest cellular functions and how the principles can be exploited to discover novel medicines.

Protein networks as engines of discovery

Protein interaction networks and their dynamics, most accurately reflect how environment and genome affect cellular functions at a mechanistic level. We study the structure and dynamics of proteins networks and using this knowledge to explain the interactions of living cells with their genomes and environment. To do this we pioneered the principles of Protein-fragment Complementation Assays (PCA) to measure thermodynamics and spatiotemporal dynamics of protein-protein interactions in living cells. These have proved a powerful discovery engine in our studies of signal transduction, mechanisms in cell fate decisions, drug mechanisms of action and now, effects of genetic variation on cellular processes with our close collaborator Adrian Serohijos.

From protein networks to biomolecular condensates and morphogenesis

Our interest in protein interaction network let to our asking how networks physically look like and what could be the consequences of those organizations. Biomolecular condensates are recently discovered non-membranous that form through phase separation of proteins and nucleic acids. These represent a new organizing principle in biology. We discovered that biomolecular condensates can do work at their interfaces with other materials, including bending membranes in endocytosis and creating transient protein uptake channels in peroxisomes and controlling gene transcription and genome stability. Genome stabilization in yeast overcomes a major challenge in synthetic biology, enabling the stable integration of metabolic pathways for the biomanufacturing of useful products, such as fuels and medicines. Currently we are exploring more examples of condensates at work, including viral particle maturation and vesicle trafficking.

Protein network medicine

Disease can be thought of as pathological aberrations in protein interaction networks due to changes in expression of genes or mutations. Can such aberrations be corrected by rewiring the network? We already know that this is true because new medicines based on recombinant antibodies and small molecules the drive unnatural associations of proteins are the most rapidly growing families of drugs. Through collaboration with protein engineer Sachdev Sidhu and Ron Geyer, we are studying Multivalent-Multi-specific Antibodies (MV-MS Abs), that bind to multiple antigens on cancer or stem cells achieving enhanced efficacy, specificity and resistance to adaptation for applications in anti-cancer and regenerative medicine applications. We have also developed a screening method to identify candidate protein pairs for development of chemical inducers of protein dimerization or ‘molecular glues’ for targeting ‘undruggable’ proteins expressed in cancers.