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

We are interested in 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. Finally, we have developed a practical strategy to integrate large protein-coding cassettes into the human genome creating a toolbox to manipulate and measure protein abundances proteome-wide and PPIs, in any dividing mammalian cell type; methods that will democratize protein biology.

Further Reading
  • Michnick, S. W., Ear, P. H., Manderson, E. N., Remy, I. & Stefan, E. Universal strategies in research and drug discovery based on protein-fragment complementation assays. Nat Rev Drug Discov 6, 569-582 (2007).
  • Remy, I., Wilson, I. & Michnick, S. Erythropoietin receptor activation by a ligand-induced conformation change. Science (New York, NY) 283, 990-993 (1999).
  • Remy, I., Montmarquette, A. & Michnick, S. W. PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat Cell Biol 6, 358-365 (2004).
  • Malleshaiah, M. K., Shahrezaei, V., Swain, P. S. & Michnick, S. W. The scaffold protein Ste5 directly controls a switch-like mating decision in yeast. Nature 465, 101-105 (2010).
  • Messier, V., Zenklusen, D. & Michnick, S. W. A nutrient-responsive pathway that determines M phase timing through control of B-cyclin mRNA stability. Cell 153, 1080-1093 (2013). https://doi.org:10.1016/j.cell.2013.04.035
  • Stynen, B. et al. Changes of Cell Biochemical States Are Revealed in Protein Homomeric Complex Dynamics. Cell 175, 1418-1429 e1419 (2018). https://doi.org:10.1016/j.cell.2018.09.050
  • Karimi, M., Saber, M., Gauthier, L., Serohijos, A. W. & Michnick, S. W. A strategy for genome-wide seamless tagging of endogenous human protein-coding genes. Nature Biotechnology in revision (2023).


Morphogenic Functions of Biomolecular Condensates


Biomolecular condensates are recently discovered bodies in cells that form through phase separation of proteins and nucleic acids. These represent a new organizing principle in biology. In 2017 we first reported 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. We also demonstrated that chromatin phase separates, mediating the movement of active gene loci and the stability of the genome. 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.

Further Reading
  • Ravindran, R., Bacellar, I.O.L., Castellanos-Girouard, X., Wahba, H.M., Zhang, Z., Omichinski, J.G., Kisley, L., and Michnick, S.W. (2023). Peroxisome biogenesis initiated by protein phase separation. Nature 617, 608-615. 10.1038/s41586-023-06044-1.
  • Bergeron-Sandoval, L. P. et al. Endocytic proteins with prion-like domains form viscoelastic condensates that enable membrane remodeling. Proc Natl Acad Sci U S A 118 (2021). https://doi.org:10.1073/pnas.2113789118
  • Bergeron-Sandoval, L. P. & Michnick, S. W. Mechanics, Structure and Function of Biopolymer Condensates. J Mol Biol 430, 4754-4761 (2018). https://doi.org:10.1016/j.jmb.2018.06.023
  • Bergeron-Sandoval, L.-P., Safaee, N. & Michnick, S. W. Mechanisms and Consequences of Macromolecular Phase Separation. Cell 165, 1067-1079 (2016). https://doi.org:10.1016/j.cell.2016.05.026
  • González, L. et al. Adaptive partitioning of a gene locus to the nuclear envelope in Saccharomyces cerevisiae is driven by polymer-polymer phase separation. Nature Communications 14, 1135 (2023). https://doi.org:10.1038/s41467-023-36391-6
  • González, L. & Michnick, S. W. Retro-evolutionary engineering of budding yeast chromatin stabilizes its genome. in revision (2023)

Network medicine

A new endeavor for us, we are exploring two approaches to network rewiring as therapeutic strategies. First, we are collaborating with Dev Sidhu’s group, who have devised ingenious strategies to engineer multivalent multi-target specific antibodies, to develop these molecules towards drug candidates. We are testing these molecules in cell-based assays for their ability to block or activate signalling networks, which in combination can produce a desired outcome, such as inhibit the growth of cancer or activate proliferation of red blood cells. We are also exploring the possibility that the multivalency of these antibodies may cause phase separation of cell surface receptor, resulting in effects greater than the sum of expected responses we would predict.

Another approach to network medicine that has arisen recently is chemically induced proximity (CIP) where small molecules drive unnatural interactions between a protein target and another cellular protein in such a way that the activity of the target is blocked. We’ve developed a strategy to identify potential protein targets for CIP across the proteome and we are specifically using this approach to identify unforeseen targets for inhibiting cancer cell growth.