Research

Yeast (S. cerevisiae) cell membrane visualized by some membrane proteins fused with RFP and GFP fluorescent markers. Imposition of light from both of markers results in yellow colour. Author:Masur

Cellular pH Homeostasis

Our lab focuses on understanding how changes in the balance of pH (acidity and alkalinity) within cells impact their function and survival, and how these changes can influence aging and age-associated diseases. We predominantly leverage Saccharomyces cerevisiae (yeast) as a model eukaryotic organism, and yeast have been used to uncover many fundamental aspects of molecular and cellular biology (e.g., cell cycle, transcription, telomerase, vesicular trafficking, autophagy).  

 

Innovative Teaching Lab Design

We also create innovative laboratory course curricula that immerse the next generation of researchers in real scientific discovery, encouraging them to develop and investigate scientific questions with unknown answers.

Homeostasis and Aging

Astonishingly, there are evolutionarily conserved pathways that be manipulated to increase lifespan, from yeast to mammals. By studying aging in model organisms such as yeast, we seek to learn about the fundamental molecular mechanisms that contribute to how cells change with age, in order to support longer-term research that will identify therapeutic targets to treat age-associated diseases.  

We are also developing yeast-based systems to identify novel compounds that can influence molecular pathways associated with aging.

Rare Diseases

Most research funding is allocated to studying common diseases. Our lab works to model suspected human rare disease-causing mutations in the simple eukaryotic model organism, yeast. This allows for a cost-effective system to with powerful genetic tools and biological screening mechanisms that allow for unbiased and rapid discovery. Yeast share many biological processes with humans, making it easier to study genetic mutations. When a clinical mutation suspected of causing a rare disease is evolutionarily conserved, we use CRISPR to alter the yeast genome to model the mutation, and then perform targeted assays to uncover fundamental biological knowledge about the understudied disease. Some areas of current ongoing research include the study of mutations in mTOR (a key regulator of cell growth and metabolism), distal tubular renal acidosis (the V-ATPase), and porphyria (caused by mutations in heme biosynthesis).

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Recent Publications

  • Breen, Anna K, Sarah Thomas, David Beckett, Matthew Agsalud, Graham Gingras, Judd Williams, and Brian M Wasko. (2025) 2025. “An MTOR Inhibitor Discovery System Using Drug-Sensitized Yeast.”. GeroScience. https://doi.org/10.1007/s11357-025-01534-8.
    Publisher's Version

    Inhibition of the target of rapamycin (TOR/mTOR) protein kinase by the drug rapamycin extends lifespan and health span across diverse species. However, rapamycin has potential off-target and side effects that warrant the discovery of additional TOR inhibitors. TOR was initially discovered in Saccharomyces cerevisiae (yeast) which contains two TOR paralogs, TOR1 and TOR2. Yeast lacking functional Tor1 are viable but are hypersensitive to growth inhibition by TORC1 inhibitors, which is a property of yeast that can be exploited to identify TOR inhibitors. Additionally, yeast lacking FK506-sensitive proline rotamase (FPR1) or containing a tor1-1 allele (a mutation in the Fpr1-rapamycin binding domain of Tor1) are robustly and selectively resistant to rapamycin and analogs that allosterically inhibit TOR activity via an FPR1-dependent mechanism. To facilitate the identification of TOR inhibitors, we generated a panel of yeast strains with mutations in TOR pathway genes combined with the removal of 12 additional genes involved in drug efflux. This creates a drug-sensitive strain background that can sensitively and effectively identify TOR inhibitors. In a wild-type yeast strain background, 25 µM of Torin1 and 100 µM of GSK2126458 (omipalisib) are necessary to observe TOR1-dependent growth inhibition by these known TOR inhibitors. In contrast, 100 nM Torin1 and 500 nM GSK2126458 (omipalisib) are sufficient to identify TOR1-dependent growth inhibition in the drug-sensitized background. This represents a 200-fold and 250-fold increase in detection sensitivity for Torin1 and GSK2126458, respectively. Additionally, for the TOR inhibitor AZD8055, the drug-sensitive system resolves that the compound results in TOR1-dependent growth sensitivity at 100 µM, whereas no growth inhibition is observed in a wild-type yeast strain background. Our platform also identifies the caffeine analog aminophylline as a TOR1-dependent growth inhibitor via selective tor1 growth sensitivity. We also tested nebivolol, isoliquiritigenin, canagliflozin, withaferin A, ganoderic acid A, and taurine and found no evidence for TOR inhibition using our yeast growth-based model. Our results demonstrate that this system is highly effective at identifying compounds that inhibit the TOR pathway. It offers a rapid, cost-efficient, and sensitive tool for drug discovery, with the potential to expedite the identification of new TOR inhibitors that could serve as geroprotective and/or anti-cancer agents.