Scientist profiles A-F

Administrative Assistant: Michael Le
Phone: 416-480-6100, ext. 85482
Email: michael.le@sri.utoronto.ca 

Education:

• B.Sc., 1979, biochemistry, University of Ottawa, Canada
• PhD, 1985, medical biophysics, University of Toronto, Canada
• Postdoctoral fellowship, 1988, cell physiology, University of California, San Francisco, U.S.

Appointments and Affiliations:

• Senior scientist, Biological Sciences (director), Odette Cancer Research Program, Sunnybrook Research Institute
• Professor, department of biochemistry, University of Toronto

Research Foci:

• Cancer research
• Molecular membrane biology
• High-content screening
• Automated image analysis
• Apoptosis

Research Summary:

Our research areas include cancer chemotherapy, the molecular mechanisms by which Bcl-2 family proteins regulate apoptosis, the assembly of proteins into the cellular membranes, high-content screening, early stage drug discovery, the development of new fluorescence microscopes and automated image analysis techniques.

We are studying the mechanisms by which the Bcl-2 family of proteins regulate selective programmed cell death (apoptosis) of cancer cells. We are particularly interested in determining how cells respond to chemotherapy drugs. The Bcl-2 family proteins that we study include those that initiate cell execution (Bax and Bak), as well as those that inhibit (Bcl-2, Bcl-XL, Mcl-1) or promote (Bim, Bid, Bad) the process. Our recent data indicate an unexpected role for binding to membranes in regulating how Bcl-2 family proteins interact with each other. We believe that by studying protein to protein interactions where they take place-in the membranes of live cells-we will be able to identify more effective therapies.

Examining protein to protein interaction is one of the most challenging areas of cell biology. To extend our analyses to live cells and to include measurements of the effects of drugs and drug candidates we have developed new approaches, instruments and software. With industrial partners we are developing new automated microscopes that provide both time and chromatic spectral data that we use to measure protein to protein interactions and to perform drug mechanism studies. These instruments generate data sets containing millions of images. In order to analyse these images we have written new machine learning software for image analysis and cell classification. Our current imaging techniques include automated fluorescence microscopy, fluorescence lifetime imaging, fluorescence correlation spectroscopy, single molecule imaging and hyperspectral imaging. Our imaging research recently culminated in the establishment of a new $9-million image-based screening facility at Sunnybrook Research Institute.

Selected Publications:

See current publications list at PubMed.

1. Pogmore JP, Uehling D, Andrews DW. Pharmacological Targeting of Executioner Proteins: Controlling Life and Death. J Med Chem. 2021 May 13;64(9):5276-5290.
2. Pemberton JM, Pogmore JP, Andrews DW. Neuronal cell life, death, and axonal degeneration as regulated by the BCL-2 family proteins. Cell Death Differ. 2021 Jan;28(1):108-122.
3. Bogner C, Kale J, Pogmore J, Chi X, Shamas-Din A, Fradin C, Leber B, Andrews DW. Allosteric Regulation of BH3 Proteins in Bcl-xL Complexes Enables Switch-like Activation of Bax. Mol Cell. 2020 Feb 20;77(4):901-912.e9.
4. Liu Q, Osterlund EJ, Chi X, Pogmore J, Leber B, Andrews DW. Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2. Elife. 2019 Mar 12;8:e37689.
5. Rapid 3D phenotypic analysis of neurons and organoids using data-driven cell segmentation-free machine learning. Mergenthaler P, Hariharan S, Pemberton JM, Lourenco C, Penn LZ, Andrews DW.PLoS Comput Biol. 2021 Feb 22;17(2):e1008630. doi: 10.1371/journal.pcbi.1008630. eCollection 2021 Feb.PMID: 33617523
6. Osterlund EJ, Hirmiz N, Pemberton JM, et al. Efficacy and specificity of inhibitors of BCL-2 family protein interactions assessed by affinity measurements in live cells. Science Advances. 2022;8(16):eabm7375. doi:doi:10.1126/sciadv.abm7375

Related News and Stories:

• The case for brakes: Why restrain the size of Bax and Bak pores in outer mitochondrial membranes? (Feb 22, 2022)
  Andrews DW.Mol Cell. 2022 Mar 3;82(5):882-883. doi: 10.1016/j.molcel.2022.02.022.PMID: 35245452
• Discovering how cancer might defy drug therapy: Scientists pinpoint protein-protein interaction as potential reason for treatment resistance (April 11, 2019)
• Manipulating the decision-makers of cell fate: Scientist at Sunnybrook Research Institute breaks new ground in chemical biology (Nov. 20, 2017)
• Personalizing therapies through imaging: Proof-of-principle study lays foundation for clinical trial in leukemia (July 11, 2016)
• Ask a scientist: "Talk about tough days: Your results didn’t pan out. You didn’t get the grant. What do you do to decompress after days like this?" (SRI Magazine, 2016)
• Canada Research Chair awarded to head biologist: Dr. David Andrews now a Tier 1 chairholder (Feb. 9, 2016)
• National agency recognizes scientific excellence at Sunnybrook Research Institute: Scientists score high with multimillion-dollar funding investment (Oct. 13, 2015)
• Field of view: Research day proclaims promise of image-guided medicine (Jan. 15, 2014)
• An incubator of medical innovation (The Globe and Mail, July 10, 2013)
• On target? The promise and challenges of molecular therapies (SRI Magazine, 2012)
• Tool kit: the Opera: SRI's head of Biological Sciences teams with industry to build high-content screening system (June 15, 2013)
• Seeing things: Federal award will allow biologist to study effects of ‘knocked-out' genes on cells (Jan. 15, 2013)
• At the edge: Federal government awards leaders in innovation (Nov. 27, 2012)
• In death, life: Suicide by cell: The drama and the promise (SRI Magazine, 2011)
• Sugar for the brain: Charité scientists decipher mechanism to prevent programmed cell death of nerve cells, Charité Press (Jan. 1, 2012)

Related Links:

• Centre for Research in Image-Guided Therapeutics
  
• High Content Cellular Analysis lab
• Andrews lab