Senior Scientist, Regenerative Medicine
Ottawa Hospital Research Institute

Professor, Department of Cellular and Molecular Medicine
University of Ottawa

Tissue-specific stem cells are required developmentally to generate a tissue or organ in the fetus and for many tissues, they function to maintain tissue homeostasis during the lifetime of the individual. We are interested in understanding the molecular control of cell fate decisions in development and homeostasis to better understand human development and disease, particularly cancer as this disease is largely driven by aberrant activation of developmental pathways. We use an unbiased “systems” or “integrative” approach to build models of cell fate decisions which we then test using reductionist approaches like CRISPR-mediated genome engineering and gene knockouts. Because the epigenome integrates external signals such as growth factors as inputs into gene regulatory networks, much of our interest in recent years has revolved around epigenetic regulation of cell fate in development and disease. Our three primary projects at this time are:
   
1)    Modeling and therapeutic development for the rare lung tumour lymphangioleiomyomatosis (LAM) and related tuberous sclerosis complex (TSC) tumours such as brain tumours known as SEGAs. Because LAM tumours cannot be propagated outside of the patient, we have used reprogramming of patient cells into induced pluripotent stem cells and CRISPR-mediated genome engineering to a library of mutant pluripotent stem cells that we have differentiated into the affected lineages to model these cancers. We are the first lab to develop non-transformed human cell models of LAM. Together Molly Shoichet’s lab in Toronto, we have developed a lung-like 3D environment to grow these tumours and performed screens that have identified a drug family capable of specifically kill our LAM model cells. Current projects include translating these novel drug hits in vivo, teasing apart disease mechanisms and a CRISPR-based synthetic lethal screen of TSC2 null cells to identify new drug targets.

2)    The epigenetic control of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). Using a combination of pluripotent stem cells, hematopoietic stem cells, and bone marrow cells from patients with acute myeloid leukemia (AML), we identified an epigenetic reader protein known as MTF2/PCL2 that recruits the Polycomb repressive complex 2 (PRC2) to regulatory sites in erythroid progenitors and an HSCs. We found that epigenetic repression of MTF2 in AML leads to epigenetic reprogramming of AML into therapy-resistant, aggressive disease, revealing a primary mechanism of refractory AML. Importantly, by drafting the gene regulatory network of MTF2 we found a therapeutic vulnerability in refractory AML, which is being tested by a phase 1b clinical trial. We are currently testing other therapeutic targets. We are exploring additional drivers of refractory AML and therapeutic vulnerabilities discovered from our gene regulatory network analyses and a CRISPR-based synthetic lethal screen.

3)    Defective epigenetic inheritance in vascular disease and aging. The transmission of epigenetic marks to daughter cells during replication, termed epigenetic inheritance, is critical for tissue homeostasis; epigenetic drift is the failure of epigenetic inheritance leading to altered epigenetic landscapes and a hallmark of cellular aging, chronic disease and oncogenesis. While this process is largely believed to be a random process, studying a rare premature aging disease known as progeria, we have found evidence that epigenetic inheritance is driven by the DNA damage response. We are using a variety of cutting edge techniques to model chromatin dynamics during vascular aging and epigenetic drift, and testing these models on cardiovascular disease patient samples.  

Dr. William (Bill) L. Stanford, PhD, was trained as a chemist (Duke), immunologist and stem cell biologist (UNC Chapel Hill), and developmental biologist (Mount Sinai Hospital, Toronto). Starting in graduate school, Bill’s research has been largely focused on two parallel, and often intersecting tracks: stem cell biology and modeling human disease. In 2002, Dr Stanford established his lab at the University of Toronto (Bioengineering), where he applied interdisciplinary approaches including molecular genetics and systems biology to stem cell research and tissue engineering. Bill moved his lab in 2011 to the Ottawa Hospital Research Institute (OHRI) to facilitate translational research growing out of his basic research program and grow his research in epigenetics.  Currently, Dr. Stanford is a Senior Scientist at the OHRI, a Full Professor at the University of Ottawa, Investigator in the Ottawa Institute of Systems Biology, Scientific Director of the Ottawa Human Pluripotent Stem Cell and High Content Imaging core facilities, and Canada Research Chair in Integrative Stem Cell Biology.  Our interdisciplinary research has been published in most of the top journals according to impact factor and standing within the journal subject category (e.g., Cell, Science, Nature, Cancer Discovery, Advanced Materials, Cell Stem Cell, PNAS, Nature Rev Genet, Nat Genet) and has garnered more than 11,000 citations (Google Scholar, h-index=44).

The complete list of published work can be found here: http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/48928908/?sort=date&direction=descending

Aging; Blood cancer; Cancer; COVID-19; Lung cancer; Lymphangioleiomyomatosis (LAM); Vascular, heart and metabolic disease

Artificial intelligence and data science; Molecular and cellular biology; Regenerative medicine; Stem cells; Systems biology