Lea Harrington, Ph.D.
Awards & Honours
- Howard Hughes Medical Institute International Scholar, 2007
- Terry Fox Foundation Young Investigator Award, 2001
- National Cancer Institute of Canada Postdoctoral Award, 1994
- Postdoctoral training with B.J. Andrews, University of Toronto, 1994-1995
- Ph.D. (1993), SUNY at StonyBrook, with C.W. Greider, Cold Spring Harbor Laboratory
- M.Sc. (1990), University of Toronto, with M.L. Breitman, Mount Sinai Research Institute
- B.Sc. (1987), McMaster University, with C.B. Harley, Department of Biochemistry
- Canadian Foundation for Innovation Leaders Opportunity Fund
- Wellcome Trust (UK)
- Medical Research Council (UK)
- Howard Hughes Medical Institute
- National Institutes of Health, National Institute on Aging
- Canadian Cancer Society Research Institute
- Canadian Institutes of Health Research
Lea Harrington moved to IRIC in 2011 from the University of Edinburgh, where she held a Personal Chair as Professor of Telomere Biology and was the Associate Director of Postgraduate M.Sc. Programmes in the School of Biological Sciences. She retains a Visiting Professorship at the University of Edinburgh and is a Professor in the Department of Medicine at l’Université de Montréal.
Since starting her laboratory in 1995, Lea Harrington and her colleagues have pursued the mechanisms by which chromosome ends, telomeres, are maintained and protected from degradation and recombination. The activity of an enzyme responsible for new telomere addition in most eukaryotes, telomerase, is increased in many cancers and conversely is decreased in many somatic tissues. Since critically short telomeres that elicit a DNA damage response are incompatible with cell viability, the regulation of telomerase activity and dosage is thus a critical determinant of normal and cancer cell proliferation.
The Harrington laboratory has employed several model organisms to dissect the dosage-sensitive regulation of telomere homeostasis and its consequences in aging, cancer, and disease. In the single-celled genetic model S. cerevisiae (baker’s yeast), her group conducted genome-wide genetic screens to identify genes whose absence affects survival when telomerase expression is reduced or abrogated. These screens identified a pathway for cell survival that acts independently of telomerase and homologous recombination (LeBel et al., Genetics 2009).
Using mammalian genetic models, Lea Harrington and her group carried out a long-term analysis of telomere dynamics and stem cell function in cells that possess only half the normal dosage of the telomerase reverse transcriptase, TERT. In this setting, telomeres erode gradually with time but do not become critically short and stem cell function is preserved (Meznikova et al., Dis Models Mech 2009). The outcome of telomere erosion, however, is context-dependent and dosage-dependent. A partial reduction in TERT dosage leads to a dramatic loss in stem cell function when telomeres begin at a shorter length (Strong et al., Mol Cell Biol 2010), or when telomerase is absent altogether (Meznikova et al., Dis Models Mech 2009; Erdmann et al., Proc Natl Acad Sci USA 2004).
In human cell models, the Harrington laboratory identified regions of TERT necessary to avoid or escape cellular senescence and to interact with other telomerase accessory factors (Sealey et al., Nucl Acids Res 2010; Ibid, BMC Mol Biol 2011). A novel human tumor model was also developed in which TERT expression is genetically controlled. This new model establishes that human tumor formation does not depend on telomerase or other means of telomere maintenance while telomeres remain at a functional length (Taboski et al., Cell Reports, 2012). However, once telomeres erode to a critical length, the tumor cells lose viability and cannot escape via activation of telomerase or other mechanisms of telomere maintenance. This discovery suggests that telomerase inhibition in tumors with longer telomeres would induce a delayed but potentially effective tumor regression.
The future direction of Lea Harrington’s research at IRIC is to use these human tumor models to identify pathways whose inhibition increases the susceptibility of cancer cells to telomere damage and cell death, or whose enhancement might improve cell viability in contexts where telomerase function is limiting as in aging or in certain degenerative diseases.