Dr. Stephen Archer
Dr. Archer is the Head of Medicine at Queen’s University in Kingston, Ontario, Canada. He is a cardiologist and translational physician-scientist. He is a recognized leader in several research fields, including oxygen sensing, vascular biology, and the experimental therapeutics of pulmonary hypertension and cancer. Dr. Archer has published over 220 peer-reviewed articles in leading journals and has given ~300 invited lectures including plenary session lectures at the American Heart Association Meeting and numerous named lectureships. He is also been an author of several key guideline documents, including the AHA 2009 guidelines on pulmonary hypertension and the 2010 guidelines on management of submassive venothromboembolism. His research, funded by NHLBI and CIHR, has an H-index of 71 and has been cited 20,000 times.
Oxygen sensing: With colleagues, notably Dr. E. Kenneth Weir, he discovered the mechanisms of hypoxic pulmonary vasoconstriction and oxygen induced constriction of the ductus arteriosus (summarized in a 2005 NEJM review that he co-authored). In both cases he showed that oxygen-induced changes in mitochondrial function alters redox signalling (diffusible hydrogen peroxide) leading to changes in the function of ion channels (Kv1.5, CaL) and enzymes (rho kinase) leading to vasoconstriction. These discoveries created new paradigm of redox based regulation of tone that was intrinsic to the vascular smooth muscle cell and overturned the belief that the mechanisms involved oxygen-induced changes in levels of circulating vasoconstrictor mediators, such as leukotrienes and endothelin.
•E. K. Weir, J. Lopez-Barneo, K. J. Buckler, S. L. Archer, Acute oxygen-sensing mechanisms. The New England journal of medicine 353, 2042 (Nov 10, 2005).
•E. D. Michelakis et al., O2 sensing in the human ductus arteriosus: regulation of voltage-gated K+ channels in smooth muscle cells by a mitochondrial redox sensor. Circulation research 91, 478, 2002).
•Z. Hong et al., Role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in oxygen sensing and constriction of the ductus arteriosus. Circulation research 112, 802, 2013).
•S. L. Archer, J. Huang, T. Henry, D. Peterson, E. K. Weir, A redox-based O2 sensor in rat pulmonary vasculature. Circulation research 73, 1100, 1993).
Nitric oxide and phosphodiesterases as therapeutic targets in pulmonary hypertension: He also discovered one of the fundamental mechanisms by which nitric oxide causes vasodilation (cGMP-mediated activation of large conductance calcium-sensitive potassium channels -published in a PNA paper that has been cited >500 times). This interest in nitric oxide led to is use of sildenafil (Viagra) for the treatment of human PAH. The 2 paper he and Dr. Evangelos Michelakis published demonstrating this therapy to be effective have been cited >800 times, informed the subsequent SUPER trial that led to the approval of this first-line oral PAH therapy. This work was summarized in an invited review he authored on therapeutic uses of phosphodiesterase-5 inhibitors in the NEJM.
•S. L. Archer, E. D. Michelakis, Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. The New England journal of medicine 361, 1864 (Nov 5, 2009).
•E. D. Michelakis et al., Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 108, 2066, 2003).
•E. Michelakis et al., Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 105, 2398, 2002).
•S. L. Archer et al., Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci U S A 91, 758, 1994).
Similarities between PAH and cancer: Along with colleagues, notably Dr. Michelakis, Dr. Archer has made discoveries regarding the basic mechanisms mediating PAH and helped shift the field from viewing it as a disease of excessive vasoconstriction to the view that it has similarities to cancer, notably excessive cell proliferation and impaired apoptosis. At the heart of this discovery is the disordered mitochondria-ROS-HIF-1α-Kv1.5 pathway. In 2010 the Archer team identified a novel and heritable mechanism underlying the abnormal mitochondrial-ROS-HIF-1µ pathway in PAH. Using human tissue and fawn-hooded rats with spontaneous PAH, they showed that the proliferative diathesis of PAH PASMC had an epigenetic basis, specifically due to methylation of 2 CpG islands in SOD2. This is the first demonstration of an epigenetic basis for a heritable vascular disease and has etiologic and therapeutic implications. This paper in Circulation (2010) was selected by NHLBI as one of its top discoveries in 2010 (http://www.nhlbi.nih.gov/new/fiscalyear10.htm).
Both PAH and cancer were found to share a metabolic shift to aerobic glycolysis (the Warburg phenomenon) that offers the tumor cells survival benefits but also suggests therapeutic targets. A prime example of these novel therapeutics is the use of inhibitors of pyruvate dehydrogenase kinase (PDK), such as dichloroacetate, to treat PAH and cancer. Archer and Michelakis have a patent for the use of PDK inhibitors to treat cancer.
•S. Bonnet et al., A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37, 2007.
•S. L. Archer et al., Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation 121, 2661, 2010.
Mitochondrial dynamics as a mechanism of human disease: Dr. Archer was also amongst the first to discover the obligatory role of mitochondrial fission in cell division and was the first to target mitotic fission, by inhibiting DRP1 or augmenting mitofusin-2, as a therapy for proliferative disorders, such as NSCLC and PAH. This work led a Mechanisms of Disease article in 2013 in the NEJM.
•J. Rehman et al., Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 26, 2175 (May, 2012).
•G. Marsboom et al., Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. Circulation research 110, 1484 (May 25, 2012).
•S. L. Archer, Mitochondrial dynamics--mitochondrial fission and fusion in human diseases. The New England journal of medicine 369, 2236 (Dec 5, 2013).
Trainees: Dr. Archer has mentored many young physicians and scientist who are now leaders in academic medicine in North America and Europe. Dr. Archer’s postdoctoral fellows have won the Comroe Cournand Young Investigator Award at the national American Heart Association meeting 5 times in the past decade.
Volunteer service: He served as a leader in the Heart and Stroke Foundation of Canada and the American Heart Association. He was council Chair for the Cardiopulmonary Critical Care Council of the American Heart Association and has served on numerous of their leadership councils and led scientific peer review and program committees. In 2010 he was elected President of the American Heart Association Board (Illinois). A highlight of his term was participating in creating a heart attack network of care (the Mission lifeline STEMI network). In 2013 he received the AHA’s Coeur D’Or Award for leading the creation of a heart attack care network for the city of Chicago. (http://www.youtube.com/watch?v=2dEU-1w2gkw)