Scientist on the Spot: Exploring the cause and cure for pulmonary arterial hypertension

Dr Rui Adão from the University of Porto (Portugal), interviews Dr Stephen Archer, Head of the Department of Medicine at Queen’s University in Ontario (Canada). Highlight: In this Onlife interview, Dr Stephen Archer speaks about his remarkable achievements in the field of oxygen sensing, mitochondrial biology, and experimental therapeutics for pulmonary hypertension, and offers young scientists insightful career advice to help achieve similar success. As a physician-scientist, Dr Stephen Archer first spoke about why he focused on pulmonary hypertension (PAH) as a specialization. His research path began serendipitously during medical residency, under the guidance of his mentor and friend, Dr E.K. Weir, with whom he worked on hypoxic pulmonary vasoconstriction at the University of Minnesota. With over 30 years of research behind him, Dr Archer considered it difficult to choose a single major milestone discovery in his scientific career. However, he emphasized some of his key findings on the common theme of the role of mitochondria in health and disease. Particularly, he highlighted the identification of a mitochondrial redox oxygen sensor in the pulmonary circulation, which modulates vascular tone in response to hypoxia by regulating voltage-gated potassium channels. He and Dr Wier showed that mitochondria are central to the mechanism of hypoxic pulmonary vasoconstriction, which optimizes oxygen uptake and tissue oxygen delivery. In addition, Dr Archer emphasized key discoveries regarding the contribution of functional and structural mitochondrial abnormalities to both rapid cell growth and apoptosis-resistance in pulmonary arterial hypertension and non-small-cell lung cancer. In particular, he noted his discoveries with Dr Evangelos Michelakis of the role of pyruvate dehydrogenase kinase in causing Warburg metabolism, and with Dr Jalees Rehman in discovering the role of dynamin-related protein 1 (DRP1) in pulmonary hypertension and cancer. The recognition of mitochondria as oxygen sensors and regulators of the cell cycle and apoptosis allowed him and his colleagues to develop innovative therapies that target metabolism (dichloroacetate) and mitochondrial dynamics (Drpitor1a). The latter small molecule works by inhibiting DRP1 induced fission for the treatment of pulmonary arterial hypertension, heart attacks, and lung cancer. Next, Dr Archer discussed how he sees the evolution of his research path. According to him, the last two decades have seen a revolution in pulmonary hypertension research, as we move towards achieving a vision of precision medicine.1 A significant proportion of PAH cases are strongly associated with rare genetic variations (mutations). He is not a geneticist but mentioned his recent research study which demonstrated that Tet methylcytosine dioxygenase 2 (TET2), an epigenetic regulator that demethylates cytosine, is mutated in some patients with idiopathic and associated pulmonary arterial hypertension. This achievement was a result of collaboration with an international team of experts that used a translational approach to demonstrate the association between deleterious mutations in genes involved in the regulation of DNA methylation and the development of pulmonary arterial hypertension. Dr Archer believes that the lofty goals of precision medicine will take time to achieve and will likely require collaborative approaches across academic research programs. Finally, he considers that love of patient care, curiosity, a very strong work ethic, and a great mentor are needed by young physician-scientists who aspire to achieve a brilliant scientific career. To be a good clinician scientist, you must be excellent in both medicine and research. For Dr Archer, creating research teams of people that you like and respect has been the key to the creation of a fruitful scientific environment and a productive career. He takes great pride in his many trainees, most of whom are now leaders in their own right in academic medicine and research. Conflict of interest: none declared. Biography: Rui Adão is a Biologist with a PhD degree in Cardiovascular Sciences obtained in 2019 at the Faculty of Medicine of the University of Porto (Portugal), where he currently works as a postdoctoral research scientist at the Cardiovascular Research and Development Center-UnIC. Rui Adão has a strong expertise in animal models of pulmonary arterial hypertension (e.g. monocrotaline, hypoxia-Sugen5416) and in in vivo and in vitro evaluation of cardiac function. Rui Adão has also maintained relevant collaborations with institutions of excellence in cardiovascular research and therapeutic innovation, including INSERM (France), Medical University of Graz (Austria), Christchurch School of Medicine (New Zealand), and Antwerp University (Belgium). As an early career researcher, he has won numerous prestigious scholarships and awards such as a Janssen Innovation Award (2018) and European Respiratory Society Short-Term Fellowship Grant (2017). His current research focuses on elucidating the role and therapeutic potential of novel small molecules (e.g. small peptides and microRNAs) in the setting of pulmonary arterial hypertension and associated heart failure. He is also a core member of the Scientists of Tomorrow Nucleus of the European Society of Cardiology. Biography: Dr Stephen L. Archer is Head of the Department of Medicine at Queen’s University and Program Medical Director for Kingston Health Sciences Centre. Dr Archer is the Elizabeth Smith Distinguished University Professor and holds the C. Franklin and Helene K. Bracken Chair in the School of Medicine. Dr Archer is a clinical cardiologist and clinician scientist with a special interest in pulmonary hypertension. He holds a Tier 1 Canada Research Chair in Mitochondrial Dynamics and Translational Medicine. His CIHR-funded research lab studies mechanisms of oxygen sensing and investigates the role of mitochondria as oxygen sensors and regulators of cell proliferation. He develops experimental therapies for pulmonary hypertension and cancer. He is very proud of his trainees, many of whom are now leaders in research and clinical medicine. His >250 manuscripts have been cited over 40 000 times (h-index 99). He is the recipient of the Distinguished Scientist Award and Coeur d’Or awards from the American Heart Association (AHA) and a Distinguished Scientist Award (translation research) from the American College of Cardiology, as well as the Research Achievement Award from the Canadian Cardiovascular Society. He was elected as a Fellow of the Royal Society of Canada in 2018.

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