Evangelos Michelakis
2018; Lippincott Williams & Wilkins; Volume: 123; Issue: 8 Linguagem: Holandês
10.1161/circresaha.118.314005
ISSN1524-4571
Autores Tópico(s)Blood Pressure and Hypertension Studies
ResumoHomeCirculation ResearchVol. 123, No. 8Evangelos Michelakis Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBEvangelos MichelakisWinding Path Leads to New Treatments for Disease Jaclyn M. Jansen Jaclyn M. JansenJaclyn M. Jansen Originally published27 Sep 2018https://doi.org/10.1161/CIRCRESAHA.118.314005Circulation Research. 2018;123:938–941Evangelos Michelakis, Professor and Vice-Chair of Research in the Department of Medicine at the University of Alberta, is focused on understanding how mitochondrial function impacts vascular, myocardial, and cancer biology. His approach to translational research is unconventional—a mix of determination and resourcefulness—blurring the traditional roles of academia and industry in drug discovery. And the results are striking, yielding novel treatments for complex diseases.Much of Michelakis's work centers on pulmonary hypertension, a rapidly progressing disease that typically results in heart failure and death within a few years, if untreated. The disease is localized to the pulmonary arteries, which conduct blood from the right ventricle to the lungs.Michelakis was instrumental in discovering new treatments for pulmonary hypertension. He found early evidence that phosphodiesterase-5 inhibitors were beneficial in treating the disease and led the first 2 clinical trials of sildenafil for pulmonary hypertension, both trials investigator-driven and industry-independent.1,2 He also found that, in addition to pulmonary vasodilatation, sildenafil had unexpected beneficial effects on the right ventricle as well.3 The drug is now the most common treatment for the disease worldwide.4Download figureDownload PowerPointEvangelos MichelakisAt its root, pulmonary hypertension is in many ways more similar to cancer than other vascular diseases. It is caused by an over-proliferation of vascular cells in the pulmonary arteries.5 Unrestrained growth causes cells to accumulate and occlude the vascular lumen specifically in the pulmonary arteries. Other blood vessels throughout the body remain unaffected. Although vasodilators like sildenafil are effective in limiting symptoms of the disease, these drugs do not target the cause of the disease.Michelakis set out to understand how this unrestricted growth arises and how to stop it. Pulmonary arteries are unique: they constrict in response to hypoxia, rather than dilating like all other blood vessels in the body because they have different mitochondria which function as vascular oxygen sensors.6 Michelakis found that the excessive vascular cell growth stems from the unique mitochondria, which also regulate cell death and growth.7–10 His work revealed the crucial role that metabolism plays in the disease, which led him to propose a metabolic theory for pulmonary hypertension.11Based on his preclinical research, Michelakis organized an early-phase clinical trial, in collaboration with the Imperial College of Medicine in London, United Kingdom, to evaluate the generic drug dichloroacetate as a treatment for pulmonary hypertension. This trial, which was completed without industry support, tested the first drug to target the mitochondria in vascular disease.12 Intriguingly, Michelakis had previously shown that dichloroacetate held promise in treating cancer, both in animals and an early-phase clinical trial.13,14 Cancer cells exhibit the same unrestrained growth and share similar mitochondrial abnormalities with the vascular cells in pulmonary hypertension.Michelakis has a unique approach to these early-phase clinical trials and, more broadly, translational research. He pursues independent, investigator-led trials to bridge the gap between molecular discoveries in the lab and patient treatments in the clinic. With funding from traditional nonprofit and government agencies, as well as crowd-sourced donors, Michelakis believes that such trials are a great avenue to test new uses of generic drugs. He is actively working to expand this type of translational research to diagnostics and personalized medicine. At the same time, he is also conducting fundamental basic research. For example, he recently showed for the first time that a mitochondrial enzyme (pyruvate dehydrogenase) can actually translocate to the nucleus to provide acetyl-coenzyme A (CoA) for histone acetylation, discovering a novel link between metabolism and epigenetic regulation.15In a recent conversation with Circulation Research, Michelakis described the path that led him into cardiology research. In a career that requires immeasurable determination, Michelakis has displayed a kind of flexible stubbornness that has allowed him to see failure as a bend in the road, making unexpected breakthroughs a reality, and pioneering new models of clinical and translational research.Where Did You Grow Up?I was born in a city called Nafplio, in Greece. My mum, an archeologist, was teaching in senior high school, and my dad had a tourist business with his two brothers. My grandfather was a mathematician, who also taught in high school. But there were no academics and no doctors in my family. My younger sister, Kostalena, is now an associate professor of Archeology at Arizona State University.When Did You Become Interested in Science?I didn't know much about medicine because there was no doctor in our family, and we were lucky that no one in our family had become very sick at any point. But for some reason, I thought that I needed to go to medical school. In Greece, like the rest of Europe, medical school replaces college. So at the age of seventeen, I began my training to become a doctor. At that age, you can't really expect kids to know what they'll do for the rest of their life. But I was lucky—I really liked it. By the age of 23, I graduated from medical school.You Were So Young. How Did You Decide What to Do Next?I felt like I had to come to the States because that's where the best education was. So I passed the required exams and left for Texas.At the time, I wanted to be a neurosurgeon. I joined a neurosurgeon's lab at the University of Texas Medical Branch, in Galveston. I studied cerebral blood vessel biology for a year with the hope that I'd get into a neurosurgery program. My supervisor was an academic neurosurgeon. When I told him of my goals, he laughed, and I realized how naive I was. It was exceedingly difficult in those days to do neurosurgery—only the best of the best would enter a neurosurgical residency.How Do You Overcome That Kind of Setback in Your Dream Career Path?That was the first time I realized I couldn't fulfill my dream, but I wasn't deterred. I decided I would first become a surgeon and rise through the ranks to follow my dream to neurosurgery. So I sat with a typewriter, and I wrote more than a hundred applications, featuring my passion and determination and all that.I got one letter back—just one—from a community hospital in El Paso that was running a surgical program. I was so happy to open the letter, and the letter said, "Dear Dr Michelakis, we're delighted that you're interested in our program. We would like to invite you for an interview, provided that you're fluent in Spanish." Of course, I knew not a single word in Spanish.I still wouldn't give up. I decided I'd pursue my second choice, which was nephrology. I began looking into internal medicine programs. One weekend I was visiting some old friends in Connecticut, and one was a fellow in the endocrinology program at Yale. It was the weekend after the matching program deadline (my application was for the following year), and he suggested that I call the internal medicine residency director. There were still some unfilled positions, and big programs don't want to be left with unmatched positions.My friend took me to the program director, and we met briefly. He told me that I could start in the program later that year. And that's how I ended up doing my internship at Yale—only because they were in danger of not filling the position, and they were sort of desperate.Nephrology is a cerebral specialty, and Yale was famous for it—probably the best nephrology program in the country in those days. But the nephrology fellowship had a waiting list. Some of my colleagues suggested that I go to the University of Minnesota, which was a good program, and I wouldn't have to wait so long. So I moved to the University of Minnesota to continue with internal medicine and do nephrology.How Did You End Up in Cardiology?Oddly enough, I stumbled upon people doing similar work with the research that I had done in Galveston: cellular electrophysiology in smooth muscle cells. And in one of them, I met my future mentor, Stephen Archer, who was a Canadian and a Professor of Cardiology. He was studying smooth muscle cells and potassium channels in the pulmonary circulation. I was fascinated by his research. Stephen saw something in me and told me I could join his lab, but I'd have to switch to cardiology.And I did. I joined the lab, applied to cardiology, and then did my cardiology fellowship at the University of Minnesota.That Was a Circuitous Path. Do You Have Any Regrets About Your Roads Not Taken?It turns out that I'm very lucky. I love this field that I'm in, but it followed a series of rejections and failures. I've come to realize, those rejections made me more flexible, more open to pursuing different directions. Perhaps this is reflected in my research—I'm always pursuing diverse pathways.I guess my advice to young scientists is to pursue their dream, but it's okay to compromise. You must have plasticity and versatility, and you can't get disappointed. Because in academic medicine, your career is essentially a series of failures—rejections in papers and grants, failed experiments—with occasional moments of pleasure in between when you succeed.You must put these rejections and failures in perspective and become immune to them, and at some point, you realize that perhaps through them you're getting better. It is also critical to have a dedicated mentor to guide you and inspire you, and I was very lucky to have Stephen Archer, now Chair of Medicine at Queen's University in Canada.Did You Ever Think of Giving Up Your Career in Medicine?No, I never thought of giving up because there were always other options. And essentially I was an immigrant. Immigrants expect nothing, so everything you get is because you pursue it. Your expectations are very low initially, which makes all your options attractive. You realize that you can do anything if you just change direction a little bit.Did You Intend to be an Immigrant? Was That Always Part of Your Plan, or Did You Intend to Return to Greece at Some Point?I love Greece, and I find myself there two or three times a year. My parents still live in Nafplio. Both my sister and I left with early intentions to come back, but when you get deep into academia in North America, it becomes very clear that you couldn't do these things back home. So returning to Greece was a hope that never materialized.As a Clinician and a Scientist, How Do You Balance Your Time Between the Two?It's true, my job requires that I split my time in many ways. I run a pulmonary hypertension clinic where I see patients several times a week. I am also on the cardiology wards service, where I treat patients with general cardiology problems.But it's more than just research and clinical time. I teach as well, and I take that very seriously. I founded and ran a translational medicine training program in our department, with weekly lectures that teach the skills and attitudes that you need to do translational research. These things are not necessarily in the standard curriculum for medical students, residents, and graduate students—but they are essential for success.For example, trainees must understand the quality standards in basic research, exactly like the "good clinical practice" standards in clinical research. They also need the ability to set basic research experiments in a way that facilitates clinical translation, like using similar end-points. They also must be able to design clinical research protocols in a way that reveals mechanistic insights, like in basic research. Bringing graduate students and residents in the same classroom allows for these concepts to be developed easily. It is very important for graduate students to understand how a clinical trial is set up and for clinical trainees to interpret basic science models and experiments.Aside from those responsibilities, I also do administrative work. I'm the vice-chair of research at the department of medicine, which is the biggest department in our university, with about 220 full-time faculty members. The rest of the time is for research. When I started, I spent about 30% of my time on clinical work and 70% on research, but now my research is 60%, and clinical is 20%. The remaining 20% is administration and teaching.That's a Very Full Workload. How Hard Do You Say You Work?You do have to put in a lot of hours. But saying that you have to work hard is confusing. If you really enjoy it, it doesn't feel like working. For me, it's like having another hobby. If I were to win a billion dollars, I would still do exactly the same thing that I do now. This is what I want to do.You really have to enjoy science. If you don't enjoy it, then don't even start, because you're not going to be successful. Even then, usually some sacrifices have to happen, typically in your personal life.Do You Consider It a Struggle to Balance Work and Home Life?No, because it doesn't feel like I'm working. I like to make an analogy for how I see this career. It's like being a musician. When a musician sits down to compose music or play, it doesn't feel like work.What Is Your Life Like Outside the Lab?My biggest passion in my life has been music. I've played instruments, and I studied classical music. But despite my passion, I realized early on that I'm not talented for music. Even still, I continue to play in my own way.Now, in a peculiar way, I have started seeing the papers that we publish as if they are beautiful songs, like a composition by Bach, or a Pink Floyd or Dire Straits song. Because, I've realized that when you make these songs, you have to be creative, comprehensive, and tell a memorable and catchy story. And these are the features of a good paper, at least in basic research. When the paper is done, it feels like a completed work of art.And when you're struggling to understand science—maybe some complex signaling pathway—I think of Bach playing the piano, or Mark Knopfler playing guitar solos, and I realize that when they do it, there is only one perfect note that follows from the previous measure and preceding the next. There is no other note that is better. The same is true in nature—most pathways have been perfected through evolution so that when you uncover something, there is no other way it could be. This is it, and it is perfect.And for right or wrong, I approach my work this way. I want it to be perfect like a perfect composition. It makes the journey of conceiving a project, doing the experiments, and writing the paper more enjoyable and satisfying. It's my way of being happy—without being a musician or a neurosurgeon.Aside From Music, Do You Have Other Hobbies?They usually have to do with music: I play the keyboard and guitar. At times, I've played in little bands, but mostly I play by myself. And that takes a lot of the free time I have. I also read a lot.When I have vacation time, I like to spend it around or inside the water. In particular, I love the sea, the Mediterranean. When I go to Greece, I'm always either in or just meters from the water. I feel I can't live without it. Of course, where I live in Edmonton, it's as far from the sea as it gets. But if you get what you really like in small doses, you enjoy it even more than if you had an unlimited supply.What Have Been the Biggest Challenges in Your Career? Is There Anything That You Would Have Done Differently?I've been lucky to get the right advice and encouragement from my mentor, Stephen Archer. A true mentor, like Stephen, has a life-long commitment to a mentee, and protects and advises the mentee in all aspects of life, beyond career and research. And now I try to show the same kind of commitment to my mentees.But in general, as I said, I don't approach failures as mistakes. There are a lot of them in science, and you'd easily get depressed. So, I approach each failure as a push in a different direction. Life isn't a straight line, but zigzags, where every turning point should be welcome.In that sense, I've done a lot of things that I could've done differently, but really, I'd probably do it the same given the chance. I would advise young scientists to welcome mistakes and failures. I would tell them: Go where your heart tells you, or where you're happy and ignore the challenges; be flexible. Because to be excited and happy about what you do is, by far, the best predictor for success.What Do You See as the Challenges for Young Scientists Today?I caution my residents and graduate students about the changes in clinical medicine and research today. It is driven by algorithms and guidelines, like a cookbook, much more than it used to be. And people are trained to follow them in every way possible. This is not just a reaction to medical malpractice lawsuits—Canada has many fewer than the United States—but medicine is the same. I think it is an effort to simplify clinical practice and make it easy. But it takes the fun from it tremendously and suppresses creativity, approaching all patients as if they were the same.A similar thing happens in research, where advances in technology have enabled the famous "unbiased screening". We can screen all the proteins, all the genome, all the metabolites—and see what you get—and try to make sense of it. This is no fun, at least to my eyes. I prefer hypothesis-driven science where you start building slowly, like the musicians with their perfect solos. Step by step—to me that is fun.I think personalized medicine is a great place for hypothesis-driven research. As a clinician-scientist, you can have your feet both in basic research and translate it into personalized clinical research. I think this is more satisfying, and, if a single person is driving it, a clinician-scientist, it is more comprehensive and efficient, and thus more likely to succeed. For example, the same scientist can set the preclinical experiments and then organize a subsequent clinical trial based on the preclinical findings. This way, you can anticipate the mechanistic or toxicity information that regulatory authorities would need to approve clinical protocols. Or you would know what the kind of biomarker is required to facilitate future clinical protocols. A clinician-scientist can design more continuous, efficient discovery programs from animals to humans, rather than fragmented ones. A team of basic and clinical scientists can also do this, but they really need to "speak the same language" and understand each others' fields.What Else Does it Take to be a Successful Research Scientist?We've discussed much of it. But I will emphasize a need for a sort of flexible stubbornness—an unwillingness to give up. Instead, you should just change direction. It is easier if you're open to new research directions. You can develop a diverse portfolio, which keeps you interested and excited all the time rather than bored and frustrated.To do this, you must really love what you do and have a passion for it. I think it is critical to look at this profession as a hobby, rather than work. Then you will succeed. I feel confident about that.DisclosuresNone.References1. Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide.Circulation. 2002; 105:2398–2403.LinkGoogle Scholar2. Michelakis ED, Tymchak W, Noga M, Webster L, Wu XC, Lien D, Wang SH, Modry D, Archer SL. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension.Circulation. 2003; 108:2066–2069. doi: 10.1161/01.CIR.0000099502.17776.C2LinkGoogle Scholar3. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St Aubin C, Webster L, Rebeyka IM, Ross DB, Light PE, Dyck JR, Michelakis ED. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility.Circulation. 2007; 116:238–248. doi: 10.1161/CIRCULATIONAHA.106.655266LinkGoogle Scholar4. Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension.N Engl J Med. 2009; 361:1864–1871. doi: 10.1056/NEJMct0904473CrossrefMedlineGoogle Scholar5. Sutendra G, Michelakis ED. Pulmonary arterial hypertension: challenges in translational research and a vision for change.Sci Transl Med. 2013; 5:208sr205. doi: 10.1126/scitranslmed.3005428CrossrefGoogle Scholar6. Michelakis ED, Hampl V, Nsair A, Wu X, Harry G, Haromy A, Gurtu R, Archer SL. Diversity in mitochondrial function explains differences in vascular oxygen sensing.Circ Res. 2002; 90:1307–1315.LinkGoogle Scholar7. Dromparis P, Paulin R, Sutendra G, Qi AC, Bonnet S, Michelakis ED. Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodeling and pulmonary hypertension.Circ Res. 2013; 113:126–136. doi: 10.1161/CIRCRESAHA.112.300699LinkGoogle Scholar8. McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis.Circ Res. 2004; 95:830–840.LinkGoogle Scholar9. Paulin R, Dromparis P, Sutendra G, Gurtu V, Zervopoulos S, Bowers L, Haromy A, Webster L, Provencher S, Bonnet S, Michelakis ED. Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans.Cell Metab. 2014; 20:827–839. doi: 10.1016/j.cmet.2014.08.011CrossrefMedlineGoogle Scholar10. Sutendra G, Bonnet S, Rochefort G, Haromy A, Folmes KD, Lopaschuk GD, Dyck JR, Michelakis ED. Fatty acid oxidation and malonyl-coa decarboxylase in the vascular remodeling of pulmonary hypertension.Sci Transl Med. 2010; 2:44ra58. doi: 10.1126/scitranslmed.3001327CrossrefMedlineGoogle Scholar11. Sutendra G, Michelakis ED. The metabolic basis of pulmonary arterial hypertension.Cell Metab. 2014; 19:558–573. doi: 10.1016/j.cmet.2014.01.004CrossrefMedlineGoogle Scholar12. Michelakis ED, Gurtu V, Webster L, et al. Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients.Sci Transl Med. 2017; 9:aao4583. doi: 10.1126/scitranslmed.aao4583CrossrefGoogle Scholar13. Bonnet S, Archer SL, Allalunis-Turner J, et al. A mitochondria-k+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth.Cancer Cell. 2007; 11:37–51.CrossrefMedlineGoogle Scholar14. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC. Metabolic modulation of glioblastoma with dichloroacetate.Sci Transl Med. 2010; 2:31ra34. doi: 10.1126/scitranslmed.3000677CrossrefMedlineGoogle Scholar15. Sutendra G, Kinnaird A, Dromparis P, Paulin R, Stenson TH, Haromy A, Hashimoto K, Zhang N, Flaim E, Michelakis ED. A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-coa and histone acetylation.Cell. 2014; 158:84–97.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails September 28, 2018Vol 123, Issue 8 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.118.314005PMID: 30355034 Originally publishedSeptember 27, 2018 PDF download Advertisement SubjectsBasic Science ResearchClinical StudiesHeart FailureMetabolismPulmonary BiologyPulmonary HypertensionTranslational StudiesTreatmentVascular Biology
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