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Dr. Robert Roberts: Recipient of the Canadian Cardiovascular Society Research Achievement Award in 2012

Editor’s note: Robert Roberts is the President and CEO of the University of Ottawa Heart Institute and founding Director of The Ruddy Canadian Cardiovascular Genetics Centre. He received his M.D. from Dalhousie University and completed his residency in Internal Medicine and Fellowship in Cardiology at the University of Toronto. Funded by a Canadian Heart Foundation Scholarship, he pursued research in heart disease and in 1982 became Chief of Cardiology at Baylor College of Medicine in Houston, Texas. As a cardiologist, educator and scientist, he developed the MBCK Test which has been used to diagnose heart attacks for the past three decades. Dr. Roberts’ research led him to molecular biology and genetics, during which time he discovered many genes responsible for heart disease. Dr. Roberts is generally regarded as one of the founders of molecular cardiology. Dr. Roberts has had a distinguished and prolific career as a Cardiologist, Educator and Scientist having published over 850 scientific articles and received many awards including the Fellowship Award from the International Academy of Cardiovascular Sciences; Canadian Cardiovascular Society 2012 Research Achievement Award; McLaughlin Medal from the Royal Society of Canada and the Albrecht Fleckenstein Memorial Award from the International Academy of Cardiology; Citation for Highly Cited Researcher from ISI Thomson Scientific in 2002; the Distinguished Scientist Award from the American College of Cardiology in 1998; and recently was honoured by his alma mater, Dalhousie University, with the degree of Doctor of Laws, honoris causa, 2005 Robert Beamish Award for Promotion of Cardiovascular Science and Eduction from the Instute of Cardiovascular Sciences, Winnipeg, Canada.

Dr. Roberts currently serves on several international committees: Medical Advisory Board, Gairdner Foundation (2009-2014); Impact Review Panel 2013 UBC Margolese National Brain and Heart Disorders Prizes; Scientific Advisory Committee Member, Fondation Leducq, Paris, France (2009-2014); Board of Directors, The Fields Institute, Research in Mathematical Science (2010-2015); Basic Science Advisory Task Force, American College of Cardiology 2013; Inter Society Task Force for Genetics, American College of Cardiology 2013; Board of Directors, Ontario Genomics Institute, Toronto, Ontario (2011-2015); Governing Board, International Society of Cardiovascular Translational Research (2010-2016). Dr. Roberts has also served many leadership roles in research, including: Chair, CANNeCTIN–Pharmacogenomics Technology Working Group (2008-present); Chairman, Data & Safety Monitoring Board of the NHLBI–sponsored, Rule–Out Myocardial Infarction Using Computer Assisted Tomography II (ROMICAT II) Trial, Washington, DC (2008-2012); Chairman, Awards Committee for Grant Reviews of the American College of Cardiology (2003-2006); Chairman of the Research Awards Committee American College of Cardiology (2002-2006); Chairman, Review Committee, ACC/Merck Fellowship Awards Program (2000-2006); Co–Chairman of the NIH Symposium on Gene Therapy and Safety, American College of Cardiology; Chairman, Joint ACC–ESC–AHA Committee Taskforce to Develop Molecular Genetics Curriculum (2000-2003); Vice–President, National American Heart Association (2001-2002); Board of Directors, National American Heart Association (1999-2002); Chair, ACC Task Force 7: Training in Cardiovascular Research (2002); Chairman, RPEC, National American Heart Association (1999-2001); Chairman, AHA Research Program and Evaluation Committee (1999-2001); Board of Trustees Member, American College of Cardiology (1996-2001); Chair, Training in Cardiovascular Research, American College of Cardiology (2000); and Board of Directors, American Heart Association (1999).

Dr Roberts is the Editor of Current Opinion in Cardiology and a member of the Editorial Board of several prestigious cardiology journals. He has lectured throughout the world including several notable plenary addresses, including: The Royal Canadian Institute for Advancement of Science, co-sponsored by the Gairdner Foundation, ‘Medicine: A Glimpse of the Future’, Toronto (2013).

Response by Dr. Roberts to presentation of the award

It is a great honour to receive such an award from the Canadian Cardiovascular Society and I am humbled to be among the many outstanding Canadian recipients of this award, which has special significance to me, as I spent a large part of my professional career in the USA. This award, from the prestigious Canadian Cardiovascular Society has a nostalgic fulfilment for me, since it is to Canada I owe my up-bringing, education and training. In fact, most of my early mentors were here, in Toronto, at the University. No award is simply the work of one individual, and this award is no exception. I have many mentors to thank and in particular, I wish to thank Dr. Robert Anderson, Dr. Don Beanlands, Dr. Eugene Braunwald, Dr. Burton E. Sobel and Dr. Antonio M. Gotto. I wish to also thank the hundreds of Fellows with whom I had the honour to rub shoulders throughout my career - not only did the work, but they were always a great source of inspiration and knowledge. Last but not least, my family, my wife Donna, without whom none of this would have been possible, and my two children Brandon and Alison, who have always been my greatest fans.

For many people, looking back on their career, there are often triggering events, or it was what they always wanted to do. Having grown-up in a small town, for me, a physician was someone who had a black bag and came around and made house calls. My decision to train as an academician and investigator was without design or prior knowledge. While finishing my Assistant Chief Residency at the Toronto General Hospital, Dr. Robert Young, a Cardiologist in the Roberts Clinic (no relationship) at St. John’s, Newfoundland called to ask if I would join the Clinic, which was quite famous in St. John’s. It was at this point that I re-read the “The Road Not Taken” by Robert Frost, and on the advice and recommendation of Drs. Don Beanlands and Susan Lenkei (my mentors), I decided to pursue further training. With their support, I secured an Canadian Heart Foundation Scholarship to do research under Dr. Gene Braunwald at the University of California, San Diego, for me, it was certainly the road least traveled. My ambition was to specialize in cardiology, having been inspired in medical school at Dalhousie University by Dr. Robert Anderson, a Cardiologist who had just returned from being with Dr. Paul Wood. I indicated to Dr. Young that I would further my training in order to pursue an academic career.

I had virtually no experience with research and no concept of what an academician would be, other than I would be expected to be a physician and educator. The place to be was San Diego, with Dr. Eugene Braunwald, Chair of Medicine along with a faculty that was driven by discovery and innovation. The focus in cardiology was on myocardial infarction, the number one killer. It was now evident from Jennings work that the amount of myocardial damage (infarct size) occurring during a heart attack evolved over several hours and might be attenuated if appropriate drugs or agents could be administered early in its evolution. Infarct size was the big buzz, research revolved around methods to quantify and limit it, everyone was convinced that Gene Braunwald would get the big prize, he was brilliant, organized and a great administrator. Little did I know then, how much I would owe to him as a lifelong mentor and friend. I arrived in San Diego and Gene assigned me to research on muscle mechanics, this time in conscious animals with Dr. Stephen F. Vatner. While muscle mechanics was fascinating, I believed it had reached its peak and the future would be in biochemistry of the heart, so I made the decision I wanted to work with Dr. Burton E. Sobel, who at that time, was very active in the field. I met with Gene Braunwald and he was extremely encouraging, saying “go for it, I am moving to Boston next year to be Chairman of Medicine, and you are most welcome to join me once you finish your training”. Burt was incredibly intelligent, driven, demanding and even more demanding of himself - he was a great mentor and became a lifelong friend.

Burt’s laboratory was receiving world-wide recognition for estimating infarct size by serially measuring plasma-CK following myocardial infarction. These estimates were based on total CK, part of which was coming from the heart (MBCK) and part from other organs, particularly skeletal muscle. One could measure MBCK, which was quite specific for the heart, however, the assays for MBCK were qualitative, and not quantitative, which was required to estimate infarct size. Thus, my first project was to develop a quantitative assay for MBCK. The qualitative assay for MBCK required separating MBCK from MM on cellulose acetate paper by electrophoreses, since MBCK was more negatively charged than MM, and despite all efforts to standardize the scans for the fluorescent bands, the results were not reproducible. Another concern related to a computer program required to predict infarct size from plasma-CK based on the first 2 to 3 samples after a myocardial infarction. If one could predict, intervene and compare the prediction with the actual observed infarct size, it would be an interesting method to evaluate the effect of interventions on infarct size. This was an exciting time for myocardial infarction and our group in San Diego was at the leading-edge of the whole effort. The excitement was clear and the competition was all too palpable. It was suggested I meet with Dr. Hagivara, a physicist in Pasadena connected with NASA during the cold war era, whose research involved determining the speed and projectile trajectory of a missile launched from Russia enabling its destruction over the Pacific Ocean before it hit the mainland of the USA. Interestingly, this would be somewhat similar to predicting the trajectory curve for plasma-CK after a myocardial infarction. In my discussions with him, although his terminology and knowledge was sometimes beyond my grasp, it became evident that to obtain an early accurate prediction of a plasma-CK curve, we would require sampling over a longer interval than was practical. This was bad news, and on discussing the problem of how to quantify MBCK by fluorometer scanning techniques, he was even less optimistic. After driving back from LA that evening, I continued to ponder the problems I had outlined to him and, while in the shower, a solution occurred to me. The separated bands of plasma MBCK and MMCK on the strips were visualized through the generation of fluorescent NADPH, a reporter molecule. It occurred to me that NADPH is water soluble and if I cut the strip into 2 pieces, one containing MB and the other MM and inserted them into separate containers of water, with a little stirring, the water soluble NADPH would elute from the strip into a homogeneous solution to be measured accurately in a spectrometer. I called Burt, we were both late nighters, he met me at midnight, we both knew this would work. Over the next few weeks, I had adequate data with reproducibility; it was presented at the American College of Cardiology and published in the American Journal of Cardiology. I moved with Burt Sobel to Washington University in St. Louis, where he became Chief of Cardiology and I became Director of the Coronary Care Unit at Barnes Hospital. Research on CK flourished and, subsequently, in collaboration with Charles Parker and Burt Sobel, we developed a radioimmunoassay for MBCK based on an antibody to the B-subunit. This was published in Science and the antibody approach became the approach for future diagnostic markers, including today’s Troponins. MBCK became the gold standard for the diagnosis of myocardial infarction and was to remain so for the next 3 decades.

There was still one agonizing problem: could MBCK be released from cardiac cells that are not irreversibly injured, such as with ischemia. To solve this problem, I purified mitochondrial-CK and generated a specific antibody in rabbits and developed a radioimmunoassay. If mitochondria released its CK, it would indicate the cells were irreversibly damaged. The paper was published in JBC, however with a rather disappointing caveat they indicated that no further manuscripts on mitochondrial-CK would be accepted unless we prove it had its own gene. There was a gene for the M-subunit, a gene for the B-subunit which obviously gave you 3 combinations, MM, MB or BB, but did not provide for a fourth combination, mitochondrial-CK. So the concern was whether mitochondrial-CK was a contaminant of ‘M’ or ‘B’ CK. In 1978, isolating a gene and elucidating its expressed product was far removed from what I considered possible at the time. However, an in vitro translation method became available and in collaboration with Arnold Strauss, we showed that mitochondrial-CK was indeed encoded by a separate gene. We submitted the paper to JBC and the editor promptly accepted it. Little did I know then, it would markedly change my research career, not because of mitochondrial-CK, but because it had exposed me to the techniques of molecular biology and recombinant DNA. I read and reread the book by Jim Watson on DNA to learn the techniques of molecular biology. I took it with me everywhere, probably read it 5 or 6 times and pondered the possibilities of its application to research problems in cardiology.

To digress for a moment, modern molecular biology really began in earnest around 1970. Many of the investigators in molecular biology left the field in the 1960s and went to neurophysiology they realized the human genome with billions of DNA sequences made it formidable to identify a gene responsible for a single protein. That would change with four discoveries from 1969 to 1971, all of which received Nobel prizes. The dogma was that one went from DNA to RNA to protein and there was no going back. The scientists David Baltimore and Howard Temin independently and simultaneously discovered the enzyme reverse transcriptase, enabling one to go from RNA to cDNA, a complementary sequence of the RNA, which was used to locate the sequence of the gene within the genome. DNA molecules are so large (~150 million base pairs), that any attempt to work with DNA induced random breaks, making experimental results un-interpretable. Kelly et al had shown that bacteria possessed specific enzymes called restriction endonucleases that would cut DNA at precise sites and provide DNA fragments of specific length. The third discovery was by Cohen and colleagues at Stanford, who made the first recombinant DNA molecule and expressed it in a bacterial vector. Lastly, Fred Sanger who had received a Nobel Prize for sequencing the first protein, insulin, had now invented a method to sequence DNA. This catapulted molecular biology into the modern era; it was now possible to isolate, clone, express and sequence genes.

After nine glorious and productive years at Washington University, I decided it was time to have my own program and I moved to Baylor College of Medicine as Chief of Cardiology. Baylor College was becoming a hub for molecular biology with Dr. Bert W. O’Malley and molecular genetics with Dr. C. Thomas Caskey. I outlined to Dr. Antonio Gotto, Chairman of Medicine at Baylor, that my plan was to develop a molecular cardiology research and training program and I am very indebted to Dr. Gotto for believing in me and in the future of molecular cardiology. In my first year or two at Baylor College, I did what I was comfortable with at that time – we cloned the genes for MMCK and MBCK which provided experience in the techniques of molecular cardiology. We were fortunate that in 1986, AHA invited grant applications for training (Bugher Centers) to train cardiologists in molecular biology of the cardiovascular system. Three were awarded, one to Children’s Hospital in Boston and two to Texas, one going to Dallas with Brown & Goldstein as Principal Investigators and the other to Baylor College, with me as the Principal Investigator. This was a major boost for molecular cardiology, my career and the cardiology program at Baylor College of Medicine. Having Tom Caskey as a collaborator and as a spokesman at the site visit was certainly a major factor in our success. We trained over 30 Bugher Fellows in molecular cardiology, many of whom today are Chiefs of Cardiology, Chiefs of Medicine, Deans or world-renowned researchers.

At that time, I was also making a connection in my mind with DNA and familial cardiomyopathies. I was convinced cardiomyopathies was an opportunistic field, as little had been done to elucidate the etiology over the previous 3 to 4 decades, except to clinically reclassify them for the sake of new questions for board examinations. Cardiac hypertrophy, a consistent feature of the cardiomyopathies, was a growth problem, and hence a DNA problem, therefore, elucidation of its etiology would require the techniques of molecular genetics. It also reminded me of my rotation with Dr. E. Douglas Wigle, in Toronto, one of the world’s experts on Familial HCM. It also gave me an idea to apply for an NHLBI grant. During my tenure at Washington University, I was an investigator in the prestigious Specialized Center of Research (SCOR) program, of which there were only nine in the USA, all dealing with ischemic heart disease. Having recently moved to Baylor College of Medicine decreased my chance of obtaining a SCOR, since it required a large multi-disciplinary infrastructure in ischemic heart disease. I thought to apply for a SCOR in familial cardiomyopathies would be novel and to our surprise, we were successful. We now had a training grant in molecular cardiology and a large SCOR program grant in molecular genetics. Dr. Christine Seidman (Cricket) would map the chromosomal location for the HCM gene to 14q1 ahead of us, however, we were able to confirm the same gene in one of our families. A lot of excitement was to follow as we mapped the first gene for atrial fibrillation, several genes for HCM and DCM as well as two genes for ARVC, and the gene for Wolff-Parkinson-White syndrome. In collaboration with Dr. A. J. Marian, currently Faculty at the University of Texas Health Science Centre at Houston, and at that time my Fellow, we developed the first transgenic rabbit for HCM which led to several studies on the pathogenesis of HCM. Cricket and I collaborated on several studies and we also became life-time friends.

The cardiology training program attracted the very best Fellows in the USA, Canada and Europe. Certainly, my 23 years as Chief of Cardiology at Baylor College and Methodist Hospital proved to be a very exciting and productive time, for which I am forever grateful.

In 2004, I returned to Canada as President and CEO of the University of Ottawa Heart Institute. I had come full circle, since Dr. Don Beanlands, my first mentor, was the Institute’s first Chief of Cardiology and on my arrival Don was Deputy Director General of the Institute. In terms of my own research career, it was now evident the technology was advancing to take on the big challenge, namely the pursuit of genes responsible for polygenic disorders, such as coronary artery disease and myocardial infarction. It was evident from the 1990s that to discover genes related to polygenic disorders would require, not families, but thousands of unrelated cases and controls and hundreds of thousands of DNA markers. At the time I was moving to Ottawa, Affymetrix was introducing a microarray with hundreds of thousands of DNA markers. Shortly after my arrival in Ottawa, I founded the Canadian Cardiovascular Genetics Center through the combination of a large donation of $5 million from the Ruddy family, a Canadian Foundation for Innovation grant of $11 million, and CIHR grants. This immediately put us in a position to be one of the early sites for genome wide association studies (GWAS) and I recruited Alexandre F.R. Stewart, PhD, a biologist from Pittsburgh. Ruth McPherson had already collected a large group of CAD cases and controls which were being genotyped through collaboration with investigators in the USA. We joined in with the first Affymetrix microarray and were fortunate to be part of the group to discover the first genetic risk variant for CAD, 9p21. This was the beginning of a terrific and exciting story, as we formed an international consortium, CARDIoGRAMplusC4D, comprised of several prestigious institutions in the USA, UK, and Germany, which proved to be an extremely productive time, with several publications in Nature Genetics and other prestigious journals. Currently, a total of 50 genes predisposing to CAD have been identified, of which well over half of them were discovered through us and the investigators in the consortium. The first major finding was that 35 of these genes mediate their risk independently of cholesterol, blood pressure or diabetes, which indicates the pathogenesis of atherosclerosis is associated with as yet unknown mechanisms, in addition to the known risk factors (such as cholesterol, blood pressure or diabetes). Due to the predisposing genes, we are identifying new pathways related to the pathogenesis of CAD which undoubtedly will provide targets for the development of new therapies.

In my activities as President and CEO of the University of Ottawa Heart Institute, I have again been fortunate to have superior faculty, staff, senior management and a visionary Board. In 2012, the Scimago Institutions Rankings (SIR) ranked the UOHI to be in the top 2% for research impact among 3,043 institutions world-wide. We tripled our research endowment to $50 million and we were recently approved for funding ($200 million project) to build an extension to the Institute which will enlarge the facility by 50%. My return to Canada has been exhilarating to say the least and I am indebted to the Board, the Senior Managers, faculty and staff for their support and sustained drive for excellence.

My advice to young investigators is to recognize that there is probably nothing more important than your training – every extra year spent in training provides several years of dividends for future success. Fortunately, medicine is a very exciting field and whether you practice medicine, with or without research, it is very rewarding and I can only recommend it with the highest enthusiasm.

--CV Network Vol 12. No 4


World-renowned Research Centre renamed

St-Boniface Hospital honoured Winnipeg visionary and philanthropist Paul Albrechtsen by renaming its Research Centre the St-Boniface Hospital Albrechtsen Research Centre. The Centre is the global headquarters of the International Academy of Cardiovascular Sciences where our Dr. Naranjan Dhalla was the founder of the Institute of Cardiovascular Sciences.

He was interviewed recently by the American Physiological Society's for their "Living History Program.

Click here to enjoy

WHAT A LECTURE!

3rd Harold Buchwald Lecture by Dr. Sharon Mulvagh, Mayo Clinic, Rochester

A STRATEGY TO AVOID HEART DISEASE!"

Click for An Important Conversation About Heart Health between Dr. Mulvagh and Marlo Thomas

If you missed the MANSHIELD CONSTRUCTION HEART HEALTH LUNCHEON featuring the 5th Harold Buchwald Lecture on October 3, 2013, please Click here for Dr Yusuf's extraordinary talk

Dr. Robert Roberts made a very special talk as the first Yetta and Jack Levit Distinguished Lecture. Click here to enjoy Dr. Roberts ' talk. On Nov. 2/15, Dr. John Cairns second Distinguished Lecture was extraordinary Click here for the lecture.

2nd Harold Buchwald Heart Health Lecture Sept. 29, 2009 ... an incredible talk by Dr. Jay Cohn which inspired Ivan Berkowitz to pursue a number of options which led to Dr. Duhamel's HAPPY Hearts Project. Click here to watch video

Read the latest bulletin from St. Boniface - excellent reports on IACS Fellows Drs. Menkis, Pierce and Kirshenbaum - great heart health advice!