My life, My heart, and My(osin) binding protein-C

Abstract

Although I currently lead a team of cardiovascular investigators at the University of Cincinnati, my beginnings were humble, as I came from a farming family in a small village in the southernmost part of India. The path I traveled was arduous, and it involved significant struggles, but I’ve finally realized many of my career goals. My story recapitulates the essence of some of the common career hurdles that many early-career cardiovascular scientists must overcome these days, and in this article, these career hurdles are discussed, as well as some strategies to overcome them.

This article presents common hurdles encountered by developing and early-career cardiovascular scientists and outlines some effective strategies to overcome these challenges. Students, whether at the undergraduate level or beyond, often do not establish clearly defined career goals, and even established long-term plans can encounter daunting, unforeseen stumbling blocks. It is convenient to blame our failure to succeed on a lack of resources, including family support or time constraints. Sometimes, however, our lack of success may simply depend on not being at the right place at the right time. Yet, fundamentally, it is the lack of resourcefulness, not resources, that poses the greatest barrier to achieving our goals. Resourcefulness is defined as the ability to find quick and clever ways to overcome difficulties. Resourcefulness involves optimizing the resources available to you by finding alternative ways to push forward. In the recesses of our minds, we all have an idea of our potential. In this sense, we are all obligated to create, make or change our environment, academic or otherwise, so that we can achieve our potential. Therefore, we must all strive to find the environment that will best nourish our innate abilities.

My life

I grew up in a village named Pattiveeranpatti located in the state of Tamil Nadu in the southernmost corner of India. This area is characterized by its fertile hand-tilled farmland, bright green rice paddies hemmed in by coconut palms, and rain. It rains nine months a year, and the air is unpleasantly hot and thickened by an unrelenting humidity. A scene from an ordinary day in my youth would consist of nonstop pounding rain creating small torrents of water running through the dirt streets in front of my parents’ dwelling. The rain would pelt our coconut leaf roof and test its resolve to keep us dry. Lacking electricity, our meals were cooked over a wood fire, and I studied in darkness huddled next to a kerosene lamp.

As the only son of farming parents, I was responsible for taking care of the cattle, typically feeding, coaxing and prodding them as needed. My early life in this farmland community was filled with duties crucial for our survival. I helped my parents with farm work before and after school and throughout the weekends. We used bullock-driven pumps to extract well water for irrigation of the crops. Frequently, I sloshed along with water buckets to the fields for planting and cultivation of coconut palms. My childhood captures the epitome of resourcefulness as I used my imaginative mind to carve out excitement in this stark environment. Long distances between farm houses limited friends and social activities; therefore, I imagined our calves to be my pets and took pleasure in watching them grow to maturity. I played in the mud, concocted games using stones and sticks, and constructed sand houses. I depended on my imagination and creativity during childhood and adolescence and, indeed, even now, as a scientist. My imagination aroused my curiosity, but my worldview was vastly limited, and I certainly harbored no grandiose visions of what I could become. Honestly, I could only realistically expect that it would involve some aspect of farming and be contained within the geographic confines of southern India.

In terms of academic and social enrichment, I did not participate in extracurricular activities or summer programs to bolster my academic potential. Since my family depended on farming for survival, education was considered a luxury; consequently, my education was not a priority for my family. All school subjects were taught in the official language, Tamil. We were not encouraged to think critically or problem solve because the education style was rote. Everything was memorized from the textbook and repeated verbatim in class. By the time I reached high school, I began to ponder where my studies might lead me, as well as contemplate my life’s ambitions. I considered diverse occupations, including farm agent, doctor or chemist. Chemistry was one subject that I enjoyed and one in which I excelled. However, when I applied to the American College in Madurai, India, to major in chemistry, my dreams were dashed because I had not earned the necessary credits in math. My only option was to pursue a degree in botany.

My undergraduate years stand in stark contrast to my life in a small farming village. My college town, Madurai, is the largest city in the state. Here, I had my first opportunity to lead my life apart from family concerns. As most subjects were taught in English, I needed to study and force myself to push outside my comfort zone. I participated in extracurricular activities, including the Naval Branch of the National Cadet Corps, which is equivalent to the Reserve Officers Training Corps in the U.S. I did not lay out a roadmap for my career or even develop any career goals by the time I graduated. As I was not in the top percentile of my class, I had little confidence in my academic potential, and my fear of failure prevented me from pursuing further studies. I lacked the ability to envision a clear future arising from my educational path. Therefore, I decided to find a job and settle into work life. The jobs I obtained were various and unfulfilling. For example, I worked in a spinning mill for a year, a restaurant for six months, and at an interior design company for another six months. During this time, I realized I was unhappy and discontented, and after consulting with friends and family, I decided that pursuing graduate studies would lay the foundation for a more fulfilling life. I immediately encountered two obstacles in that I had squandered away two years, and my academic record was less than outstanding. Consequently, the upper tier schools were completely out of reach, but my resilience and persistence was rewarded by obtaining the last seat in a panel of sixteen students admitted to a Master’s Program in Botany at the VHNSN College in Tamil Nadu. My matriculation into graduate school turned out to be a game-changing experience, as I became steadfast in my resolve to master my studies. In comparison to my undergraduate studies where my lack of ambition and drive was requited with unsatisfying job opportunities, my hard work and fortitude in the pursuit of graduate studies was recognized and rewarded. I graduated with distinction and received a prestigious gold medal for academic achievement. Here, by allowing innate self-driven motivation to take control, it was possible for me to set a goal and focus on a pathway toward successfully realizing it.

My heart

After completing my Master’s degree, I decided to pursue doctoral studies in plant biochemistry, focusing on strategies to improve photosynthesis of winter crops. I took up the idea after encouragement from my teachers as I had yet to develop a personal passion. In the absence of such resources as mentors and career advisors, or even the Internet, I began to understand the importance of resourcefulness and the need to make decisions that would best allow me to pursue doctoral work, and I chose to pursue plant biochemistry. Therefore, it was with that expectation that I joined the Department of Biochemistry at Madurai Kamaraj University, India. However, shortly after beginning my studies in Professor Rajamanickam’s lab, I learned that most of his PhD students were studying cardiac hypertrophy, a topic completely foreign to me as one who had never even taken courses in anatomy or physiology. Despite this, Dr. Rajamanickam was adamant that these studies would soon emerge as a vastly important field in the future based on the increasing mortality statistics, and encouraged by this, I committed myself to the study of pathological cardiac hypertrophy. For two years, I worked as a research assistant, supporting graduate students, learning about RNA and proteomics, and training in the technique of transverse aortic constriction surgery in rats to induce pressure overload. In the meantime, I qualified for my PhD thesis after taking the national level graduate aptitude test. My thesis project was entitled “Molecular aspects of cardiac hypertrophy.” Based on his international recognition and collaborations, most PhD students from Dr. Rajamanickam’s lab were able to pursue their postdoctoral studies in the United States, a goal I, too, hoped to realize.

Part of my PhD project required the collection of blood samples from patients with heart failure with the aim of discovering a novel biomarker. Every day, I went to the local government hospital to collect blood samples, which I would then take to the lab for ELISA analysis. I collected nearly twenty-five samples within six months, but this represented a very small cohort, and protein detection by ELISA was the only aim of the study. While this was not particularly exciting, I was concurrently reading papers from the Seidman Lab at Brigham and Women’s Hospital in Boston and the Schwartz Lab at the Institut national de la santé et de la recherche médicale (Inserm) in Paris, describing mutations in cardiac β-myosin heavy chain (MYH6) and cardiac myosin binding protein-C (MYBPC3) genes, resulting in familial hypertrophic cardiomyopathy (HCM). As an example of my growing resourcefulness, I approached my mentor with the idea that we could also perform mutation screening on these genes in Indian patients with HCM. Since the school had no facilities or resources to accommodate this type of study, I applied for an Indo-German Exchange Fellowship (DAAD) to visit the Max-Planck-Institute in Bad Nauheim, Germany, to work with the Professor of Medicine Hans-Peter Vosberg.

During the final year of my doctoral studies, I spent seven months as a visiting student in the Vosberg Lab. Through this rich experience, I broadened my knowledge of cardiovascular genetics and initiated a large collaborative project between Germany and India. I reasoned that the size and the genetic/ethnic variability within the Indian population would significantly broaden the scope of both genetic and clinical epidemiology. This population is also valuable and unique by its centuries-long cultural practice of supporting consanguineous marriages, which substantially raises the frequency of recessive mutations that contribute to HCM within this population. As a result of these studies, I identified four novel mutations, two in the MYH6 gene and two in the MYBPC3 gene in Indian families exhibiting HCM.¹

My(osin) binding protein-C

To bring the story back into perspective, it was this one big idea that launched the beginning of my career studying myosin binding protein-C (MyBP-C). Contractile proteins first caught my interest during my graduate studies when I discovered genetic alterations in sarcomeric protein coding genes in Indian patients with HCM. In the classic case of being in the right place at the right time, the Vosberg Lab was heavily invested in studying the regulation of cardiac MyBP-C (cMyBP-C) with respect to HCM. I finished my PhD in India and then returned to the Vosberg Lab for my postdoctoral studies. This decision was easy, owing to the familiarity of place and staff, but still difficult, as it meant a more permanent decision to leave my family and country. At this point, I return to the central thesis of this viewpoint: that we are all obligated to create, make or change our environment, academic or otherwise, so that we can achieve our potential and that we must all strive to find the environment that will best nourish our innate abilities. In this case, the Vosberg lab was precisely the venue that would give my research definition and purpose. Indeed, I was charged with establishing a mouse model expressing a mutation found in one of the Indian families in the MYH6 gene. To generate a cardiac-specific transgenic mouse model, I received the cardiac α-myosin heavy chain promoter from Dr. Jeffrey Robbins at Cincinnati Children’s Hospital for cardiac-specific transgenic expression of the mutant protein.

However, while this yielded the opportunity to learn about transgenics, I felt the trajectory of my career begin to stall after three years, particularly since I had made no major breakthroughs in my project and could claim no discoveries or major publications. This period of stasis motivated me to analyze this reversal and revisit my career goals, finally deciding to follow the steps that would take me to the next level. I traveled to the States and joined the lab of Dr. Robbins, a leader in cardiac transgenesis. Being willing to choose the right mentor at the right place and at the right time is a very critical step in the training program of early-career cardiovascular scientists. In my case, this was the second such “door-opening” opportunity to further define my career ambitions. Indeed, my initial project involved cardiac troponin I phosphorylation and function, and I built upon that knowledge to study cMyBP-C phosphorylation and function, which has remained the focus of my studies ever since.

Because heart failure is the number one cause of death worldwide, my long-term research career goal is to completely prevent and cure heart failure. My short-term goals are focused on studying the regulation of cMyBP-C in myocardial infarction and ischemia-reperfusion injury. Scientists often focus on a disease model, gene of interest, or some fundamental question during their research career. This is called establishing a branding or niche area. After publishing several articles about cMyBP-C based on my studies with Dr. Robbins,² I became recognized as a leader in the field of MyBP-C, believing with all my heart and soul that this would be my contribution to the search for novel interventions to prevent and cure heart disease. It is here that I found my research niche, and impelled by my own resourcefulness, combined with ample institutional resources, I was equipped to grow as an independent investigator. Since then, I have been working to unravel these mysteries as an independent scientist, starting at Loyola University Chicago with Dr. Pieter de Tombe³ from 2009 to 2016 and now at the University of Cincinnati.⁴

In summary, the cardiovascular field has unlimited training opportunities, and those who are resourceful, as noted previously, can take advantage of those opportunities, irrespective of origins or background. Resources can be provided by your mentor and institutions; however, resourcefulness has to come from you. As recounted above, my pathway was uneven at best, but at critical points, I made difficult decisions, which shaped my career along the way. Even though my early life was characterized by few resources, limited opportunities, and lack of a clear life plan, I firmly believe that my success is a product of self-motivating internal, not external, forces that allowed me to make decisions appropriate to my goals and take advantage of serendipity whenever it came along, as it did at least twice in the story I’ve told. Therefore, if you are unsatisfied with your present circumstances, know that you have the wherewithal to make course corrections, steer and push forward. With enough persistence, self-motivation and hard work, together with the skills you are now building, you can be successful and find your branding, your niche.⁵ It is my hope that this story will inspire early- career cardiovascular scientists to seize the opportunities before them and see where the road leads. Tomorrow’s priorities will change, so seize the day.

Figure.

A time series of Dr. Sadayappan’s career journey from farming community in the southern part of India, to the Max-Planck-Institute, Germany, Cincinnati Children’s Hospital, Loyola University Chicago and then to his present position at the University of Cincinnati, Cincinnati, USA.