Sunny Hartwig's blog

Dr. Sunny Hartwig is a new investigator at the University of Prince Edward Island. She obtained her Ph.D. from the University of Toronto and completed her Post-Doctoral Fellowship with Dr. Jordan Kreidberg at the Children’s Hospital Boston, Harvard University. In her research, Dr. Hartwig will study the role of SoxC genes in early kidney development and how these genes are regulated by WT-1, to help provide new insights in the development of Wilm’s Tumour during childhood and lay the foundation for new therapeutic strategies that will treat, reverse and ultimately prevent kidney disease in these children.

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Our first manuscript

It has been a busy year, a busy summer, and today is a busy Monday. There are grants to be written, students to teach, data to analyse, experiments to plan, problems to address, and meetings to attend. But the words of Herman Hesse ring like a quiet bell: The greatest crime is an unreflected life.  And so I stop; and I acknowledge a very special moment for our lab, and for me as a young investigator. Last Friday, we submitted our lab’s first manuscript for publication. As I consider the journey that has brought us thus far, it is one marked by hardship and anxiety, but it has been more deeply marked by providence and grace, by the wonderful contributions of extraordinary people committed to our research and committed to one another.

I remember the day I met Dr. Jordan Kreidberg, who gave me the opportunity of a lifetime – to join his lab as a postdoctoral fellow at Harvard Medical School. One of Dr. Kreidberg’s research aims is the study of the pediatric kidney malignancy Wilms’ tumor (nephroblastoma), which, with an incidence of 1 in 10 000 in North America, is the most common solid cancer in young children. 10-20% of Wilms’ tumour cases are caused by mutations in the gene scientists have named Wilms’ tumour suppressor-1 (WT1). Genetic studies have demonstrated that WT1 is a ‘master regulator’ that instructs the developing kidney to differentiate and develop into a mature organ. One analogy that resonates with me is the likening of WT1 to the orchestral conductor who gives the ‘cues’ that enables the musicians to perform the musical piece in harmony and unity. In the same way, WT1 executes the genetic cues that orchestrate the miraculous transformation of an undifferentiated mass of embryonic tissue into an organ of magnificent complexity and function. Thus, when WT1 function is lost, those critical genetic ‘cues’ are not executed, leading to a failure of normal differentiation. Instead, developing kidney cells become locked in a continual cycle of proliferation, leading to tumor formation.

As a KRESCENT-funded postdoctoral fellow in Dr. Kreidberg’s lab, I had the privilege of using cutting-edge technology and state-of-the-art facilities to ask a simple question: What are those genetic ‘cues’ with which WT1 instructs developing kidney cells to differentiate? More concisely, my research aim was to identify novel kidney genes that are activated by WT1 to control normal kidney differentiation, and by corollary, whose loss of function could be the ‘smoking gun’ that causes WT1-related human kidney disease.

At the end of my 3 years of research in Dr. Kreidberg’s lab, I had generated a list of over 400 potential candidate genes – any one of which might play a critical role in normal kidney development and disease. It was my task to choose which ones I would pursue to study as the basis of my own research program as a new investigator. While none of these 400 genes had been studied in the kidney, I hoped that by studying their function in other developing organs, I could gain clues about what they might be doing in the kidney.

I was still finishing my research project with Dr. Kreidberg, so my ‘detective work’ had to be done on evenings, and almost every weekend for almost 6 months. I smile as I write these word, remembering the long nights, the sweat, the tears, the knots in my stomach, and the hope of discovery - as over the course of 6 months, I painstakingly and prayerfully studied all of the published information about each of these 400 potentially very important kidney genes! Even as I write these words, I am so grateful for the incredible patience and understanding of my husband Daniel - who did all of the housework, all of the grocery shopping on top of his own full-time job, and who so lovingly cared for his sleep-deprived and anxious wife through those 6 months of late night study.

I remember the day I came across the gene called Sry-related high mobility group (HMG) Box (Sox)-4 (Sox4). I had organized the 400 genes by alphabetical order, and began my examination of Sox4 after 6 months of previous study. (If only I had arranged my list in reverse alphabetical order!) What immediately arrested my attention was the discovery that other members of the Sox gene family have been shown to play master roles in a multitude of developmental processes, including controlling the process of cell differentiation of the developing brain, heart, spleen, gonads, spinal cord, and axial skeleton. But no one had looked at Sox genes in the kidney yet!  [A little side bar: When I was younger and still single, my big sister would always tell me that when it came to finding the right person, ‘you’ll just know’. Her words, though spoken kindly were at the time unhelpful (and not well-received I’m afraid), but were nevertheless true, as I later discovered. And it was the same kind of ‘eureka!’ moment when I ‘just knew’ that I had discovered a gene that was important, perhaps very important in the developing kidney.]

Then began the intensely humbling, incredibly arduous, yet paradoxically hope-ridden process of ‘grant writing.’ As I look back on that time, writing my first Kidney Foundation grant in 2009, I am thankful beyond words for having been a KRESCENT trainee. One year before I began writing my grant in 2009, I had spent 2 intense days with the other KRESCENT trainees in November 2008, learning from our nation’s top kidney scientists what constitutes a good grant, and then, what elevates a good grant to the level of excellence. At the end of our training session, we were given the assignment of writing a complete mock Kidney Foundation grant for peer review in six months time. So, in early 2009, I and the other trainees submitted our mock grants, and then reconvened in April 2009 at the KRESCENT training session to participate in a mock grant review panel. What an eye-opening education to sit at a round table discussion with my peers and with world leaders in kidney research, critically appraising the merits and weaknesses of each grant that was submitted for peer review – a powerful and practical exercise that taught each of us how to improve the level of our grantsmanship. I am thankful to recognize that this granstmanship training was instrumental in my own successful Kidney Foundation grant in the 2010 competition. When one considers how many hours and how much effort our KRESCENT mentors have invested into our professional growth and training as scientists – and how many responsibilities our KRESCENT mentors have as physicians, researchers, leaders of their institutions, as well as simply human beings with families – one cannot help but be humbled and inspired by their examples of unselfishness, service, and commitment to the future of kidney research in Canada. I am grateful to recognize the impact that the servant leadership of our KRESCENT mentors has made on my own life both professionally as a human being.

Fast track ahead 3 years to June 2012. A few months ago I had the privilege of speaking at the AGM for the Atlantic Canada Chapter of The Kidney Foundation. It was an honour to be able to share what we have accomplished in the lab, with people who have literally gone door to door to support our research. It was such a special moment when I could share with them that just a few weeks before, we had discovered that animals lacking Sox4 develop end-stage renal failure – genetic evidence that Sox4 indeed plays an essential role in normal kidney development, and in disease. In many ways, our work has just started, but as I look back, the journey started back in 2006 when as a KRESCENT trainee I was given the opportunity of a life-time to study with Jordan Kreidberg. Then in 2008, again in the KRESCENT program, I was taught by world experts, how to write a strong grant. And then, 6 years later, we realized that the risk we had taken to base our research program on the faith of ‘I just know’ that Sox4 is a key gene in the developing kidney – we realized that it was true. And now, August 2012, the paper is submitted for peer-review and publication.

We live in a cynical world, and it is so easy to look at the challenging economy, the pressing deadlines, the high expectations that at times seem impossible to meet. As I look back on our journey thus far, I do recognize that the journey has been marked with hardship and anxiety, yet I am reminded that it has been more deeply marked with providence and with grace. I will write in another entry about the incredible people who have joined our research group, how at each pivotal moment - when we hit an obstacle and I was at a loss as to what to do -  an extraordinary person has come along, and lent their dedication, their expertise, and above all their commitment to the research and to one another, to help us overcome each obstacle we have faced, one step at a time.

A Few Words About the Father of Dialysis

At a dialysis research conference this spring, I was both fascinated and moved to learn a little about the ‘father of dialysis,’ Dutch-born physician Willem Kolff. In the 1930s while working at the University of Groningen Hospital, the young Dr. Kolff witnessed the slow and painful death of a 22-year-old man with acute kidney failure. This singular experience was a watershed moment in Dr. Kolff’s medical career, leading him to invent one of the foremost life-saving developments in the history of modern medicine – the hemodialysis machine . Working clandestinely in a small rural hospital in Nazi-occupied Holland, Dr. Kolff persevered to build the first artificial kidney in 1943, at significant risk to his own life as well as the lives of his family and colleagues. Wartime scarcity of materials was exemplified in the component parts of the early Kolff drum dialyzers, which remarkably included sausage casing, orange juice cans, wooden drums, as well as parts taken from a car, a downed fighter plane and a washing machine! In 1945, Dr. Kolff conducted the first successful dialysis treatment.

Dr. Kolff moved to the US following World War II, where he continued his research at Mt. Sinai Hospital in New York. Through collaboration with Dr. George Thorn at the Peter Bent Brigham Hospital in Boston, and others, the updated Kolff-Brigham became the standard of kidney care by the late 1940s, changing kidney failure from a fatal condition to a treatable disease in the United States.

As a Korean-Canadian myself with an uncle who was killed in action in the Korean war, I was personally touched to know that the Kolff-Brigham dialyzers were used to save the lives of Allied soldiers in frontline hospitals during the Korean War - including men who had acute potassiumintoxication following massive emergency blood transfusions, or those who had suffered post-traumatic renal failure following exposure to carbon tetrachloride contained in poison gas.

When I read the announcement of the 2002 Albert Lasker Award for Clinical Medical Research (unofficially considered by many as the ‘American Nobel Prize’), which was jointly awarded to Dr. Kolff and to Dr. Belding Scribner, I was amazed to learn that another incredible medical breakthrough in the field of nephrology could also be traced back to Dr. Kolff’s invention. In fact, the success of the Kolff-Brigham dialyzer in treating renal failure in the 1950s opened the door for the establishment of the first major program for hemodialysis in the United States, which in turn paved the way for the first kidney transplant in 1954!

Dr. Kolff’s story encapsulates the incredible significance of clinical kidney research. For me as a scientist, his story is also an object lesson from history, demonstrating the potential far-reaching, life-saving benefits to human health of every new biomedical discovery, even those that may not immediately relate to bedside interventions. Today, the foremost areas of clinical kidney research continue to be improvement of patient outcomes and quality of life via advances in current dialysis practices, transplant tolerance, and early detection of kidney disease.

  Dr. Willem Kolff

Yet despite the great advances that have been made in the clinical arena, we are still a long way from understanding some of the most basic biological questions about how kidney disease occurs. What goes wrong inside a normal kidney cell that ultimately causes the entire organ to fail? What are the cellular and molecular mechanisms that become pathologically activated in kidney disease? Clearly, in order to answer what goes wrong in disease, we need a normal frame of reference for the sake of comparison. In other words, we first need to understand normal biology before we can understand the pathobiology of disease.

And that is why another major arm of kidney research is basic biomedical research – or ‘basic research’ for short. By definition, basic research explores the fundamental or ‘basic’ biological mechanisms that govern normal kidney function and development, and from this basis investigates pathological deviations that may lead to disease. The overarching aim of this type of basic kidney research is to identify strategic areas where we can intervene before the kidneys fail - to design interventions to treat and reverse the progression of disease, so that someday, there will be less patients with kidney disease.

I once heard a man pose the rhetorical question “Which wing of the airplane is more important for flight?” I am certain that just as a plane needs both wings to fly, the future of kidney health both in Canada and the world depends on the equal partnership of clinical and basic research to advance patient care and quality of life and, ultimately, to reduce the number of future patients by reversing and preventing disease altogether. For myself, it is this hope and conviction that keep me in the research field, despite all of the mental, emotional, and physical challenges of research. Thomas Edison said that “Genius is 1% inspiration, 99% perspiration”. If my life’s work ends up being like the sausage casing, or used car part that a genius like Dr. Kolff can use to save someone’s life or improve the quality of life of a kidney patient, it will have been worth the lifetime vocation of perspiration and dare I say it, dedication :O)




An Update on Teaching
As of yesterday, I have just completed my first year of teaching clinical renal physiology to the first year students in the Doctor of Veterinary Medicine (DVM) program at AVC (Atlantic Veterinary College). It has been an incredibly edifying, albeit singularly arduous journey these past three months as a basic scientist specializing in embryonic kidney development, to learn to speak the language, however falteringly, of adult kidney disease. As a trainee in the KRESCENT program for the past 4 years, I have been so privileged to learn alongside clinicians, epidemiologists and basic scientists specializing in adult kidney disease. Yet throughout this time, I have keenly felt the gap in my knowledge of adult renal physiology and adult kidney disease. So in spite of the past three months of study and preparation (and the exponential increase in my grey hair count as I’ve wrestled to teach the material to the students in a way that will engage and inspire them), I look back on this past season with a rare sense of accomplishment, and with gratitude. The gaps of my knowledge of the kidney are diminishing. I feel better equipped and empowered, both as an educator and as a scientist, as my knowledge grows in three key areas in human kidney research, namely adult renal physiology, pharmacodynamics of drugs actions in the kidney, and the pathophysiology of adult kidney disease.  

According to Albert Einstein, wonder is the beginning of Science. I believe he was right. I’ve thought of his words quite often as I’ve studied these past months, in the many moments that I have been wonderstruck at the incredibly intricate, integrative and simply beautiful design of our kidneys. I am amazed at how many essential functions of the human body are overseen by our kidneys – like the regulation of salt and water balance, which in turn keeps our muscles working, our neurons and nerves signaling and keeps our hearts beating. How our kidneys play such a key role in second-to-second blood monitoring to keep our blood clean from harmful toxins – and how in this context as a giant blood ‘filter’, the kidneys receive more blood on a  per kilogram basis than the heart or even the brain - that’s how important our kidneys are! How about the central role our kidneys play in maintaining a healthy blood pressure and normal blood volume, how our body’s pH (our body’s acidity), our red blood cell count and even the health of our bones, are all intimately connected to kidney health. Over the past 19 centuries, our understanding of the kidney as a vital organ has certainly progressed from the Aristotelian observation that the kidneys are not essential for the existence of a living organism…

Along this three month journey, I have also become convinced, as I’ve learned more about the pathophysiologic mechanisms that underlie kidney disease, that simple genetic errors in the embryonic developmental program of the kidney in utero, left unchecked, are responsible for much of the kidney disease observed after birth. I am left with a renewed sense of conviction that the efforts of scientists around the world to understand the genetic developmental program that directs normal kidney formation, are truly important efforts. For once we define the battery of key genes and the cellular and molecular mechanisms by which they direct normal kidney growth, branching and differentiation in utero, we will be able to understand what goes wrong when these genes fail to perform normally, which in turn will provide the first clues of how to correct these genetic errors. This knowledge of the genetic code underlying kidney development and disease can then be translated into clinical interventions to practically correct genetic errors and re-establish normal kidney development in affected individuals, so that after birth, renal function will be saved. I am so hopeful that we will see these life-saving interventions within our lifetime.

I have included a photo of the class of 2014. I have had the privilege of teaching 60 extraordinary first veterinary year students for the past semester, and it has been an honour to contribute to their learning, to learn their stories, to learn from them, even for this brief time. They come from such diverse backgrounds, but for all of them, veterinary medicine has been a life-long dream, and to journey with them as they pursue their dreams, has thus far been a very precious highlight of my (short) career. Emerson wrote that “what lies behind us and what lies before us are tiny matters compared to what lies within us.” At this juncture of my career, there is still so much I need to learn as an educator and as a scientist. It helps me to remember that no matter how inexperienced we may be in career and in life, we each of us have something significant to give, because we all have love to share. We can come along side and encourage others on the journey, and we can help those beginning their paths as we ourselves have been loved, encouraged, and helped.
This is not a grant. This is not a paper. This is a lab meeting!

Hello folks,

I’m sorry it’s taken me so long to write.  It’s been with a rueful chuckle that I finally understood (at least part of) my hesitation in writing my next blog entry. I shall now try to use my tardiness in blogging as a platform to share my life as a fledgling PI (principal investigator) and also explain the three major forms of scientific writing!

Sunny and members of her lab

As basic scientists, we devote our efforts and energy in trying to solve meaningful biological problems. As a kidney researcher, my passion is to understand the mechanisms underlying human kidney disease. One generally starts with an overarching, big-picture question like “what is the function of Gene X in the developing kidney and how do mutations in Gene X give rise to tumour formation?”

Next, one discovers all one can learn about Gene X by performing a comprehensive literature search. To perform a literature review is a daunting task (at least it is to me), by virtue of the seemingly endless numbers of articles published on Gene X in so many different journals, often with conflicting results. It is for this reason, namely of helping rank a given article’s scientific merit, that the peer-review process is so important. Articles must pass through a review process by multiple experts within the same field in order to be accepted for publication. As a general rule, the higher the standing of the journal to which the article is submitted, the more rigourous the review process. Therefore, the journal in which a given article is published, necessarily informs as to the article’s scientific merit (how good is the science?) and its importance (what impact will this work have on human health?).

Now having ascertained what is publicly known about Gene X, the scientist then interprets the results and formulates specific, testable hypotheses about what Gene X might be doing in the kidney, and then rigourously tests these hypotheses in various models, using all the technology and molecular biology tools available (and within budget!!). Based on promising, positive results from preliminary experiments, one then sits down and begins that most critical, and singularly arduous and stressful of tasks: writing a grant!

Please believe me when I say that grant-writing must be one of the most excruciatingly painful necessities of life as a scientist.  Though I can’t speak for anyone else, as a junior PI, my grant is the culmination of years of work, sweat and tears. It represents my hope for making a meaningful contribution to kidney research, and encapsulates my dreams and vision for the future of my research program.  A wise man once said that the people who influence you the most are the ones who believe in you most. I have certainly found this adage to be true in my own life. In this light, getting our research funded is a tremendously encouraging affirmation, for in a very real sense, it means that your peers believe in you, and believe in the value of your work. Painfully, on the flipside, I can think of few things in the life of a scientist more disheartening or demoralizing than having a grant rejected, for in one sense, it is a rejection of your vision as a scientist. Another wise man, King Solomon, said that without a vision, the people perish.

My next door neighbour Verna Bruce (a very wise and beautiful soul) continually encourages me to change a negative into a positive. So let us imagine that the grant has been funded, thank heavens, and we have been actively engaged in research for the past year! At the beginning of the blog I mentioned that there are three major forms of scientific writing. The second major form of scientific writing is initiated once the current research project is near completion. At this stage, our goal is to share our findings with the kidney research community in an abstract presented at scientific meetings such as the annual meetings of the Canadian Society of Nephrology (CSN) or American Society of Nephrology (ASN). In so doing, we help disseminate knowledge within the kidney research field, we receive helpful advice and criticism about our work, and we forge collaborations with other researchers across the different kidney research disciplines.

Finally, once our work has passed the rigours of peer-review at a major scientific meeting, our goal is to publish our work as a peer-reviewed article in a journal of high scientific standing. Now the article submission is the culmination of all our grant-writing, our subsequent research to fulfill the grant objectives, and our presentations at international scientific meetings. Ultimately, our goal is that our article tells a meaningful story, one that contributes valuable information to the current fund of knowledge within our discipline of kidney research.

By virtue of the fact that these last two forms of science writing (the abstract and the article) represent the completion of a job (hopefully) well done, these writings, while being equally important as grants, have the magnificent benefit of being far more enjoyable to write!

In the process of struggling with my reluctance to write a new blog entry, I stumbled upon the realization that I have unconsciously categorized all my writing as a scientist into one of these three boxes: grant, abstract, article. My first blog was like a grant – I had shared my dreams and my vision. In my mind’s eye, the next submission needed to be Results! Or Completed Research! Or at least A Scientist Who Doesn’t Feel Like She is Just Learning to Navigate Managing Her Own Research Program!!

No more! I have invented a new category of science writing for myself: The Electronic Lab Meeting!

Now the lab meeting is not about Completed Research, or even about Great Results all the time. It is more about What have you been doing? What have you been learning,? If I’ve failed, how did I turn a negative into a positive? If I’ve succeeded, let’s celebrate the victory! The lab meeting is a time for cookies and coffee (and pizza once in a while), and for sharing breakthroughs, frustrations, funny stories and moments of revelation. It’s about celebrating the journey with your lab mates. And it’s also a Regularly Scheduled Meeting. So if you don’t mind sharing lab meeting with me, I’ll be in touch soon(er)…

New beginnings
On November 4, 2009, following completion of my postdoctoral fellowship, my husband Daniel and I left Boston in a 24-foot Penske moving truck, and began the long trek home to Canada, to ‘the Island’ (as Prince Edward Island is called around here). Gradually, the gray silhouettes of high rise buildings, the clamourous traffic, and confused maze of Boston roadways, gave way to an open landscape of big sky and silence, along a single straight road, heading north. Two days later, we crossed the Confederation Bridge onto the Island and were greeted by a landscape of rolling hills, red soil, and everywhere, a sense of quietness and peace.

How wonderful to be back in Canada, our home, and to hope and believe that I may play my part, however small, in the nation-wide research effort to improve the lives of children and adults with kidney disease. As I begin my career as an independent kidney researcher, I am deeply grateful to all of the men and women across Canada who have so faithfully gone door-to-door, and given up evenings and weekends, to help raise the funds needed to support kidney research in Canada. What a privilege to be able to begin paying forward the outstanding training that has been entrusted to me by the Kidney Foundation and by my KRESCENT mentors – to play my part both as a basic scientist in understanding the mechanisms underlying kidney disease, and as a teacher, to help inspire and equip the next generation of kidney scientists in Canada.

It is hard to believe that it has almost been 6 months since I began working in the Department of Biomedical Sciences at the Atlantic Veterinary College (AVC), at the  University of Prince Edward Island (UPEI).  There have been so many ‘firsts’ here. First faculty position. First office. First laboratory. First experiment in the lab. First result! First class. First students! First grant applications. First grant! First kidney researcher on the Island! It is an overwhelming experience to be so new in every area, to have a learning curve that is so steep. With so many things to learn, so many new responsibilities and expectations (both from within and without), and so many new ‘hats’ to wear, one of the most important lessons I am learning during this process is to ‘keep the first things first.’ A wise man once said that in every life, there are things of first importance, and things of second importance. ‘First’ things are the foundation, the cornerstones upon which the ‘second’ things must stand. Always keep first things first. If we make second things first, we will achieve neither the second nor the first things, but by keeping first things first, we may by earnest effort and perseverance, achieve both.

As I now begin my own research program, the first things are clear and simple. To begin with, I must build a strong and effective research team. Thankfully, I have been blessed with a truly wonderful and dedicated technician, Ms. Nicole MacDonald, whose 12+ years of molecular biology experience in our university and whose generosity of spirit have been invaluable to me as I learn to navigate in a new environment. More recently, 5 earnest, bright, and incredibly dedicated students have also joined our lab. As a junior faculty member, I am grateful to be surrounded by a warm-hearted and supportive community of senior colleagues and mentors; I am very grateful to our Dean, Dr. Don Reynolds, and the Chair of our department, Dr. Tarek Saleh, for their outstanding research support and mentorship.

Finally, as the leader of my fledgling kidney research team, I must provide the vision of my research program, and I must inspire and direct its course. Our short-term vision (3-5 years) is clear: to carry out to peer-reviewed publication the research outlined in my Kidney Foundation grant, namely, to define the function of a novel family of kidney development genes called SoxC genes in the critical processes of self-renewal and differentiation of kidney progenitor cells during embryonic kidney development. In the long-term, it is my earnest hope that this research will contribute foundational knowledge that can be translated into regenerative therapies that will treat, reverse, and someday, prevent kidney disease in patients.

A few days ago, I attended the Canadian Society of Nephrology conference in Montreal, and was officially welcomed back into the KRESCENT Program. KRESCENT mentorship has been truly transformative for me on my research journey, and in an upcoming blog entry, I will do my best to share with you what KRESCENT has meant and continues to mean to myself and the other trainees.

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