Science as a Lifestyle
Ronglih Liao studied hard as a teenager in Taiwan, but science was just one among many wide-ranging interests. At age 17, however, her focus abruptly became clear when her father was diagnosed with lung cancer, eventually leading Liao to a career in basic science with the potential to translate understanding into therapies for both rare and common cardiovascular diseases.
After obtaining a chemistry degree, Liao fulfilled a promise to her late father to obtain an advanced degree overseas. For her PhD thesis at the University of Alabama Birmingham, she examined the interaction of troponin I with troponin C in bovine cardiac muscle.1 Then, Liao was recruited by 2 amazing mentors with independent laboratories and complementary expertise, Drs Judith Gwathmey and Joanne S. Ingwall, to undertake a collaborative project in cardiac physiology and myocardial energetics at Harvard Medical School. At the time, the concept that failing hearts were energy-starved was not yet accepted, and Liao deployed P31 nuclear magnetic resonance to detect decreased energy reserve in a model of dilated cardiomyopathy—baggy and sick turkey hearts—and establish its relationship to contractile performance.2
Liao set up her first independent laboratory at the Boston University School of Medicine, where she benefited from the university’s status as an internationally recognized center for the study of amyloidosis. Perfusing human immunoglobulin light chain proteins (amyloid precursors) into mouse heart, her laboratory was the first to demonstrate what the amyloidosis experts at Boston University had suspected—that amyloid light chain proteins were cardiotoxic and contributed directly to the pathogenesis and rapid progression of amyloid cardiomyopathy, independent of fibril formation and deposition.3
In 2005, Liao moved to Harvard Medical School, where she is now professor of medicine. At Brigham and Women’s Hospital, she directs the Cardiac Muscle Research Laboratory (since 2005), the Cardiovascular Flow Cytometry Core (since 2007), and the Cardiovascular Physiology Core (since 2010), aiming to bring innovative technologies to the cardiovascular research community. Liao continues her work on cardiac amyloidosis, identifying key stress-activated signaling pathways responsible for the light chain–mediated cardiac toxicity and subsequent dysfunction.4
Addressing the far-larger group of patients who may someday develop heart failure after myocardial infarction, Liao’s laboratory strives to understand the molecular mechanisms that mediate the transition from a normal to a failing heart. The laboratory identified a subpopulation of progenitor cells within adult myocardium that were capable of differentiation into functional cardiomyocytes.5 Her current research is focused on understanding the signaling pathways that regulate cardiac stem cell proliferation and differentiation in normal development, as well as after injury, and in developing approaches to manipulate and promote cardiac regeneration in vivo. In a recent article, the group revealed microRNA-34a to be a critical regulator of cardiac repair and regeneration in neonatal rodents after myocardial infarction, suggesting that modulation of miR-34a might be harnessed for cardiac repair in adult myocardium.6
In 2006, Liao became an editorial board member of Circulation Research, where she has published regularly since her first cardiac physiology paper was accepted there in 1993. She joined the American Heart Association’s Basic Cardiovascular Sciences Council in 1997, and begins a 2-year term as chair in July.
In a recent interview, Liao discussed her background, her plans for the Council on Basic Cardiovascular Sciences (BCVS), and the goal she has held since she first became excited about science—to translate her work to somehow help patients.
Where Did You Grow Up?
I was born and raised in Tainan, the major city in southern Taiwan, until I went to college at age 17. In many ways, Tainan is a museum in the midst of modern civilization. One can find footprints of history on every street corner with historic sites and temples, traditional industries, old stores and, most of all, tiny plates of traditional Taiwanese foods (such as dan-zai noodle soups, sticky rice wrapped in bamboo leaves, and oyster omelet), all juxtaposed with modern city life. In many ways, it is quite similar to Boston, my current hometown.
Tell Me About Your Family.
My father taught engineering education at National Taiwan Normal University. My mom was an accountant in her father’s company and a fashion designer in her spare time. As with many traditional Taiwanese women, my mother’s career took something of a backseat after she married my father, and her primary job was one of caretaker—of my grandparents, my father and her children. I have a younger brother who is a computer engineer. He and his wife and three children live in Taiwan.
What Were You Interested in as a Child?
I loved reading, playing piano, and art—watercolor and carbon sketch. However, after starting junior high school, much of my attention was focused on studying. Back in those days, entering college was quite competitive, and reserved for the few (about 10%) who passed a very rigorous senior high school examination and college entrance examination.
When Did You First Become Interested in Science?
Funny enough, I was interested in many subjects, including science, but it wasn’t originally my primary subject. When we took our college entrance examination, we had to rank list our area of study, and from this list and our examination score, we were automatically matched and enrolled in a certain department and university.
During this time, my father was diagnosed with lung cancer, and his illness had a profound effect on my perspective. So, I initially decided to apply for medical school but, somewhere along the line, I heard from someone (I can’t honestly recall who) that a doctor saves one life at a time, but a scientist can save millions from their discoveries. In the naiveté of youth, perhaps, I applied in the science category and was matched in the Chemistry department.
My four undergraduate years passed quickly, and I then fulfilled a promise to my late father that I would go abroad for an advanced degree.
What Appealed to You About the PhD Biophysics Program at the University of Alabama Birmingham (UAB)?
This program was introduced to me by a good friend who was several years my senior in college and was a PhD student in Biophysics at UAB. I always liked mathematics and physics and was intrigued by the combination of biology and physics. As a result, a college classmate and I both applied and were accepted to the program. We both ultimately joined Dr Herb Cheung’s laboratory for our graduate studies.
Why Did You Decide to Pursue a PhD Rather Than an MD? Do You Have Any Advice for Young People Trying to Make That Decision?
I really did not make a decision between a PhD and MD per se, because I came from overseas and the education system is a bit different. What I tell every student that comes to my lab, whether a high school, college or advanced degree student, is that either a PhD or MD requires hard work, persistence and dedication. If you don’t have the passion, neither one is for you. As for pursuing either a PhD or MD, it is critical that one really has good personal insight and understands what they truly enjoying doing. In the end, research can be pursued from either degree; I know exceptional basic scientists who are MDs and translational investigators who interact with patients that are PhDs. Of course, if clinical care is important to you, then the decision becomes a bit clearer and an MD is required.
How Did You Get Interested in the Heart? Were You Already Interested When You Started Looking at Troponin C With Dr Cheung?
My thesis work was focused on contractile proteins in the bovine heart. But rather than studying cardiac physiology, the work was very focused on biophysical properties at the protein level. And, to be honest, I had very little idea of what the heart actually was or what it did on a systems level. As a postdoctoral fellow, I became very involved in cardiac physiology. After I had the chance to perfuse a beating turkey heart using a Langendorff system, it was just magical to watch the heart beat for hours. Of course, the second and third heart I tried to perfuse in the same manner went into fibrillation and failed completely. The resilience and fragility of the organ were just fascinating to me.
How Did You End Up Doing Your Post-Doc Training in Two Different Labs, Under the Dual Mentorship of Judith Gwathmey and Joanne Ingwall?
I was recruited by Dr Gwathmey to take on a collaborative project with Dr Ingwall to measure cardiac energetic status in a failing heart. At that time, it was the beginning of what is now a more accepted concept that the failing heart was energy-starved. Dr Ingwall was a leader in myocardial energetics and her laboratory pioneered methodologies using P31 nuclear magnetic resonance (NMR) to measure energetic status in isolated hearts. Dr Gwathmey had a well-characterized turkey model of dilated cardiomyopathy. Therefore, I spent much of my postdoctoral time at Dr Ingwall’s NMR laboratory studying these baggy and sick turkey hearts. The dual mentorship I experienced was quite unique and beneficial.
How Did Working With Both of Them Allow You to Better Approach the Research Questions You Asked While a Research Fellow?
I was inspired by both of these wonderful mentors, and specifically their scientific wisdom, passion and devotion to science and their fellows. Dr Ingwall was an established investigator while Dr Gwathmey was a bit more junior at the time. I witnessed their academic career advancement, Dr Ingwall’s promotion to full professor and Dr Gwathmey’s to associate professor. As a female scientist, I considered myself very fortunate to be mentored by two female scientists with very different but complementary expertise.
Are There Specific Things You Learned From Each of Them That You Have Tried to Apply as You Set Up Your Independent Lab and Began Teaching and Training New Generations of Researchers?
The major things that they have in common are their passion for science and their devotion to their trainees. I learned resilience and courage in the face of hardship from Dr Gwathmey. I learned clarity of thought and how to overcome scientific hurdles from Dr Ingwall.
What Has Been Your Most Surprising Finding? Was Anything Completely Unexpected That Sent You Off on an Unanticipated Path?
There have been a number of surprising findings during my academic career, several of which came quite early on. As a young faculty member, before the concept of cardiac stem cells or induced pluripotent stem cells (iPSCs) had been proposed, we worked on a very rudimentary forms of cell therapy. We collaborated with a local biotech firm to transplant skeletal myoblasts into the heart. We were quite skeptical that this approach would work at all; it was all very science fiction to us. We were blinded to the animals in each group and, only after completing a battery of experiments, were we unblinded to find that there were clear differences. Skeletal muscle implantation had somehow improved functional recovery of hearts post myocardial infarction.7 We were so skeptical that we repeated the experiments and found the same results. These cells, once implanted in the heart, didn’t transdifferentiate into cardiac cells, but rather formed what appeared to be skeletal muscle. These observations were the initial studies that prompted my interest in endogenous repair mechanisms within the heart. Soon afterward, we were able to identify and characterize a population of cells within the heart, called side-population cells, which retained the capacity for endogenous cardiac repair.
How Did You Get Interested in MicroRNA-34a as a Player in Cardiac Repair and Regeneration?
This interesting molecule was uncovered from our studies on endogenous cardiac repair. As many are aware, an interesting aspect of the heart is that, right after birth, the heart still has amazing regenerative capacity, which is lost over time. By profiling cardiac side-population cells isolated from neonatal hearts, and looking for differences in microRNA species relative to adult hearts, we stumbled upon the tumor suppressor miR34a as a potentially interesting regulator of cardiac regeneration. We found that, by manipulating miR34a levels, we could induce better cardiac repair and perhaps regeneration.
What Is the Next Step in Understanding This Mechanism and Evaluating MicroRNA-34a as a Possible Target in Therapy After MI?
Our ongoing work is to test whether using locked nucleic acid (LNA) with nanoparticles to antagonize the entire miR34 family is able to enhance cardiac regeneration following chronic MI in an adult heart. Related to this, we are also keeping our eyes on the results of an ongoing multicenter clinical trial using a miR34a mimic (MRX34, Mirna Therapeutics) for antitumor therapy for primary liver cancer. With the introduction of biological therapies for cancer, there have been new cardiac toxicities; these observations can teach us much about specific signaling pathways in the heart.
You’ve Been Working on Amyloid Cardiomyopathy for Many Years. Can You Describe How Basic Research Has Changed Our Understanding of the Disease and Where Things Stand in the Identification of Potential Treatments?
Yes, absolutely. Our work in amyloid cardiomyopathy was brought about by a rather serendipitous interaction with Dr Rodney Falk, who is a world expert in this relatively rare disease, and Dr Carl Apstein, a mentor during my early career at Boston University, a world-class center for the study of amyloidosis. For decades, if not centuries, the belief was that amyloid-related diseases were the result of passive deposition of mutant proteins in tissues and, in the case of the heart, passive restriction of filling. During some chance meetings, Dr Falk relayed a rather curious observation—that the degree of cardiac dysfunction in patients had little relation to the degree of infiltration within the heart, and Dr Falk hypothesized that certain mutant proteins may be inherently toxic. We had the tools in the lab to test this idea, and we quickly obtained some human light chain proteins from patients with and without amyloid cardiomyopathy and infused them into a beating mouse heart.
What we found was that the proteins that caused amyloid cardiomyopathy in humans also caused cardiac dysfunction when acutely fused into a heart, independent of any deposition. This launched the idea that amyloidogenic proteins are inherently cardiotoxic and, over the last decade or so of work, we have tried to understand this cardiotoxic process. This area of study has truly been gratifying, in that it is organically translational. The project stemmed from an astute clinical observation, and we have been able to leverage human biosamples, notably amyloid protein, to uncover some of the mechanisms at play in cellular systems. Our very understanding of the disease pathophysiology has shifted from a restrictive cardiomyopathy caused by passive filling to one that has a clear cardiotoxic component as well. As we continue to uncover the signaling pathways that mediate this disease, we are perhaps identifying critical aspects that may be targeted with new therapies. I am hopeful that several of these new therapies will be tested in the not too distant future in early human trials, especially given the very poor prognosis and lack of targeted therapy for patients with AL amyloid cardiomyopathy.
What Are You Working on Now? Is There an Element of Your Work That You’re Most Excited About?
We are particularly excited about our efforts to identify markers for the earlier diagnosis of AL amyloid cardiomyopathy. In collaboration with Dr Sharmila Dorbila, a cardiovascular imaging physician at Brigham and Women’s Hospital (BWH) and her team, we are testing whether noninvasive imaging can detect proteotoxicity in patients with amyloid cardiomyopathy. What is exciting about this work is that the imaging techniques may not only allow us to monitor cardiac function but may also lead to a readout of actual active proteotoxicity from external mutant proteins. Moreover, we are developing experimental toxicity assays and molecular imaging to guide therapy in patients with amyloid cardiomyopathy. This work is immediately translatable to patients and really is exciting to us.
Mechanistically, we have established a number of collaborations with laboratories around the world to work together to understand the mechanisms underlying amyloid cardiomyopathy. These collaborations span clinical centers, protein biochemists, cardiac biologists, and even former mentees of our laboratory!
What Are Your Goals for the Lab in the Next Few Years?
As has been the case in biomedicine previously, especially with monogenic diseases, understanding rare conditions can provide insight into more common forms of disease. The insights that we uncover in studying amyloid light chain (AL) amyloidosis may be readily applicable to other amyloidogenic proteins that affect the heart, as well as amyloid proteins that affect the brain and other tissues. I am really excited about the idea of external proteotoxic stress, especially since the signaling pathways activated by this response may be unique and may, in the coming years, help us understand cardiac health and disease. Along the same lines, we are also continuing our efforts to understand endogenous repair mechanisms. It is likely that these different areas of science and biology will converge in the upcoming years.
How Hard Do You Work? Can You Give Me a Rough Idea of How Your Working Hours Divide Between Hands-on Research, Supervision, Teaching, Writing Grants and Articles, Reviewing Articles, etc?
(Laughs.) It is hard to count hours of “work” when you are doing something you love and want to keep going until it is finished. I typically arrive at my office before 7 am and spend 12 to 13 hours at the office and laboratory. Almost all my time is spent supervising my students and fellows, writing grants and manuscripts, and reviewing papers and grants. The exact breakdown varies substantially from day to day and week to week. I also spend some time in my role as Director for the Cardiovascular Physiology Core and Flow Cytometry Core at BWH.
What Do You Like to Do in Your Spare Time?
Although my spare time is markedly decreased these days, I like to read whenever I can, especially history or science fiction. My mother stays with me more than half the year. When she is with me, I try to spend as much of my spare time as possible with her, walking in the park, window shopping at the mall, and watching her favorite cooking and travel shows (which I translate, as she doesn’t speak much English).
Can You Tell Me About Your Family? Are You Married? Are There Any Budding Scientists?
Oh yes, I am married to science and have a big family. All of my students and fellows are my “kids,” and I lost count of how many of them there have been over the last couple of decades! Most of them, if not all, are budding scientists, and I am very proud of each and every one.
What Does It Take for Young Researchers to Succeed?
The recipe for success in the research world, I believe, is the three Ps—Passion, Persistence, and Perseverance. Follow your heart to choose a research topic you find so interesting that it makes you wake up in the morning and think. Science is a lifestyle as much as a job, and you have the burden and reward of truly loving what you do. I always tell my students and fellows, the key to a successful career and life is to be able to work hard and play hard—that means you must work smart and work collaboratively. Before we can find a cure or treatment for a disease, we first need to help each other as teamwork is a very important part of the research endeavor.
As This Goes to Press, You Will Soon Have a New Role as the Chair of the AHA’s Council on Basic Cardiovascular Sciences (BCVS). What Are Your Plans for the Council?
The BCVS is the home for cardiovascular basic and translational research. I am very humbled to have this opportunity and pledge to lead our council to the best of my abilities. The top priorities of BCVS are to mentor trainees, to promote early-career-stage investigators, and to invigorate mid-career-stage investigators as well as to recognize the accomplishment of established investigators. I would also like to promote greater participation in the council by female trainees and scientists as well as under-represented minorities at all career stages.
We are actively raising funds to provide council membership and admission to the annual scientific meeting for 50 to 75 trainees/early-stage investigators/minority members during the two years that I serve as council chair. We will announce the program formally once we raise sufficient funds. Last but not least, as a female scientist, I plan to organize an informal gathering of “Women in Science” to promote the exchange of knowledge and ideas—from scientific questions to career development and work/life balance issues among women at all stages of their careers. Building a strong and better council is a team effort. If you are not yet a member of BCVS, I encourage you to join and participate!
- © 2016 American Heart Association, Inc.
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