Academic Spotlight: Hongmei Ruan, MD, PhD
Coaxing Secrets from Pacemaker Cells
Hongmei Ruan, MD, PhD, wanted to become a doctor to help people with cardiovascular disease, but her career path led her in a slightly different direction.
Born in China, she earned her medical degree from North China Institute of Science and Technology. “We had one year of clinical rotations in the hospital, and I realized that it was really hard to get a good outcome from [existing] treatments for some diseases,” said Dr. Ruan. “That was kind of disappointing, and made me want to focus on research so maybe I could help improve those outcomes.”
So after graduating from medical school, instead of pursuing an internal medicine residency, she earned a doctoral degree in cardiovascular pharmacology from Sun Yat-sen Medical School at Zhongshan University in Guangzhou, China. Dr. Ruan became an expert in cardiac physiology, learning how to conduct electrophysiologic studies of the heart in animal models. She also taught physiology to medical students for more than 10 years, lecturing before classes of hundreds of students and teaching them how to conduct experiments during lab sessions.
Dr. Ruan also kept developing new skills. One year during graduate school, she spent several weeks during spring break working with a postdoctoral scholar in her lab learning how to conduct patch clamp studies. This technique was developed in the late 1970s, and can be used to study currents in living cells. It is especially useful in excitable cells such as neurons, muscle cells and heart cells, which are able to generate electrical signals. The patch clamp utilizes a hollow glass tube called a micropipette, which needs to attach to a cell and create a tight seal to measure various currents flowing through the membrane.
“At that time, the patch clamp was kind of a new technique,” said Dr. Ruan. “It was in our physiology textbook and I taught students about it, but I thought, ‘Maybe I can learn how to do it.’ It was really interesting to learn.”
After completing her PhD, Dr. Ruan was accepted as a postdoctoral scholar in a neuroscience lab at UCLA in part because of her demonstrated skills in patch clamp. Dr. Ruan then completed another postdoc training in the lab of Yibin Wang, PhD, now professor emeritus in the Department of Physiology at UCLA, focusing on studying the cellular and molecular mechanisms of cardiac arrhythmia and hypertrophy. Her projects included investigating the role that genes such as Giα1, PTEN and PP2ce might play in various forms of heart disease.
Investigating Pacemaker Cells
In 2017, Dr. Ruan was recruited to UCSF, becoming a research specialist in the lab of UCSF cardiac electrophysiologist Vasanth Vedantham, MD, PhD. His lab investigates the development and function of cardiac pacemaker cells, which are responsible for initiating the electrical signals which prompt each heartbeat. Those pacemaker cells are located in the sinoatrial (SA) node – the heart’s natural pacemaker. “Vasanth’s research was very fascinating to me,” she said. “Previously, I had studied hypertrophy and arrhythmia in the ventricle, but here it’s focused in the SA node. That was really new to me, and I wanted to learn about it.”
Dr. Ruan built on her previous experience to tackle the challenge of working on pacemaker cells, which are very difficult to study. They are surrounded by many other cell types in the heart, including cardiomyocytes, which are heart muscle cells; fibroblasts, which make up the scaffolding of the heart; nerve cells; and endothelial cells, which line the interior of blood vessels and heart valves. Even in the SA node, pacemaker cells are relatively rare, making up only about 1 to 2 percent of the cells. To study their electrical properties, it is first necessary to separate them from all the other kinds of cells. Dr. Vedantham’s lab was among the first to conduct genome-wide expression profiling and other investigations that require substantial numbers of these special cells.
Part of this isolation process includes using special enzymes to dissolve or digest the cells surrounding the pacemaker cells, without harming the delicate pacemaker cells. Like Goldilocks, this requires the digestion process to be not too much or too little, but just right. “If the pacemaker cells are underdigested, which means there’s still some other tissue around the cell, then you can’t get a good seal on the pacemaker cell with the patch clamp,” said Dr. Ruan. “But if the pacemaker cells are overdigested, the membrane could get damaged, and once you touch it, it will start an irregularly rapid beat and die within seconds.”
Isolating the pacemaker cell is just the first step. Dr. Ruan has also developed finesse in working with these tiny, irregularly shaped cells, which continue beating while she is attempting to record electrical measurements. When she first joined Dr. Vedantham’s lab, it took her about three months to successfully make her first patch clamp recordings of a pacemaker cells. Now on a really good day, she can isolate and patch clamp three or four pacemaker cells.
“Beyond being a talented scientist, her biggest asset is her technical facility and skill set that includes cellular physiology of these hard-to-isolate, hard-to-study cell populations,” said Dr. Vedantham. “You need to have very good fine motor control, a high frustration tolerance, and an intuitive feel for troubleshooting a lot of very sensitive electrical equipment. It takes a lot of time, experience and patience to do this work. People like Hongmei who do it well went through an apprenticeship where they were trained by someone with expertise. Today, not that many people have trained in it, and Hongmei is one of the few practitioners of the original art.”
Collaborative Research Environment
Because of her niche skill set, she has helped the Vedantham lab collaborate with other labs, such as finding out more about the acute and chronic effects of alcohol consumption on atrial fibrillation in an animal model, as well as other partnerships beyond UCSF.
Dr. Ruan is currently working on several projects related to gene networks that are involved in making pacemaker cells behave differently from other types of heart cells. For example, she is studying a transcription factor which is expressed in the SA node in an animal model, and trying to figure out a way to turn on this transcription factor in atrial myocytes. “If we could reprogram these cells to make them behave more like pacemaker cells, maybe in the future we could use this approach for disease treatment,” she said. Dr. Ruan is also investigating a receptor that the lab identified as active in pacemaker cells, trying to figure out more about its physiological function.
With her deep expertise in cardiac physiology, Dr. Ruan helps teach and train many younger scientists in the lab, and serves as a resource person for setting up experiments and isolating cells. “I like the people I work with, because they have the same interest in science and are very dedicated to the work,” she said. “There’s a lot to figure out, and we can support each other. Everyone has different areas of expertise, and they also help me figure things out. I really enjoy this research, because I’m not just doing routine work. I get to explore the potential of different things.”
Outside the lab, Dr. Ruan enjoys swimming, hiking in the mountains, cooking Chinese food, and playing Ping-Pong.
- Elizabeth Chur