Faculty Spotlight: Arun Padmanabhan, MD, PhD

“Every single cell in your body has the exact same DNA, but how does thisArun Padmanabhan same genetic material allow for such a broad repertoire of different cell types?” asks physician-scientist Arun Padmanabhan, MD, PhD.

Dr. Padmanabhan is delving into this complex question, whose answers may yield new insights into how the human heart is formed before birth, as well the genetic programs that play a role in turning healthy heart cells into sick ones.

He joined the UCSF Division of Cardiology faculty in 2018, and also is completing a postdoctoral fellowship at the Gladstone Institute for Cardiovascular Disease, a UCSF-affiliated research institute. Dr. Padmanabhan worked in the lab of Division of Cardiology faculty member Saptarsi Haldar, MD, who holds a joint appointment at Gladstone and was recently recruited to Amgen (please see sidebar), and now works in the lab of Deepak Srivastava, MD, president of the Gladstone Institutes.

“I’ve long been interested in the molecular mechanisms that govern how a cell decides what kind of cell it’s going to be,” said Dr. Padmanabhan. “Somehow a heart muscle cell knows how to turn off all the genes for other cell types and turn on all the heart muscle genes. That’s all governed by transcriptional regulation – how genes are switched on and off at the correct time and in the correct place, based on a cell’s specific function. I’m interested in the mechanisms that allow a cell to do that.”

Dr. Padmanabhan is currently examining how one gene, called BRD4, plays an important role in this process. Each person’s DNA is incredibly long – if all the base pairs from a single cell’s nucleus were laid end to end, they would stretch for about six feet. In order to pack all this information into the nucleus, the DNA is wrapped around proteins called histones, and the histones are themselves folded into larger structures. It’s a bit like gossamer-thin filaments spun into thread, which are then braided into yarn and then twisted into rope.

Most of this DNA is tightly coiled and inaccessible to the cellular machinery that activates genes. Each cell unfurls the specific genes it needs at a particular time. The study of this elaborate process is called epigenetics, and plays a key role in health and disease throughout an organism’s lifespan.

But how do cells orchestrate this intricate process? “It turns out that cells place tiny molecular bookmarks, a bit like Post-It notes, in the genome,” said Dr. Padmanabhan. “BRD4 and other similar proteins are responsible for reading these Post-It notes.”

Cell Fate and State

He hypothesizes that BRD4 plays a critical role in two essential aspects: determining cell fate and cell state. Cell fate is determined when stem cells – which can turn into any kind of cell in the body – commit to a path of differentiation, which is usually irreversible in humans. For example, a stem cell may become a specialized cell type such as a cardiomyocyte, also known as a heart muscle cell. Each cell type has a collection of Post-It notes which flag parts of the genome that need to be activated in order to differentiate into that kind of cell. “We know that in congenital heart disease, these Post-It notes may be absent or put in the wrong place,” said Dr. Padmanabhan, referring to birth defects of the heart.

BRD4 may also play an important part in determining cell state – where the cell type remains the same, but its function changes. “How does a stressed cardiomyocyte in a failing heart behave relative to a normal, unstressed myocyte in an appropriately functioning heart?” asked Dr. Padmanabhan. “You can think about cell state transitions as being similar to developmental cell fate decisions. Rather than turning on and off large swaths of genes to make an undifferentiated cell a more differentiated cell, you’re doing that to make a happy cell a sick cell. Coactivators like BRD4 drive these processes and provide a window that we can use to try to understand the underlying biology.”

For example, Dr. Padmanabhan and colleagues from Dr. Haldar’s lab explored how a drug compound called JQ1 might affect sick cardiomyocytes. JQ1 was previously shown by other researchers to help rein in overactive growth in cancer cells. They wondered if JQ1 might also help dial down overexuberant scarring and inflammation responses in sick or injured heart cells. These are responses that might be useful when trying to heal from an acute injury like a wound, but which actually create more problems when they develop to ongoing conditions associated with aging, such as high blood pressure and coronary artery disease. “JQ1 blocks the ability of BRD4 to read the Post-It notes, and had some promising results in helping a sick heart muscle cell in a failing heart forget to respond as if it’s sick,” said Dr. Padmanabhan.

He is also interested in learning more about the role of BRD4 in normal cells. For example, in addition to turning on scarring and inflammation responses in sick cardiomyocytes, Dr. Padmanabhan hypothesizes that BRD4 plays an important role in cardiac development during fetal life. To test this idea, he placed stem cells in a dish and added a standard cocktail of drugs and growth factors that can encourage them to turn into cardiomyocytes. However, when he added JQ1 to this mix, he found that fewer cardiomyocytes emerged.

Because JQ1 affects not only BRD4 but the function of related genes called BRD2 and BRD3, Dr. Padmanabhan engineered mouse models that allowed him to delete BRD4, and to zero in even more closely by deleting BRD4 only in developing cardiomyocytes. “It’s one thing to delete the protein and realize that the heart function gets better or worse, but what’s really interesting is trying to understand mechanistically why that happens,” he said. “What’s happening on a molecular level? Where does BRD4 sit in the genome? What pieces of DNA is it binding to? What genes is it turning on, and how is it doing that? I’m interested in all these questions.”

In addition to his research into BRD4, Dr. Padmanabhan is interested more broadly in other factors that may affect the three-dimensional structure of the coiled DNA, and how glitches in this process may affect either cardiac development or how disease develops later in life.

Besides providing fascinating topics for research, there are practical applications for these investigations: learning more about how cardiomyocytes develop could provide insight into how congenital heart disease develops, and avenues for better treatments.

Similarly, heart failure is one of the most common forms of heart disease, and occurs when the heart is unable to pump enough blood to the rest of the body. Unfortunately, when heart cells become sick or die, the body is unable to regenerate new cardiomyocytes on its own. However, learning more about how these cells form and what goes wrong when they become diseased could yield clues to regenerative medicine approaches – such as teaching the heart to “remember” how to grow new cardiomyocytes, or culturing biopatches of beating heart cells in a dish that could be grafted onto a failing heart. “In order to develop any kind of useful therapy, you first have to understand the molecular mechanisms of disease pathophysiology,” said Dr. Padmanabhan.

Falling in Love with Science

Dr. Padmanabhan was initially drawn to medicine rather than science. He was inspired by his father, a cardiologist in rural New Mexico. “We would go to the grocery store, and people would come up and say, ‘Your dad saved my mom,’ which made me think that medicine was a noble profession,” he said.

He studied biochemistry and molecular biology at Washington University in St. Louis, then enrolled in medical school thinking he would return home to New Mexico to become an internist. However, a faculty advisor encouraged him to apply for a summer internship at the National Institutes of Health (NIH).

“I had an awesome experience!” said Dr. Padmanabhan. “There were really smart people doing cool stuff, and I learned a ton.” When he enthusiastically described his internship, his advisor suggested taking time to focus full-time on research. Dr. Padmanabhan was selected as a Sarnoff Cardiovascular Research Foundation fellow, and spent two years in the middle of medical school working with Jonathan Epstein, MD, a physician-scientist at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. Dr. Epstein’s laboratory studies genetic regulation of heart development, and what can go awry with congenital heart disease.

“It was incredible!” said Dr. Padmanabhan. “Jon was a phenomenal mentor, and the cadre of postdocs and graduate students in the lab were some of the most thoughtful scientists I’ve ever met. I also worked on a project that gained a lot of momentum, which made it all that much more exciting…. There is nothing quite as exciting as doing an experiment and discovering something that nobody knew before you just figured it out. I fell in love with that feeling.”

Dr. Padmanabhan went on to earn a PhD in cell and developmental biology from Penn, in addition to his medical degree. He enjoyed caring for heart patients in the coronary care unit (CCU) during internal medicine residency at Massachusetts General Hospital, convincing him to become a cardiologist.

He came to UCSF for cardiology fellowship. Among his many mentors was Paul Simpson, MD, a cardiologist and researcher based at the San Francisco Veterans Affairs Medical Center. “Dr. Simpson developed the neonatal rat ventricular myocyte culture system, one of the most critical in vitro model systems in all of cardiology,” said Dr. Padmanabhan. “It’s incredible that he was my preceptor. In addition to teaching me a lot of clinical cardiology, we also just sat around talking science. I learned a lot from him about what questions one should try to pursue to be relevant and make meaningful contributions to the field.”

“Dr. Padmanabhan has a brilliant mind, a very engaging personality, and astute clinical skills,” said Dr. Simpson. “He has proven excellence in science. Of the more than 100 trainees I have had in 40-plus years, I consider him highly likely to make significant contributions to science and cardiology.”

“Arun is an extremely high-potential physician-scientist in training,” said Dr. Haldar, who continues to serve as one of his mentors. “He was a real star during his MD/PhD at the University of Pennsylvania in the laboratory of Dr. Jonathan Epstein, who is one of the most distinguished cardiovascular investigators in the world. I was absolutely thrilled when Arun chose to train in Cardiology at UCSF and subsequently decided to join my laboratory. He’s bright, fearless, curious and enthusiastic. He has a natural ability to make connections between disparate fields of science, think outside the box, and continuously generate creative new ideas.  Perhaps even more importantly, he is a wonderful colleague who is generous with his time and intellect. His love of science is truly infectious and influences everyone in the Department. It’s a joy to watch him develop and grow.

“Arun has been the recipient of two major fellowship awards, including a highly prestigious and competitive award from the A.P. Giannini Foundation,” said Dr. Haldar. “Through this work, he is making seminal insights into how the heart develops, creating foundational knowledge that is highly relevant to understanding why some children are born with heart defects. In addition, this same biology has clear implications for treating heart disease in adults, including creating approaches to regenerate new heart muscle cells. In order to figure out how to regenerate new heart muscle cells in a diseased heart, it’s really important to know how these cells are created in the first place. Overall, Arun is really off to the races, and will be someone we have our eyes on as a future leader in cardiovascular biology and medicine.”

Research and Clinical Care

“UCSF has just a phenomenal scientific environment,” said Dr. Padmanabhan. “There are people doing cutting-edge things in everything you could think of. I love this place and am really excited to be here.”

As much as he loves research, Dr. Padmanabhan also appreciates the joys of clinical medicine. He spends two days a month in cardiology clinic, and also serves as an attending physician a few weeks a year. “In cardiology, we have lots of solutions,” he said. “If a patient isn't feeling well, you can often diagnose what it is and give them something that makes them feel better. That’s fulfilling in a way that’s more immediate than some of the rewards you get from the lab.”

“Dr. Padmanabhan is very passionate about discovery in cardiac development and disease,” said UCSF cardiologist Don Grandis, MD. “He translates that passion into innovative research and exceptional patient care.”

Dr. Padmanabhan looks forward to pursuing a career as a physician-scientist in academic medicine, and hopes to establish his own laboratory. “I enjoy teaching residents and medical students,” he said. “I have had great mentors who were really invested in my academic development, and one day I would like to be in a position to pay that forward for another generation of trainees, getting them to consider pursuing a career in science and thinking about problems deeply and mechanistically.”

Outside of the lab and clinic, Dr. Padmanabhan is an avid comic book collector, and enjoys brewing his own beer, which he describes as “an experiment you can drink.” He and his wife, UCSF ophthalmologist Sriranjani Padmanabhan, MD, have a young son.

– Elizabeth Chur