Faculty Spotlight: Saptarsi Haldar, MD

June 18, 2018

Heart failure affects nearly 6 million people in the U.S., and about half die within five years of diagnosis. The condition occurs when the heart is unable to pump enough blood and oxygen to adequately support the rest of the body. Current treatments can help alleviate symptoms, but cardiologist Dr. Saptarsi Haldar has a more fundamental question: can we develop drugs to change the genetic programming of ailing heart cells to make them better?

Dr. Saptarsi Haldar
Photo credit Elisabeth Fall.

Much of Dr. Haldar’s research focuses on cardiovascular epigenetics, which is the complex study of how genes are turned on and off in both healthy and diseased hearts. “The central theme of our lab is understanding mechanisms of gene regulation,” he said. “Part of the fun of being a scientist is that you chase things down that are striking and that you believe are important. If you dig deep, you never know what you’re going to find.”

Dr. Haldar was born near Calcutta, India, then moved with his family to New Jersey. A self-described “science geek,” he majored in engineering at Cornell University in Ithaca, N.Y., taking extra classes in biochemistry and biomedical engineering. He earned his medical degree at Johns Hopkins University School of Medicine, where his initial interests shifted from orthopedics to cardiology after meeting several influential mentors in that field, including Drs. David Kass and Charlie Lowenstein.

During medical school, he spent an extra year as a Sarnoff Fellow, conducting basic cardiovascular research in the laboratory of Dr. Thomas Michel at the Harvard Medical School-affiliated Brigham and Women’s Hospital in Boston. “I got my first hands-on immersion in cell biology and molecular biology, and got hooked,” said Dr. Haldar. “I realized that I wanted to be a physician-scientist.”

After finishing his internal medicine residency at Johns Hopkins, Dr. Haldar went on to complete his cardiology fellowship at Brigham and Women’s Hospital. He then followed his postdoctoral research mentor, Dr. Mukesh Jain, to Case Western Reserve University and University Hospitals in Cleveland, where he also served as a faculty member from 2007 to 2015.

While he loved working at Case Western, a few years ago he attended a scientific meeting and met researchers from UCSF and the Gladstone Institute of Cardiovascular Disease, a UCSF-affiliated research entity. “We ended up talking science, hanging out, and I just hit it off with them,” said Dr. Haldar. He was invited to give a talk at UCSF and Gladstone, and in 2015 was jointly recruited as an associate investigator at Gladstone as well as an associate professor in the UCSF Division of Cardiology.

Applying Cancer Discoveries to Heart Disease

Dr. Haldar has always gained inspiration by reading journals and attending lectures outside of his field to cross-pollinate new ideas. He was particularly inspired by a paper published by oncology researcher Dr. James Bradner. It described a small molecule compound that inhibited cancer growth by targeting what are known as BET proteins. Cancer cells genetically rewire themselves to grow like crazy, but the BET inhibitors reined in this overactivation of cancer genes. “I simply made the connection to say, maybe there is a parallel mechanism at work in heart failure,” said Dr. Haldar.

Like most of the body’s organs, the heart is highly evolved to heal itself from wounds and protect against infection – critical defenses against traumas such as the proverbial attack from a saber-toothed tiger. Unfortunately, in the modern era, the heart evokes these same processes of scarring and inflammation in response to many forms of injury that are often associated with aging, such as high blood pressure, heart attacks and coronary artery disease. “The heart muscle cells send out alarm signals – ‘Help! I’m getting injured!’ and it activates all these damage control processes that are only meant to be short-term adaptations,” he said.

Those injury responses are controlled by a number of genes which get excessively turned on under stressful conditions. Dr. Haldar’s hypothesis was that BET inhibitors could act like a dimmer switch, dialing down this overexuberant response just enough to prevent lasting damage, while still allowing the heart to function.

Dr. Haldar’s lab first tested this approach in cultured heart cells in a dish, finding that the stressed-out heart cells looked better within 24 hours of being exposed to BET inhibitors. Then they conducted a randomized, blinded study in mice with heart failure, giving one group a placebo and the other the BET inhibitors – yielding similarly dramatic results. “Those were some of the most striking findings that I’ve had in my career so far,” he said. “My trainees were all very excited to see how robust the effects of these BET inhibitors were in mice with heart failure. The effect size and reproducibility were crystal clear.”

He is excited about these BET inhibitor studies because they’re the first example of a new class of molecules targeting the machinery that excessively turns genes on during heart failure. “What’s cool about BET inhibitors is that, unlike traditional drugs that block a receptor or enzyme, these actually work by directly interfering with the ability of one protein to dock onto another protein,” said Dr. Haldar. “It’s a completely different type of strategy.”

His lab is now doing a deep dive into understanding the heart’s gene regulatory machinery during normal health and in diseases such as heart failure, while also figuring out whether BET inhibitors and similar compounds can be translated into treatments for heart disease. One of the biggest challenges is that BET proteins are important for nearly all cells in the body, not just the heart, so any intervention would need to maximize efficacy in treating heart failure while minimizing toxicity to other tissues.

“Dr. Haldar has been a wonderful addition to the Gladstone, the Cardiovascular Research Institute (CVRI), and the Division of Cardiology at UCSF,” said Dr. Brian L. Black, interim director of the CVRI. “Part of his research program, focused on mechanisms of cardiac gene regulation and heart failure, brings a mechanistic and rigorous approach to understanding heart failure. His research is unique and important in that it focuses on fundamental discovery, but it also has very strong translational implications for heart failure. The discovery by Dr. Haldar and his team that the small molecule JQ1, a BET inhibitor which targets the bromodomain chromatin remodeling factor BRD4 to suppress heart failure in mice, suggests that bromodomain proteins and possibly other transcription factors may be viable druggable targets for treating heart failure and other disorders in humans.”

By better understanding cardiovascular epigenetics, Dr. Haldar hopes that he and his colleagues can also discover ways to encourage heart muscle cells – known as cardiomyocytes – to regenerate themselves after injury. “If you cut your skin, it regenerates, but for some reason, evolution made a choice that it was going to fashion human cardiomyocytes without that robust inherent capacity to divide and replenish themselves,” he said. “A lot of this ability to divide and regenerate is governed by epigenetics. Trying to unlock that potential is a huge area of scientific interest which has obvious therapeutic implications.”

Investigating a Metabolic Regulator

In another area of investigation, Dr. Haldar’s lab focuses on KLF15, a gene that plays a key role in regulating how the heart, skeletal muscles and other tissues metabolize nutrients. Dr. Haldar began this work in the laboratory of his mentor, Dr. Mukesh Jain, a pioneering physician-scientist who first discovered KLF15’s role in metabolism.  “We mammals have evolved incredible adaptive mechanisms to deal with not having food around for long periods of time,” said Dr. Haldar. “One really critical thing KLF15 does is to drive the breakdown of amino acids in your skeletal muscle and funnel them to the liver to get turned into glucose for the brain.”

Dr. Haldar and his team are delving into the details of how KLF15 regulates how genes get turned on and off during normal metabolism, and how those processes go awry in disease. “If KLF15 isn't doing its job in the skeletal muscle, animals can’t exercise properly, and if it isn't doing its job in cardiac muscle, the heart will metabolically fail,” he said. His research also has shown that low KLF15 can make muscular dystrophy worse, and that increasing KLF15 can protect against this disease, suggesting that part of the problem in this condition may be disruptions in the way muscles metabolize nutrients.

Among other intriguing findings, Dr. Haldar and his colleagues from Case Western found that KLF15 levels in mice varied according to the time of day, and that too much or too little KLF15 could contribute to abnormal heart rhythms. This might provide one clue about why the incidence of sudden cardiac death increases a few hours after waking in the morning, and also in the evening. They also found that KLF15 deficiency was associated with a collapse of the architecture of the wall of the aorta, the largest artery of the body. This can lead to aortic aneurysm, a bulge or ballooning of the aortic wall that can burst and cause life-threatening bleeding or even death.

 “We’re still trying to figure out how KLF15 works,” said Dr. Haldar. “KLF15 is really fascinating, because it’s a master regulator of metabolic flexibility in mammals. I have a lot of interest in abnormalities of metabolic physiology, because these are at the root of chronic cardiovascular diseases, metabolic syndrome and obesity.”

Mentoring and Collaborating

Even though moving across the country to join UCSF and Gladstone was a big leap, Dr. Haldar is very excited to be here. “One of the best things about UCSF and Gladstone is the quality of trainees and colleagues,” he said. “The environment is fantastic. I have the privilege at any time to be in a room full of people who are smarter than me. They are motivated, bring new ideas to the table, and get stuff done.”

While he devotes most of his time to the laboratory, he relishes the weeks he gets to spend as an attending physician in the hospital at UCSF. “It keeps me in touch with clinical medicine so I can stay abreast of unmet needs that need scientific attention, and also allows me to interface with UCSF medical students, residents and fellows,” he said. “They are the cream of the crop. In addition to supervising them as an attending cardiologist, I get to talk with the trainees about their career development. It’s the same thing my mentors did for me and is one of the best parts of my job.”

Dr. Haldar is a passionate supporter of physician-scientist training across disciplines and campuses. He provides mentoring to rising physician-scientists through the Molecular Medicine Pathway to Discovery, MD/PhD program, and Biomedical Sciences Graduate Program. “These bright young people are my colleagues, and they are the future,” he said.

“My colleagues at the faculty level also push me and have great ideas,” said Dr. Haldar. “We have deep expertise in so many different areas here, but everyone is so collegial. People collaborate and want to hear about your work.” He especially appreciates leveraging the expertise at Gladstone, UCSF and UC Berkeley in his research. “We’re in the epicenter of CRISPR-based genome editing, genomics technology, and stem cell technology,” he said. “It’s a revolution in biology.”

In addition to mentoring the next generation, caring for patients, and pursuing new knowledge in the lab, Dr. Haldar is an avid soccer player.  Outside of biomedicine, he is fascinated by astronomy and enjoys reading about the latest discoveries in astronomy and physics.  Most of all, Dr. Haldar enjoys spending time with his family, taking advantage of all the diverse things to do in the Bay Area.

– Elizabeth Chur