Faculty Spotlight: Alan Baik, MD

Oxygen, the Heart and Cancer: Understanding Complex Systems

From clams eking out a living on the silty floor of the Atlantic Ocean to hearts bracing themselves against oxygen deprivation, cardio-oncologist Alan Baik, MD, has always been fascinated by the ways that organisms have evolved to adapt to environmental stressors. Now he is on a quest to better understand how both the cardiovascular system and tumors respond to low and high oxygen levels, and how to best take care of patients with both heart disease and cancer.

Dr. Baik grew up in Los Angeles, and developed an early interest in biology and medicine. A first-generation college student, he earned his bachelor’s degree in biology from Harvard, then completed medical school, internal medicine residency and cardiology fellowship at UCSF.

During college, he worked in the lab of Colleen Cavanaugh, PhD, an evolutionary biologist who studies how invertebrates and bacteria living in harsh, low-oxygen environments survive by collaborating and developing endosymbiotic relationships – in which one organism lives inside another organism, usually to mutual benefit. As an undergraduate, Dr. Baik helped discover more about the interrelationship between one type of bacteria and a clam-like bivalve called Solemya velum.

“These bivalves live in sulfur-rich environments, and are able to provide a home for endosymbiotic bacteria living in their gills,” said Dr. Baik. In exchange for housing, these bacteria pay “rent” by using chemosynthesis to turn sulfur into nutrients for their bivalve hosts. “I’ve always been interested in how the environment affects organisms,” he said. “That’s an overarching theme of my work.”

Responding to Low Oxygen Levels

During medical school at UCSF, he had the opportunity to pursue his passion for science, spending an additional two years as a Sarnoff Cardiovascular Research Fellow in the laboratory of medical oncologist William Kaelin, Jr., MD at the Dana-Farber Cancer Institute in Boston. Dr. Kaelin won the Nobel Prize in Physiology or Medicine in 2019 along with two other physician-scientists for their discoveries about how cells sense and adapt to hypoxia, or low levels of oxygen in body tissues.

Hypoxia sensing is so critical for normal development and survival that two elements of the hypoxia response – oxygen-sensing prolyl hydroxylase domain (PHD) enzymes and the transcription factor hypoxia-inducible factor (HIF) – are found in almost all multicellular animals, as well as all mammals. Much of Dr. Kaelin’s work focuses on how hypoxia sensing and response pathways contribute to the development and progression of cancer – including a form of inherited cancer called von Hippel-Lindau disease, in which both benign and malignant tumors grow in many parts of the body. However, he has also studied hypoxia sensing in the cardiovascular system with two cardiologists who conducted postdoctoral research in his lab – Javid Moslehi, MD , and Benjamin Olenchock, MD, PhD.

During his Sarnoff Fellowship, Dr. Baik worked with Dr. Kaelin, Dr. Moslehi and Dr. Olenchock, using an animal model to better understand the role of the PHD-HIF pathway in a phenomenon called remote ischemic preconditioning. This clinical scenario occurs when the oxygen supply is briefly reduced or cut off to a distant organ in the body – for example, the skeletal muscle – an insult that actually appears to help protect the heart later during a heart attack. It’s almost as if the initially deprived organ sends out a memo, alerting the rest of the body to prepare for a potentially stressful event, like a heart attack.

“When a specific organ is hypoxic, it adapts to that state and tries to protect itself from ongoing insults of lack of oxygen and nutrients,” said Dr. Baik. They found that activation of the hypoxia response in the skeletal muscle led to upregulation of a metabolite called kynurenic acid – a metabolite of tryptophan – that was secreted into the blood and had a cardioprotective effect. “We’re learning that particular insults due to hypoxia, ischemia or cancer have systemic effects,” he said. “The responses to these insults are not just localized to one tissue – the body responds via different metabolic, cell signaling and inflammatory pathways. It really shows that an organism is not just defined by cells or tissues that act in isolation. It’s a whole system of complex interactions.”

In addition to the thrill of discovery during his Sarnoff Fellowship, Dr. Baik was inspired by his mentors. “I was surrounded by exceptionally intelligent, creative physician-scientists who not only took care of patients, but also pushed the envelope and tried to understand the mechanisms of disease, with the ultimate goal of translating findings to patient care,” he said, noting that discoveries in Dr. Kaelin’s lab have helped lead to new treatments for cancer and anemia. “It exemplifies that basic science and pre-clinical models can have broad implications for therapies. That experience had a long-lasting impact on me, and inspired me to continue along the path of becoming a physician-scientist.”

Dr. Baik absorbed Dr. Kaelin’s meticulous approach to research. “He instilled in me that your science should be carefully planned,” said Dr. Baik. “Though it sounds simple, he really encouraged us to include both negative and positive controls for all our experiments. In addition, he would ask, ‘What’s the most trivial explanation for the data?’ Meaning that we should investigate the most logical, straightforward way to explain data based on what is already known, and then try to dissect more complex explanations if our initial hypotheses turn out to not be true.” A few years ago, another Kaelin lab alum, William Y. Kim, MD, compiled a list of “10 Top Kaelinisms.”

Oxygen: Not Too Little, Not Too Much

Dr. Baik continued his hypoxia research during the third and fourth year of his cardiology fellowship at UCSF, joining the lab of Isha Jain, PhD, an assistant investigator at the UCSF-affiliated Gladstone Institutes. He continues to conduct research with her as a postdoctoral scholar, and has received support from the Sarnoff Scholar Award as well as the Chan-Zuckerberg Biohub Physician-Scientist Fellowship Program as he works towards launching his own independent lab.

“One of the driving themes of Dr. Jain’s work is trying to understand how cells and organisms adapt to long-term hypoxia,” said Dr. Baik. Her lab investigates the idea that every organism, and every tissue type within that organism, may be tuned to an optimal oxygen tension which allows it to perform at its best. Having too little oxygen, or too much, could lead to pathology.

“The air we breathe in is about 21 percent oxygen, but as it moves through the lungs and blood, the amount of oxygen starts to decrease in the tissues,” said Dr. Baik, noting that internal organs such as the brain are exposed to oxygen levels that are much lower. “The thought is that every organ is adapted to these particular oxygen tensions, and disease can develop if there is too little or too much.” Induced hypoxia could potentially be used as a therapy for some conditions. For example, in animal models of a rare, severe neurological disorder called Leigh syndrome, Dr. Jain discovered that placing the animals in an environment with an oxygen level of about 11 percent – the equivalent of an altitude of about 17,000 feet above sea level – actually extended the animals’ lifespans by fivefold. Amazingly, this approach also reversed their brain pathology.

With Dr. Jain’s mentorship, Dr. Baik is trying to better understand how too much oxygen can be toxic for humans. “Early on in my medical training, oxygen therapy was thought to be fairly benign,” he said. “If someone came in with chest pain, it was almost a reflex to give them supplemental oxygen, regardless if they were truly hypoxic or not. There has been accumulating data in the last five years or so that supplemental oxygen in the absence of hypoxia is associated with adverse outcomes. This seems to be true for those who present with heart attacks, cardiac arrest, brain injuries, and extended intubation for hypoxic or non-hypoxic primary causes.”

The reasons for this are not yet well understood, though it may be related to the way that oxygen leads to the creation of reactive oxygen species, a type of unstable molecule that can damage DNA, RNA and proteins. Dr. Baik and his colleagues are trying to understand if there are other mechanisms of oxygen toxicity, with the ultimate goal of finding effective treatments for excess oxygen.

“Alan is a powerhouse when it comes to both facets of his career,” said Dr. Jain. “He’s a phenomenal clinician and an absolutely brilliant researcher. His ability to seamlessly merge these aspects of his work make him a formidable force. There is no doubt that he will continue making high-impact and translational breakthroughs for years to come in the fields of cardiology and metabolism.”

Cardio-Oncology Research and Patient Care

After completing his cardiology fellowship at UCSF in 2021, he was recruited to the UCSF Division of Cardiology faculty as a member of the recently created Cardio-Oncology and Immunology section within the Division of Cardiology, which was founded by his longtime mentor, Dr. Moslehi.

Some lifesaving cancer treatments, including many newer therapies such as immune checkpoint inhibitors, CAR T-cell therapy, and monoclonal antibodies, can also cause cardiovascular side effects. In response, the emerging discipline of cardio-oncology has emerged to promote the cardiovascular health of cancer patients and survivors. “Cardio-oncology integrates many topics I found interesting in cardiology, including general cardiology, electrophysiology, and heart failure, as well as scientific fields I’m especially interested in, such as metabolism and immunology,” said Dr. Baik.

Continuing a theme from his previous work, he enjoys the challenge of looking at entire systems, rather than just individual cells or organs in isolation. “There’s an interconnectivity between the cancer, the heart and the cardiovascular system,” said Dr. Baik. “Cardio-oncology is amazing because you have the opportunity to integrate all these different fields of science and medicine to understand the effects of cancer and treatment in a very broad way. And because it’s a newer field, a lot is still unknown, and it’s ripe for discovery. As a physician-scientist, it’s a great opportunity to use what I see clinically to motivate my scientific questions.”

Dr. Baik sees patients in the Cardio-Oncology Clinic in the UCSF Bakar Precision Cancer Medicine Building. He works closely with oncologists and the rest of the care team to parse out whether patients who develop heart failure, cardiac arrhythmias, hypertension or other cardiovascular problems acquire these additional issues because of their cancer treatments, or if there are other contributing factors. “It is often complicated, because you don’t want to prematurely stop cancer treatments,” he said. “We work with the oncologists to determine whether we can continue treatment by starting cardiac medications, or whether cancer therapies should be stopped or modified while we work up and treat their cardiovascular problems. We collaborate to optimize both the patients’ cardiovascular and oncologic care, to give them the best possible short- and long-term outcomes.”

The team also conducts surveillance of patients who are receiving cancer therapies that are known to be cardiotoxic, as well as those with underlying heart disease who are at increased risk of developing cardiotoxicity. “We try to be proactive,” said Dr. Baik. “If the patient has underlying cardiovascular disease risk factors or if we see even small changes in cardiac function, prior to it becoming symptomatic we can consider initiating treatment to see if we can prevent heart problems from getting any worse.”

He finds it deeply rewarding to help patients during one of the most challenging times of their lives. “I often see patients in a very vulnerable state, and helping them during that time is one of the most fulfilling aspects of my clinical practice,” said Dr. Baik. “Hopefully I can make their experience with cancer less confusing and worrisome, and can guide them in optimizing both their cardiovascular and oncologic care. I appreciate the opportunity to take care of patients in a very holistic way, and to work as part of a multidisciplinary team.”

One intriguing question he would like to better understand is the long-term cardiovascular effects of vascular endothelial growth factor (VEGF) inhibitors, a class of systemic cancer treatments which can cause heart problems. VEGF helps stimulate blood vessel growth, and tumors that are hypoxic increase VEGF expression to increase blood supply to themselves. “VEGF is an incredibly important signaling molecule for the entire body, and by inhibiting it, there can be long-term systemic effects,” said Dr. Baik. “Some of the mechanisms are not well-understood, and I am interested in investigating the cardiovascular effects of long-term VEGF and HIF signaling inhibition.” Interestingly, tumor hypoxia, upregulation of HIF, and abnormal VEGF signaling are associated with more aggressive and metastatic disease, which make this a rich field for cardio-oncology research.

“Ultimately, one of my goals is to understand hypoxia signaling and oxygen metabolism as it relates to both cardio-oncology and cardiology in general,” said Dr. Baik. “I hope to use the approaches I’m learning in my postdoctoralship to take a very integrative, systems-wide approach to science, using unbiased techniques like metabolomics and proteomics, as well as targeted molecular biology tools, to delve deep into cardiovascular disease, and how dysregulated oxygen metabolism can lead to pathologic outcomes.”

He is also excited about the ways that new insights in cardio-oncology could shed light on cardiovascular disease not related to cancer, as well as other aspects of health and disease. For example, he and Dr. Moslehi recently wrote an article about the immunologic side effects from certain cancer treatments. They hypothesize that there may be similarities between the underlying mechanisms of cytokine release syndrome experienced by some patients who receive CAR T-cell therapy, and COVID-19 patients who develop hyperimmune activation – which could suggest therapeutic possibilities for treating patients with severe COVID-19.

“I am ecstatic that I was able to recruit Alan to our new section,” said Dr. Moslehi, chief of the Cardio-Oncology and Immunology section and William Grossman, MD, Distinguished Professor. “He is compassionate, a terrific physician, and is outstanding in every way. Even as a medical student, he had exceptional insights into the science of hypoxia. As a Latinx physician-scientist, he represents a major asset to our division and UCSF in general. He has already proven to be a national leader in the burgeoning field of cardio-oncology.”

“I have had the pleasure of working closely with Dr. Baik for three years,” said Mandar Aras, MD, PhD, another faculty member in the Cardio-Oncology and Immunology section. “He is a kind, caring and compassionate clinician whom patients absolutely love. He is also an inquisitive, productive, successful scientist, working tirelessly on uncovering novel mechanisms of hypoxia-mediated signaling and oxygen metabolism as they relate to cardiovascular disease. Dr. Baik is a rising star.”

Launching a Career as a Physician-Scientist

Dr. Baik is excited to join the faculty at UCSF. “The collaborative clinical and scientific environment is amazing,” he said. “I get to work with world-class clinicians and scientists, and having access to that expertise from both sides has been incredibly important for me.” He also appreciates the ways that both UCSF and the Division of Cardiology have provided time and resources to develop expertise in the related, yet distinct realms of clinical care and scientific research.

“UCSF is truly invested in promoting the careers of physician-scientists, and [Chief of the UCSF Division of Cardiology] Dr. Jeff Olgin has been very supportive,” said Dr. Baik. “He understands the pressures that early physician-scientists face, and that we need a lot of dedicated time to hone the skills to become a successful scientist, after focusing on clinical training for a number of years. I’m very grateful for that kind of leadership, which will help optimize my success in this pathway.”

He is also delighted that Dr. Moslehi joined the UCSF faculty in 2021 to establish the Cardio-Oncology and Immunology section. “Since working with Dr. Moslehi when he was a postdoc in Dr. Kaelin’s lab, he has become one of my closest sponsors and mentors over the last ten years,” said Dr. Baik. “He’s really shaped the way that I think about science and cardiology, and I’m looking forward to ongoing mentorship and collaboration in the years to come.”

Besides his work in the lab and clinic, Dr. Baik enjoys running and spending time with his dog, a Chihuahua mix named Baxter.

-       Elizabeth Chur