New Frontiers in Cardiovascular Research: Jennifer M. Kwan, MD, PhD and Nathan Chen

Yale cardiologist and cardio-oncologist Jennifer M. Kwan, MD, PhD, seeks to understand how a somatic mutation condition known as CHIP (clonal hematopoiesis of indeterminate potential) increases the risk of heart disease.

She recently launched a video campaign with three-time world champion figure skater and Olympic champion, Nathan Chen to increase visibility for the importance of biomedical research and physician scientists. We asked her about the challenges facing physician-scientists today and emerging therapeutic targets to improve cardiovascular outcomes.

Jennifer Kwan: I was already interested in cardio-oncology as a field, then I learned about CHIP during fellowship and saw how it was both an independent risk factor for both cancer and cardiovascular disease. It was also shown to worsen outcomes in cancer patients. I got interested in what those mechanisms were in affecting heart conditions like heart failure and how that impacted cancer patients’ cardiovascular outcomes.

The Kwan Lab works on evaluating novel somatic variants and how they contribute to disease, particularly cardiovascular disease. We have identified some variants that are associated with adverse cardiovascular outcomes as well as variants that are protective. Now that we have efficient gene editing tools and improving delivery approaches, there may be a possibility to slow down aging and reduce the burden of heart disease using gene editing approaches in the future by editing these variants

JK: I visited Dr. David Liu's lab at the Broad Institute with friend and mentee, Nathan Chen. Dr. Liu is the Thomas Dudley Cabot Professor of the Natural Sciences at Harvard University and a Howard Hughes Medical Institute (HHMI) investigator. He pioneered base and prime editing, which are DNA editing techniques that do not create double stranded DNA breaks like CRISPR/Cas9 does, which can lead to many off-target effects including deletions, insertions, and mutations, which is less optimal for trying to correct a single base pair of interest.

My lab is investigating CHIP and novel somatic variants and their effects on cardiovascular health and outcomes, so I was interested in seeing whether these gene editing technologies could help correct some of these somatic mutations. Our data shows that they can impact patient outcomes, including increasing the risk of heart failure or the risk of death.

The ability to correct genetic variants that can cause disease will likely impact the future of medicine. I wanted to expose Nathan to this cutting-edge gene editing technology because of his interest in biomedical research and medicine as a possible career. We are grateful that Dr. Liu was so welcoming and excited to show us the technology that he developed in his lab as well as give us a personal tour of his start-up company, Prime Medicine, which aims to leverage prime editing in treating genetic diseases.

Nathan Chen: Working with Dr. Kwan has been very inspiring, and I am incredibly fortunate to be exposed to such excellent science. Getting to explore the work that the Liu lab is doing is one example of this; I got a glimpse into the pioneering frontier of gene editing. My sister, Janice Chen, utilizes CRISPR-based DETECTR technology in her company, Mammoth Biosciences. It's fascinating to learn about CRISPR from my sister's perspective and then observe another application of gene editing technology. During our trip to the Liu Lab, we had the honor to engage in a discussion with the former director of the National Institutes of Health, Dr. Francis Collins and Sammy Basso, a researcher and patient with progeria. Witnessing first-hand how Dr. Liu and his team of collaborators interact with patients underscored the impact of their work on addressing disease and how gene editing can potentially improve their lives.

JK: I invited him to speak about precision medicine and gene editing in a session for the AAP/ASCI/APSA joint meeting in 2022. He gave an inspirational talk on the potential of base and prime editing. So, I got to know him through organizing that event.

JK: The scientific process can be very rewarding in helping us understand how diseases occur and what we can do to treat it. However, science has also gotten more and more complex with new technologies that allow us to investigate biology in ways we were not able to before. One person cannot be an expert in every field. I recently spoke with our American Heart Association undergrad fellowship trainees about the physician-scientist pathway journey. And one of the strengths of these conferences I mentioned was that they bring together physician-scientists from different disciplines. For example, at the AAP/ASCI/APSA joint meeting, we feature the top cardiologists, endocrinologists, gastroenterologists, oncologists, and hematologists, who are invited to present their work. These conferences allow people to learn from each other in terms of how they approach their science, which fosters ideas, and enables interdisciplinary research and collaboration. It also provides opportunities for mentorship across institutions and fields.

JK: We see patients and the medical problems and the challenges they face. But we also see the limitations in terms of what we can do for them right now. Traditionally, there wasn't that much we could do for those with genetic forms of heart disease, but potentially in the future with gene editing — we could potentially correct causal genetic variants that contribute to their disease.

A recent example was these two patients. The father has PRKAG2 syndrome and has a variant of unknown significance in that gene. The son also has that same variant of unknown significance, and also has a similar phenotype as his father.

PRKAG2 syndrome is a condition where you have this triad of hypertrophic cardiomyopathy, glycogen accumulation in the cardiomyocytes, and accessory pathways that contribute to supraventricular tachyarrhythmias, including, Wolff-Parkinson-White syndrome.

The father developed end stage heart failure requiring a heart transplant.

And the son, who has the same mutation, developed supraventricular tachycardia leading to syncope. Nathan helped with some of the genetic analysis for these patients. In silico modeling predicted that this variant is deleterious.

We were wondering whether base editing or prime editing would be able to help correct that mutation. We’re now exploring that possibility with Dr. Liu’s lab members. And if it proves out in animal studies, this can potentially be a therapy for our patients with this condition.

NC: It’s been interesting to see how my background in data science and statistics applies to the world of bioinformatics. I’m working on a project looking into different somatic variant calling pipelines to determine which is the most effective for accurate variant calling, especially as it pertains to heart disease and heart failure.

JK: Nathan is investigating a new area of research methodology to help us identify the strengths and weaknesses of somatic variant calling algorithms and tweaking them to enable us to have the most complete picture possible. He's helping to innovate in the area of somatic variant detection in cardiovascular disease as well as the pathways somatic variants affect. Working together with Drs. Hongyu Zhao and Jianlei Gu, we’ve also been optimizing CHIP calls on the Yale Generations data in several 1000 patients and validating on larger datasets like UKB.

JK: A large portion of ideas come from seeing patients and shortfalls that exist in the current state of the art management of their conditions and how it can be further improved. A second area for my research ideas comes from reading biomedical research articles, from genomics to imaging to gene editing to the microbiome. I spend a lot of time reading to stay up to date on clinical papers but also science papers.

JK: Find mentors who are looking out for your career development. Find an area of medicine and research that excites you and keep learning and honing new skills. This is a helpful mindset for anyone regardless of what field you go into.

Related: Training the physician-scientist: views from program directors and aspiring young investigators