Sharika Bamezai (2022-23 Fellow)

First-Author in Nature Communications

A simple conversation in the operating room served as a catalyst for me to dive back into the lab and seriously explore opportunities like the Sarnoff Fellowship. 

My initial desire to delve into scientific research stemmed from a personal interest in congenital vascular and lymphatic anomalies that led me to join a vascular biology lab as an undergraduate. In medical school, preconceived uncertainty about successfully intertwining a career as a proceduralist and scientist drove my initial hesitation to immediately jump back into lab research. However, I am deeply grateful to my mentor Dr. Andrea Obi, a vascular-surgeon scientist. 

The Sarnoff year has felt like a professionally defining experience. I moved across the country to California to start in Dr. Nicholas Leeper’s lab at Stanford and contribute to a project investigating the molecular parallels between cancer and atherosclerosis. I joined an incredibly supportive lab community and, eager to make the most of my time in the lab, began helping with a few small experiments while my project ramped up. One of these experiments was the histological processing, staining, and imaging of vascular tissue from an atherosclerotic pig model treated with a targeted, pro-efferocytic nanotherapy.

Learning about the series of discoveries leading up to this translational porcine study was deeply inspiring to me as a budding scientist. Seminal work from Dr. Weissman’s lab characterized the role of CD47, a “do not eat me” ligand found to be constitutively upregulated on the surface of certain tumor cells, as a mechanism to evade clearance by phagocytes like macrophages. Dr. Leeper’s lab subsequently postulated and discovered that a similar mechanism contributes to the pathogenesis of atherosclerosis – specifically, that dying cells which accumulate and form a necrotic core within the plaque evade engulfment by phagocytes by upregulating CD47. However, a clinical trial investigating the efficacy and safety of anti-CD47 therapy and rituximab to treat non-Hodgkin’s lymphoma highlighted a major limitation of translating anti-CD47 therapy in humans. Anti-CD47 therapy was found to cause anemia by inducing the clearance of healthy red blood cells. To get around this Achilles heel, in collaboration with Dr. Bryan Smith (Michigan State University), the lab leveraged our understanding of the downstream signaling pathway. To improve specificity of the drug we targeted a downstream effector molecule SHP1 and leveraged single walled carbon nanotubes (SWNTs) that would allow for cell specific delivery to inflammatory Ly6c high monocyte/macrophages, as previously characterized by Dr. Smith.

Given the promising results in the published murine study, we aimed to evaluate the safety and efficacy of this SWNT-SHP1i nanotherapy in a porcine model of atherosclerosis. First, we confirmed that we could successfully scale production of the nanotherapy without impairing key SWNT physicochemical properties. At an early stage of atherosclerotic disease, although we did not observe a difference in atherosclerotic lesion size, we found that our nanotherapy reduces carotid artery vascular inflammation as measured by 18F-FDG PET/CT imaging. Furthermore, treatment with SWNT-SHP1i was associated with significantly lower apoptotic cell accumulation in the early atherosclerotic lesion. Most importantly, SWNT-SHP1i therapy did not induce anemia or thrombocytopenia. Ultimately, our findings support the potential of this targeted nanotherapy to deliver a high concentration of drug to the inflamed blood vessel without causing off target toxicity.

I am grateful to Dr. Leeper for the opportunity to both contribute and challenge myself by taking on a leadership role as this project progressed. I am also thankful for my post-doctoral mentors in the lab Drs. Caitlin Bell, Shaunak Adkar, Lingfeng Luo, and Yoko Kojima as well as for the support from our generous funders at the Falk Foundation and Greathouse Family Foundation. I am finally deeply grateful to my Sarnoff advisor Dr. Aaron Aday (2008-09 Fellow) who helped me navigate my Sarnoff year as well as to the Sarnoff Foundation for the chance to join this incredible community.

“We are incredibly proud of the work that Shar did during her time with us as a Sarnoff fellow.  She enthusiastically dove in and became an immediate contributor to the team.  The fact that she was able to publish a high impact, first author publication after just a year with us speaks to her remarkable native intellect and fantastic work ethic.  We are grateful for the support from the Sarnoff Foundation and the generosity of our funding sources, the Falk Foundation and the Greathouse Family Foundation.  We will miss having Shar in the lab, but are excited to see what she accomplishes as she embarks on her clinical training.  There is little doubt she is well on her way to becoming a successful physician-scientist

- Nicholas Leeper, MD