Week 1: Discovering Lymphedema and Clinical Relevance

Though I have passed through New York City as a tourist or overnight visitor on many occasions, never would I have imagined that I would have the honor of sojourning in the medical epicenter of the city, surrounded by the very patients and clinicians I engineer and tinker for in lab. Fortuitously enough, my clinical mentor Dr. Babak Mehrara, the Chair of Plastic and Reconstructive Surgery at Memorial Sloan Kettering Cancer Center, happens to specialize in the niche area where my lab at home in Ithaca has expertise, the lymphatic system, in the even more overlooked procedure of breast reconstruction for the associated cancer. I was introduced to Dr. Mehrara via a developing collaboration with my graduate mentor, Dr. Esak Lee, due to our shared interests in lymphatics, but had relatively little knowledge arriving here concerning the surgical procedures of breast reconstruction and lymphedema treatment, much less the connection between the two. 

After meeting the members of my clinical mentor's dedicated lab at the Zuckerman Research Center, my limited perspective has begun to broaden. There are two primary types of breast reconstruction, namely implant or autologous tissue transplant based, with each presenting advantages and disadvantages. Regardless, lymphedema is a significant complication for breast cancer reconstruction, and can manifest 1-5 years after treatment, rendering it difficult to detect and treat properly. Therefore, Dr. Mehrara's team is focused on examining lymphedema from many perspectives, one of which involves the role of intracellular pathways within lymphatic endothelial cells in lymphedema development. A typical hallmark of lymphedema is lack of lymphangiogenesis and tissue fibrosis, which a medical student in the lab whom I have been shadowing believes is the product of negative regulation of VEGFR3 in response to VEGFC influx, as shown in the figure below. Throughout my first week, I observed the monolayer culture of primary lymphatic endothelial cells treated with VEGFC to test this hypothesis, as well as western blotting to measure the level of change in intracellular pathway proteins. In regards to the fibrosis aspect of lymphedema, I surveyed the isolation of keratinocytes from mice tails induced with lymphedema. 

Most importantly, I gained an appreciation in just my first week for the myriad of considerations involved in clinical studies and research in a hospital setting. For instance, the medical student whom I was shadowing explained a conundrum he was facing in which he was able to observe upregulated VEGFC in vitro and with mouse lymphatic endothelial cells, but not so with human patient samples collected from the lymphatic surgeries at MSK. I was not aware of how many confounding factors complicate data collection from clinical samples, including biopsy depth, length of treatment, race, gender, and comorbidities. I also found that even methods of sample collection can vary immensely amongst clinicians. For Dr. Mehrara's research group, lymph fluid is collected by liposuction and subsequently centrifuging down the fluid from fat in order to collect a few milliliters. However, a visiting clinician from Belgium in the lab has been able to collect up to an astounding 9 liters of lymph fluid from lymphedema patients in cases untreated for a decade. It would seem that different stages of lymphedema can be as heterogeneous as being classified as different diseases altogether. In upcoming weeks, I hope to witness some of the breast reconstruction and lymphedema treatment procedures I have heard much about.