Four from Hopkins BME recognized at Young Investigators’ Day

Akshaya Vijaya Annapragada

Research discovery: Repeat elements, which comprise more than half of the human genome, have long been implicated in disease, but have historically been excluded from whole-genome analyses because of incomplete references and computational challenges. I developed a new method (ARTEMIS) to study genome-wide repeats and identified alterations in 820 elements not previously implicated in cancer. I then used ARTEMIS to develop blood tests for early detection of cancer, when tumors can be most effectively treated. Early in my Ph.D. work, I and others developed accessible cancer blood tests using machine learning and whole genome sequencing to analyze tens of millions of cell-free DNA (cfDNA) fragments from less than 1mL of blood (DELFI). Here, I used ARTEMIS to expand the scope of these tests, combining ARTEMIS and DELFI to noninvasively detect lung, liver and other cancers. Finally, I piloted liquid biopsies beyond oncology for detection of fibrotic liver disease. This work has illuminated genome-wide repeat elements in cancer and cfDNA, and provides a proof-of-concept for their use in noninvasive detection of cancer and other diseases. This work was done in the Cancer Genomics Lab, mentored by Victor Velculescu and Rob Scharpf.

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Mohammad Amin Fakharian

Research discovery: Damage to the cerebellum is known to cause dysmetria, errors that worsen at the end of movements, first described by Gordon Holmes during World War I. Yet cerebellar neurons often stay active beyond movement end, raising the question of how precise control is achieved. My research investigated how the cerebellum achieves this precision for rapid eye movements, saccades. Using high-density electrophysiology in behaving marmoset monkeys and recording from multiple cell types in the cerebellar cortex, we found that neurons form interconnected groups that share learning signals; with some spikes driving behavior and others canceling unwanted effects. By analyzing population activity, we revealed how groups of neurons collectively compute movement timing and termination. This work was carried out in the laboratory of Professor Shadmehr.

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Didhiti Mukherjee

Research discovery: The development of the sensory brain relies on early periphery-generated spontaneous neural activity and later sensory-evoked activity. In Professor Patrick Kanold’s lab, my research explored how the developing auditory cortex (ACtx) — a designated area in the brain to process sound — is shaped by self-generated ultrasonic vocalizations, a sound produced abundantly by newborn animals, including mice, during the early postnatal weeks when their ear canals are still closed. By performing live imaging of the brain in awake, week-old mouse pups, I found that the ACtx is strongly activated by the copious number of vocalizations that the pups produce, and this activation is remarkably stronger than external-sound driven activation. Moreover, vocalization-associated activation is also present in pups with congenital deafness, suggesting the activation does not rely on hearing the sound, instead follows a central pathway inside the brain. By performing a series of experiments, I discovered that vocalization-associated activation of the ACtx is linked to signals from motor-related brain regions, namely the anterior cingulate cortex (ACC) and the secondary motor cortex (M2). ACC/M2 produces commands that generate vocalizations in pups and sends a copy of those commands to the ACtx to activate it. Pharmacological inactivation of the ACC/M2 reduces vocalizations and ACtx activation. Together, my results identify a novel source of early ACtx activity that can shape development and early neural plasticity, expanding our understanding of how the sensory brain is shaped during early development.

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Christine Wei

Research discovery: mRNA vaccines delivered by lipid nanoparticles (LNPs) have transformed modern vaccinology, most notably through COVID-19 vaccines, and are now being actively explored for cancer and infectious diseases. A key challenge in this field is generating durable immune responses in the specific organs affected by disease. Working in Dr. Hai-Quan Mao’s lab, I investigated how the composition of LNPs influences where they travel in the body after vaccination and how this shapes tissue-specific immune responses. Through this work, I discovered that intramuscularly administered mRNA LNP vaccines exhibit formulation-dependent systemic trafficking to major organs such as the liver and lungs. Importantly, this trafficking behavior was linked to tissue-specific immune activation and long-term immune memory, including the generation of tissue-resident memory T cells, a population that provides durable local protection. This discovery advances our understanding of how mRNA LNP vaccines function in vivo and opens new opportunities to develop targeted vaccines and immunotherapies for cancer and other diseases where durable, localized immune protection is critical.

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