At a prestigious Californian university, in the heart of innovation and scientific discovery, research pushing the boundaries of medicine was recently presented. Young scientists, PhD students at the University of California, San Francisco (UCSF), were given the opportunity to summarize years of complex work in just a few minutes before an audience and judges at the annual Grad Slam competition. This event not only celebrates academic excellence but also emphasizes the importance of conveying complex scientific findings to the general public in an understandable and engaging way. In an environment where world-changing ideas are born, such as UCSF located in dynamic San Francisco, such events attract the attention of the scientific community as well as visitors from all over the world. The city, known as a global center for biotechnology, also offers a wide range of accommodation options for those coming for studies, research, or such events; from hotels near campuses like Parnassus Heights and Mission Bay, to apartments and alternative accommodations distributed throughout vibrant neighborhoods, tailored to different needs and budgets.

Decoding the Immune Response to HIV

One of the studies that attracted particular attention was that of Sophia Miliotis, a PhD student in the Pharmaceutical Sciences and Pharmacogenomics program. Her work sheds new light on the immune system's fight against HIV, the virus that causes AIDS. Miliotis uses an intriguing analogy with dating apps to explain the complex "matching" process within our bodies. Specifically, molecules of the Major Histocompatibility Complex (MHC), key players in our immune system, constantly "scan" protein fragments, known as peptides, within our cells. When an MHC molecule encounters a peptide originating from a virus, like HIV, it binds to it and transports it to the cell surface.

This MHC-peptide complex acts as a signal flag, alerting specialized immune cells, killer T-lymphocytes, that the cell is infected and needs to be destroyed. However, HIV is extremely adept at evading this surveillance. The virus mutates at an incredible speed, creating millions of different peptide variants. This vast diversity confuses the immune system; MHC molecules struggle to find suitable peptides that they can effectively present to T-cells. As a result, some infected cells remain undetected, transitioning into a latent, "dormant" state. These hidden cells form so-called viral reservoirs that can persist for decades, even with antiretroviral therapy, and can reactivate if treatment is interrupted, representing the main obstacle to a complete cure for HIV infection.

Previous approaches to identifying key HIV peptides that the immune system can recognize often boiled down to trial and error, testing individual candidates from a sea of possibilities. As Miliotis vividly describes, it's like "infinite scrolling" in search of the ideal partner. Her goal is to develop a more systematic approach. Using advanced high-throughput screening technology in her lab, she introduces thousands of different HIV peptides into genetically modified cells, such that each cell carries only one specific peptide. She then observes which peptides MHC molecules bind most effectively and present on the cell surface. The idea is that stronger binding and presentation indicate peptides that might be most visible to the immune system in vivo. By isolating cells with the most MHC-peptide complexes on their surface and identifying these specific peptides, Miliotis hopes to uncover key targets for future therapeutic strategies, such as therapeutic vaccines or immunotherapies aimed at eliminating latent HIV reservoirs. Her presentation, titled "Finding HIV: A Swipe in the Right Direction," won not only first place according to the judges but also the People's Choice award, confirming the success of communicating complex science.

Innovative Approaches in Treating Brain Tumors

Another significant contribution came from Maggie Colton Cove, also from the Pharmaceutical Sciences and Pharmacogenomics program. Her research focuses on one of the biggest challenges in oncology: treating brain tumors. She presented work titled "Building Biological 'Sleeper Agents' to Fight Brain Tumors," focusing on improving CAR-T cell therapy.

CAR-T therapy represents a revolutionary approach in cancer treatment, especially for blood malignancies. It involves genetically modifying a patient's own T-lymphocytes to express chimeric antigen receptors (CAR) on their surface. These receptors allow T-cells to recognize specific proteins on the surface of tumor cells and destroy them selectively. Despite exceptional success in leukemias and lymphomas, the application of CAR-T therapy to solid tumors, particularly brain tumors like glioblastoma, faces significant hurdles.

One of the main problems is the suppressive microenvironment within brain tumors. Tumor cells and other cells in their vicinity release molecules that actively inhibit the function of immune cells, including CAR-T cells. This leads to their exhaustion and reduced effectiveness. An additional challenge is the blood-brain barrier, which hinders the penetration of therapeutic cells to the tumor. There is also a risk of "off-tumor" toxicity, where CAR-T cells attack healthy tissues that might express the target antigen to a lesser extent.

Colton Cove, working in the lab of Dr. Hideho Okada, a recognized expert in brain tumor immunotherapy, is developing a strategy to overcome these limitations using a sophisticated genetic switch known as the synNotch system. The idea is to create CAR-T cells that are initially inactive, like "sleeper agents." They express a synNotch receptor that recognizes a specific antigen present exclusively in the brain tumor microenvironment. Only when the synNotch receptor recognizes its target does it trigger the expression of the CAR on the T-cell surface. In this way, CAR-T cells become fully active only when they reach their destination – within the tumor. This approach preserves their strength and longevity, as they are not prematurely exhausted by fighting outside the tumor environment, and reduces the risk of attacking healthy tissues. "These cells are completely normal until they travel to the brain, hear their 'code phrase,' and activate into tumor-killing machines," explained Colton Cove. Preliminary results in the lab show that such inducible CAR-T cells clear tumors faster and prevent their recurrence, offering hope for more effective treatment of these devastating diseases.

Mapping the Development of the Blood-Brain Barrier

The third award-winning research, presented by Kaylee Wedderburn-Pugh from the UCSF Biomedical Sciences Program, delves into the fundamental processes of early brain development. Her presentation, "UNDER CONSTRUCTION: Mapping the Blood-Brain Barrier's Blueprint in Development," deals with uncovering the mechanisms of blood-brain barrier (BBB) formation during pregnancy.

The blood-brain barrier is a highly selective, semipermeable boundary that separates circulating blood from brain tissue. It consists of specialized endothelial cells lining the blood vessels in the brain, supported by pericytes and astrocytes. Its primary role is to protect the sensitive nervous system from potentially harmful substances, pathogens, and abrupt changes in blood composition, while simultaneously allowing the passage of essential nutrients like glucose and oxygen. Proper formation and function of the BBB are crucial for normal brain development and function.

Disruptions in BBB development during the fetal period can have serious consequences, linking to various neurodevelopmental disorders, congenital defects, and increased brain susceptibility to infections or toxins. However, the molecular and cellular processes governing the establishment of this vital barrier are still not fully understood. This is precisely the focus of Wedderburn-Pugh's research – detailed mapping of the "blueprint" according to which the BBB is built.

Understanding how the BBB normally develops could open doors to new diagnostic and therapeutic approaches. For example, it could enable early detection of subtle defects in the barrier in fetuses or newborns, potentially identifying children at risk for developing neurological problems. Furthermore, knowledge of the specific molecular pathways involved in BBB formation could inform the development of targeted therapies for treating prenatal or early-onset brain disorders. This includes finding ways to safely deliver drugs across the BBB to the fetal or infant brain when necessary, which is currently a major challenge. Kaylee Wedderburn-Pugh's work therefore has the potential to significantly advance prenatal and neonatal care, offering better protection and treatment options for the most vulnerable patients during the most critical period of brain development.

These three examples from the UCSF Grad Slam competition illustrate the breadth and depth of research conducted at leading global institutions. From combating global threats like HIV, through the development of smart therapies for incurable diseases like brain tumors, to fundamental research into early human development, young scientists are pushing the boundaries of knowledge and offering hope for the future of medicine.

Source: University of California