Associate Professor Brian Lawson, Ph.D. Antiretroviral therapy currently on the market is highly effective in the treatment of HIV, lowering viral loads and inhibiting disease progression; the problem is that these drugs do not affect dormant HIV hidden in host immune cells and, over time, are associated with significant toxicity. Therefore, how do we completely eliminate HIV, active and latent, from an infected person? One exciting approach to achieve that goal is the use of chimeric antigen receptor (CAR) T cell immunotherapy, which gained broad recognition as a new treatment modality for certain blood cancers. CAR T cells are derived from a patient’s own cells, and are engineered to identify and kill specific target cells. These T cells are especially suited to finding and killing cells that express very low levels of target proteins. Moreover, their self-sustaining nature and ability to traffic and surveil virtually the entire host are highly beneficial aspects for controlling a chronic systemic pathogen such as HIV. Indeed, in recent unrelated cancer trials, functional CAR T cells were documented in many purported HIV sanctuary sites, including the central nervous system, the digestive tract, genital tracts, secondary lymphoid tissues, etc. CAR T cells can safely stay in humans for a surprising length of time (>16 years), and thus could be excellent and safe platforms to act as long-term anti-viral sentinels. Continue reading

"It's a wrap!" - Scintillon's summer high school student research program excites young minds and comes to an end for 2022. Every year, Scintillon’s research faculty perform exciting biomedical research pushing for a cure of many major disease conditions, including neuroscience, immunology, virology, and aging-associated diseases. Towards these ends, the faculty has to secure new grants and new philanthropy to resource these efforts. In addition to these difficult challenges, every summer the faculty also joins together and donates a significant amount of their time and effort to teach and host a growing number of very highly motivated local San Diego high school students in Scintillon’s research laboratories for an intensive 4-week training program. The small number of high school students accepted into the highly-competitive program are some of the highest performing students in the entire county, and past alumni of the program have, not surprisingly, gone on to attend elite universities, including Dartmouth, Johns-Hopkins, Stanford, and Yale. This year’s SUmmer REsearch (SURE) program had its highest number of applicants to date—twice as many as last year. While that is great news for the program, we at Scintillon had to use every possible resource at our young Institute to accept and serve this class of 2022, the largest class in our 5-year program’s history. It wasn’t easy! Continue reading

San Diego – A new study reveals that a protein long known to play a role in communication between cells in the brain is also capable of obliterating cells if left unchecked because of its penchant for twisting and puncturing the cell membranes. The protein — known as complexin — if left alone is so toxic it can shred cells. Yet, in the brain, a suite of controls makes sure the protein plays nice and helps neurons communicate by aiding in the release of neurotransmitters. The findings are published Feb. 7 in Nature Structural and Molecular Biology. "We argue that’s the most interesting membrane fusion event in our bodies, because it’s the one that underlies this conversation. It controls remembering and forgetting. It is everything," says Ed Chapman, professor of neuroscience at the University of Wisconsin School of Medicine and Public Health. "Yet to this day, nobody knows just how the proteins involved in this process really work." In trying to better understand these proteins Chapman's lab and their collaborators discovered the surprising power of complexin. They found that it dramatically bends and reorders membranes. Live videos show the protein pinching off small bubbles of membrane while simultaneously poking holes in them.  Ultrahigh-resolution 3D images produced by the laboratories of Dorit Hanein and Niels Volkmann at the Scintillon Institute in San Diego also revealed, directly through Cryo-EM imaging, that complexin induces the formation of twisting curlicues of broken-apart membranes. Continue reading

Rapid tool for cell nanoarchitecture integrity assessment Detailed three-dimensional contextual information of molecular processes is often necessary to understand these processes well enough to develop efficient drug-targeting and disease intervention strategies in all medical fields. We developed a tool that significantly accelerates studies providing such information (Gaietta et al., 2021 Journal of Structural Biology). Structural basis of aE-catenin–F-actin catch bond behavior A better understanding of how cell-cell contacts are maintained or broken is essential for unraveling the detailed mechanism of cancer progression. For example, cells need to detach to become metastatic and need to maintain contacts within a tumor. Our study significantly deepened our understanding of how cell-cell contacts work and thus potentially opens new opportunities for medical intervention in cancer progression (Xu et al., 2020 eLife). The actomyosin interface contains an evolutionary conserved core and an ancillary interface involved in specificity The knowledge obtained in our study has direct impact on drug-targeting strategies for malaria by telling researchers which regions of the interface are promising targets for disrupting the function of the malaria proteins while, at the same time, minimizing the potential of disrupting human protein interaction, thus preventing potential side effects (Robert-Paganin et al., 2021 Nature Communications). Continue reading

Scintillon Institute researchers uncover an evolutionarily conserved brain region that puts a “brake” on food intake which may advance therapeutics for obesity and related disorders with excessive eating such as Prader-Willi syndrome. Do you ever wonder why you stop eating even when there are appealing foods available? The cerebellum compares hunger state with after-eating nutritional status in the gut to regulate dopamine reward signals in the striatum to control meal size. click here for higher-res image credit: Aloysius Y. T. Low A multi-institution collaboration led by Associate Professor Albert I. Chen at the Scintillon Institute, Assistant Professor J. Nicholas Betley and Postdoctoral Fellow Aloysius Low at the University of Pennsylvania searched for brain regions that might provide a stop signal for feeding and identified the cerebellum, a brain region outside of the conventional feeding network, as an important regulator of meal size. Neural activity of this region directs the suppression of food intake in mice, and this activity is abolished in human subjects with insatiable appetite. Their findings were published in the journal Nature on November 17, 2021. Continue reading

Metabolism or the set of life-sustaining chemical reactions defines the very wellbeing of humans. But can we better understand how cellular metabolism goes awry in various human diseases? The National Institute of General Medical Sciences just granted Scintillon’s Dr. Valentin Cracan $2.4 million to find out more! The National Institute of General Medical Sciences (NIGMS) has recognized Dr. Valentin Cracan as one of the nation’s highly talented and promising scientists to receive a Maximizing Investigators’ Research Award for Early-Stage Investigators (R35 MIRA-ESI).  This grant provides about $2.4 million over five years to support the ongoing work at the Cracan’s lab that has received a number of NIH grants already since it was established about 3 years ago. We spoke with Valentin as we were interested in his research in the context of his new, special grant.    PATH TO SCINTILLON Valentin received his undergraduate degree in Biology and Biochemistry from the Moldova State University in the Republic of Moldova in 2005 and his Ph.D. in Biological Chemistry from University of Michigan in 2012, where he studied the intracellular pathway for trafficking of vitamin B12 (cobalamin) in the laboratory of Professor Ruma Banerjee.  While in graduate school, Valentin significantly contributed to our understanding of vitamin B12-dependent cell metabolism. In 2012, he joined the laboratory of Professor Vamsi Mootha at the Massachusetts General Hospital and Harvard Medical School. There, he obtained further training in studying mitochondria, the energy factories of our cells and major hubs of cellular metabolism. In the winter of 2018, Valentin joined the Scintillon Institute faculty as an Assistant Professor. Continue reading