The fourth annual Next Generation in Biomedicine Symposium brings together emerging, talented scientists at the intersection of biomedical disciplines, to share their research and discuss exciting new directions. Twenty early career scientists will present their innovative research across a wide range of fields relevant to biomedicine, including biology, immunology, biomedical engineering, and computer science.
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November 2021 Symposium Presenters
HHMI Hanna Gray Postdoctoral Fellow, University of California, San Francisco
The neural coding and molecular properties of pain in behaving animals
Pain is a complex, multidimensional percept that requires integration of incoming sensory information from the spinal cord and other areas with ongoing brain states to initiate appropriate protective behaviors. To elucidate spinal cord neural pain codes, we established longitudinal, in vivo spinal cord imaging in awake, behaving animals, allowing us to image calcium activity (analyzed with my CIAtah software) along with neural structures and glia over extended periods of time. Then, to understand the molecular changes induced by chronic pain causing injury and identify novel therapeutic targets, I will present ongoing studies to characterize pain-related proteomes of each node in the pain neuroaxis.
Postdoctoral Scholar, University of California, Berkeley
DiMeLo-seq: a long-read, single-molecule method for mapping protein-DNA interactions genome-wide
Molecular studies of genome regulation often rely on the ability to map where specific proteins interact with genomic DNA. Here we developed a new protein-DNA mapping method, called Directed Methylation with Long-read sequencing (DiMeLo-seq), which utilizes cutting-edge long-read DNA sequencing technologies to reveal a target protein’s binding sites with high resolution on long, single, sequenced DNA molecules. This amplification-free method provides a proportional readout of protein-DNA interaction frequency, retains endogenous CpG methylation information, and enables mapping of protein-DNA interactions in highly repetitive regions of the genome.
Chrystian Junqueira Alves
Postdoctoral fellow, Icahn School of Medicine at Mount Sinai
Investigating the differentiation of stem cells and cancer migration by force-mediated mechanosignaling
Plexins are classically known as axon guidance receptors. However, Plexins originated in unicellular organisms greater than 600 million years ago. My work is to understand the mechanobiology of Plexin-B2 in human embryonic stem cells, cerebral organoids and cancer stem cells. I discovered that during the neurodevelopment, Plexin-B2-deficient human neuroprogenitors undergo spontaneous neuronal differentiation due to low cytoskeletal tension. Strikingly, in cancer stem cells, Plexin-B2 is critical for cytoskeletal dynamics and nuclear mechanotransduction during cancer invasiveness. As an independent investigator, I will develop novel strategies to accelerate the differentiation of stem cells by manipulating intrinsic cell mechanics and exploring how a force-dependent rearrangement of the nuclear envelope can lead to epigenetic changes that promote neuronal differentiation. I will also explore the role of nuclear mechanotransduction for the migration of cancer stem cells. My research has broad potential to accelerate the generation of subtype-specific neurons to disease modeling and to understand new mechanisms of cancer migration through confined spaces for drug development.
Postdoc, University of California San Francisco
Antibody modulation of the SARS-CoV-2 fusion machinery
The SARS-CoV-2 Spike protein mediates viral fusion, but also pathological cell-cell fusion leading to formation of syncytia (giant, multi-nucleated cells) that are a hallmark of tissue damage in severe COVID-19. We report SARS-CoV-2 neutralizing antibodies that either inhibit or enhance Spike-mediated membrane fusion, and show how these antibodies control fusogenicity by altering the Spike protein conformational cycle.
Postdoctoral Researcher, University of California San Diego
An in vitro platform enables catalytic characterization of an intramembrane rhomboid protease
Rhomboid proteases are ubiquitous intramembrane serine proteases that directly cleave misfolded membrane substrates within the lipid bilayer. They have vast functions in growth factor signaling, mitochondrial homeostasis, protein quality control and parasite invasion. Here, I will provide fundamental insights into the catalytic activities and substrate preferences of a human rhomboid protease, implicated in diseases like breast cancer and Alzheimer’s, utilizing an in vitro platform. This comprehensive study will pave the way for future drug targeting against such critical proteases.
HHMI Hanna H. Gray Fellow, Harvard Medical School
Evolution of the human brain: Transposable elements as drivers of genome evolution
The human brain has evolved remarkable cognitive capabilities, yet our understanding of how changes in genome sequence through evolution have led to the structural and functional changes in the brain remains weak. We are studying how transposable element insertions, overlooked contributors to genome evolution, have given rise to new regulatory elements controlling gene expression programs in human neurons.
Ph.D. Candidate, University of Minnesota - Twin Cities
Programmable Fusion of Synthetic Cells to Construct Genetic Circuits
We have developed a unique method for regulating gene expression inside liposomal bioreactors, or synthetic cells, that relies on the construction of programmable fusion events. With this technology, we construct simplified models of mating and pluripotency within synthetic cells, two relatively complex systems that would not be possible with classical genetic regulation elements
Eric Villalón Landeros
Postdoctoral Fellow, Johns Hopkins University School of Medicine
The Neuronal Membrane Proteasome Modulates Sensory Neuron Activityin the Peripheral Nervous System
This is my work on the identification of the neuron-specific membrane localized proteasome (NMP) in the peripheral nervous system and the investigation of its role in mediating neuronal signaling. I share my findings that demonstrate that the NMP has the capacity to modulate sensory neuron activity via release of signaling peptides in response to stimuli in a non-cell autonomous manner. This work changes our understanding of the function of proteasomes in the PNS and suggests new roles in mediating neuronal communication.
Stanford Science Fellow, Stanford University
Somatic evolution in Pearson Syndrome revealed via single-cell multi-omics
Utilizing single-cell multi-omics, we chart the somatic evolution of Pearson Syndrome, a congenital disorder caused by large deletions in mitochondrial DNA (mtDNA). We observe multiple modes of purifying selection in mtDNA across three patients, including in peripheral effector-memory CD8 T cells and in hematopoietic stem and progenitor cells. Our results establish a conceptual model for metabolic determinants underlying cell fate transitions and differentiation.
Postdoctoral Fellow, Friedrich Miescher Institute for Biomedical Research
How do transcription factors interpret and influence chromatin structure?
Eukaryotic DNA is wrapped around histone proteins to form nucleosomes which occludes large parts of the DNA surface. While it has long been known in the field of epigenetics that transcription factors (TFs) are able to engage DNA motifs when sterically occluded or ‘hidden’ in chromatin, the molecular mechanisms have remained elusive. To study how TFs bind nucleosome-occupied motifs we focused on the reprogramming factors OCT4 and SOX2 and determined their engagement throughout a nucleosome at base-pair resolution in vitro, enabling cryo-EM structure determination at two preferred positions to reveal how TFs distort nucleosomes to access chromatinized motifs.
Research Associate, The Rockefeller University
Sending Proteasomes to fight Neurodegeneration
There are more then 10 known mutations in Fbxo7/PARK15 that cause a severe form of Parkinsonian Pyramidal Syndrome in humans, and mice mutant for Fbxo7 replicate the human pathology. We show that PI31, a regulator of proteasome function, robustly suppresses neuronal degeneration in Fbxo7 mutant mice. These findings uncover a new target for therapeutic intervention in the treatment of neurodegenerative diseases.
María Angélica Bravo Núñez
Postdoctoral Fellow, Harvard University
The Effect of Meiotic Factors in Ploidy Dynamics
Errors during chromosome segregation can lead to cells with the wrong number of chromosomes, a condition known as aneuploidy. Aneuploidy is a driving force in cancer progression and has been linked to the rapid emergence of drug resistance in fungal pathogens. In this talk, I will illustrate how meiotic genes may contribute to mitotic segregation errors and show that meiotic genes can drive ploidy changes outside of gametogenesis.
Mary Schwalm / AP Images for HHMI
Postdoctoral Fellow in Neurobiology, Harvard Medical School
A neuronal activity-dependent NPAS4 complex protects the aging genome
Neuronal activity is critical for adaptive circuit remodeling but poses an inherent risk to the stability of the genome across the long lifespan of post-mitotic neurons. Using a combination of new genetic mouse models, biochemistry, and single-cell genomics, we discover a neuronal protein complex that protects the genome from accumulating DNA damage during periods of heightened synaptic activity. Our findings identify a previously unrecognized mechanism of DNA repair in neurons that targets each cell type’s most vulnerable regulatory sites, synchronizes with neuronal activity, and whose disruption may contribute to mammalian aging and neurodegeneration.
NCI F99 Predoctoral Fellow, University of California San Diego
Mapping cell structure across scales by fusing protein images and interactions
The cell is a multi-scale structure with modular organization across at least four orders of magnitude. Two central approaches for mapping this structure – protein fluorescent imaging and protein biophysical association – each generate extensive datasets, but of distinct qualities and resolutions that are typically treated separately. We have recently developed a novel machine learning approach to integrate immunofluorescence images in the Human Protein Atlas with affinity purifications in BioPlex to create a unified hierarchical map of human cell architecture, paving the way to incorporate diverse types of data in proteome-wide cell maps.
Sofia Agustina Quinodoz
HHMI Hanna H. Gray Postdoctoral Fellow; Princeton University
SPRITE: Mapping the 3D organization of RNA and DNA throughout the nucleus
Arranging DNA, RNA, and proteins in various structures within the nucleus is essential for regulating diverse cellular functions; however, we have lacked high-throughput tools to map nuclear organization. We developed a novel split-pool-based genomics approach, SPRITE, to generate global, high-resolution maps of RNA and DNA in the nucleus. Using SPRITE, we have uncovered two major “hubs” of genes coming together at two nuclear bodies, the nucleolus and speckles, and we showed that RNAs play key roles in organizing nuclear structures and controlling gene regulation.
Postdoctoral Scholar, University of California San Francisco
Leveraging systems-level live-cell microscopy to identify regulators of membraneless organelle dynamics
"Membraneless organelles (MLOs) assemble through molecular condensation to create dynamic microenvironments that exhibit a diverse range of material properties thought to be essential for health, as MLO dynamics are often disrupted in neurodegenerative disease. Here, I will describe a platform for identifying regulators of MLO dynamics in living cells, leveraging systems-level perturbations and fluorescence recovery after photobleaching adapted for high-throughput screens. We have applied this platform to determine the role of RNA helicases in modulating the assembly of multiple MLO compartments, revealing extensive crosstalk between different MLOs and suggesting that their structure may be finely tuned by diverse changes in RNA homeostasis. "
Howard Hughes Medical Institute Fellow of the Damon Runyon Cancer Research Foundation;Dana Farber Cancer Institute
Horizontal Transfer of Histone H3 by Mammalian Cells
While developing proximity ligation experiments to detect secreted proteins from cancer cells, I noticed an intracellular control (Histone 3) wasn't behaving as expected. We subsequently discovered that Histone 3 (but not other histones) is secreted by autophagic cells, and this secreted H3 can be transferred to and incorporated into the chromatin of independent "destination" cells. Here I will present data from experiments that: 1) identify, and characterize the cell biological mechanisms of this H3 Secretion, 2) investigate the biological relevance of Histone-transfer to destination cells and 3) leverage the Histone-transfer pathway for macromolecular delivery.
HHMI Hanna H. Gray Fellow; Harvard University
Immunologic control of physiology and behavior
The mammalian intestine is a multi-kingdom cellular ecosystem in constant contact with the outside world, requiring that it balance its two main functions – host defense and nutrient uptake – in response to environmental change. Achieving this balance is particularly challenging for omnivores, whose diets change on daily, seasonal, and lifelong timescales, alongside encounters with ingested toxins, enteric pathogens, and commensal microbes. I will present studies that address a fundamental question in intestinal biology – how does the gut adapt to the food we eat? – identifying an unexpected role for the immune system in regulating physiology, and discuss ongoing work that explores the role of the immune and nervous systems in coordinating behavioral responses to environmental threats.
HHMI Hanna Gray Postdoctoral Fellow; Fred Hutchinson Cancer Research Center
How the host fights back: evolutionary landscape of host-virus arms races
To understand how antiviral proteins compete in evolutionary arms races against rapidly evolving viruses, I mapped the evolutionary landscape (the outcome of all possible amino acid mutations) in TRIM5, an antiviral protein that inhibits HIV. I found that TRIM5's virus-binding surface is highly adaptable and resilient to mutation, such that most missense mutations improve recognition of one virus without negatively affecting detection of other viruses. My findings suggest the novel possibility that antiviral proteins have been selected for such permissive landscapes to maximize the odds of their success in evolutionary arms races.
Alex's Lemonade Stand Young Investigator, Postdoctoral Fellow, Massachusetts General Hospital
Zebrafish Avatar of Human Cancer
Xenograft cell transplantation experiments has become the gold-standard for assessing regenerative capacity of stem cells and pre-clinical efficacy for new drugs. We have recently created immunodeficient zebrafish models that can robustly engraft a wide variety of human cells, including cancer cell lines, patient-derived xenografts and primary hematopoietic cells. Applications of these mutants ranges from preclinical small molecule drug discovery studies to cancer immunotherapies including CAR T cell therapy and bispecific T cell engagers.