Current Fellows

Lauren Aguado

Laboratory of Virology and Infectious Disease, The Rockefeller University

Read more

Entering the unknown: How do viruses transition to new hosts?

All viruses require the vast resources of a cell to complete their lifecycles, carrying with them only the tools essential for their replication that cannot be found in a host. While many viruses infect only a single or few closely related species, arboviruses constantly cycle between an insect vector and a vertebrate host. This requires that a virus be able to take advantage of two unique cellular environments while evading entirely different defense systems to do so. Many of the host factors essential for viral replication in the insect vectors remain entirely unidentified; of those that have been defined, only a subset is required in both insect and vertebrate species. Many more are utilized in only one species, leading to the hypothesis that arboviruses have found multiple ways to achieve the same ultimate goal of replication and dissemination in these dual hosts. My work seeks to understand how these disparate environments can support the replication and transmission of a single virus and how viruses can adapt to new host species.

Andrew Anzalone HHMI Fellow

Department of Chemical Biology and Therapeutics Science, Broad Institute/MIT/Harvard

Read more

Genome editing with single nucleotide precision

Juan Barajas Jane Coffin Childs

Department of Pathology, St Jude Children's Hospital

Read more

Functional evaluation of clonal hematopoieses of indeterminate potential

Karl Barber

Department of Genetics, Brigham and Women's Hospital

Read more

dCas9-mediated assembly of protein microarrays for viral diagnosis

Emily Bayer Jane Coffin Childs

Department of Biozentrum, University of Basel

Read more

Neural plasticity underlying socual dominance behavior in cichlids

Intuitively, humans seem aware of the fact that visceral sensations are related to their emotional or stress perceptions of the world. English idioms such as the heart “leaping” reflect excitement, the heart “sinking” reflects despair, and “gut feelings” reflect intuition. This conscious awareness of the reactions of the viscera suggests a two-way relationship between perception of the body and reaction of the brain, but the biological underpinnings and relevant neural circuits are still understudied.

The zebrafish has the great advantage of external fertilization and optical accessibility during development, which I will utilize to study how sensory inputs from the body shape brain state and activity. I hope to understand the kinds of sensory information transmitted from the body to the brain, and the ways that this affects how the brain generates behaviors.

Nathan Belliveau HHMI Fellow

Department of Biology, University of Washington

Read more

Functional genomics of directed 3D cell migration

Julianna Bozler

Department of Cell and Developmental Biology, University of Pennsylvania

Read more

Molecular regulation of behavioral and reproductive plasticity in ants

Joshua Brickner Jane Coffin Childs

Department of Chemical and Systems Biology, Stanford University

Read more

Mechanisms of R-loop mediated innate immune response in non-dividing cells

Cori Cahoon

Department of Biology, Institute of Molecular Biology, University of Oregon, Eugene

Read more

Defining mechanisms of heat-sensitive synaptonemal complex in spermatocytes

Sexually reproducing organisms faithfully transmit their genome to the next generation by forming haploid gametes, such as eggs and sperm. In contrast to oogenesis and other developmental processes, spermatogenesis is sensitive to small temperature changes, requiring a narrow isotherm of 2-7ºC below basal body temperature. Although failure to precisely thermoregulate spermatogenesis or exposure to elevated temperatures are strongly linked to both male infertility and an increased risk of testicular cancer, the mechanisms behind temperature-induced damage on male reproductive health remain unknown. Recent studies indicate that the composition and/or function of chromosome structures differ during oogenesis and spermatogenesis, which may contribute to the temperature-sensitivity of spermatogenesis. In Caenorhabditis elegans, we have found using structured illumination microscopy that the synaptonemal complex (SC), a meiosis specific structure central to the proper execution of key meiotic processes, is destabilized specifically in spermatocytes and not oocytes following heat-stress. My ongoing studies seek to understand the differences in SC organization and composition that render it temperature sensitive only in spermatogenesis. Overall, these studies will illuminate how temperature specifically affects genome integrity in developing sperm and identify the mechanisms that underlie temperature-associated infertility and cancer risk of the male germline.

Jinxun Chen Jane Coffin Childs

Department of Gennetics, Stanford University

Read more

Dissecting the mechanisms of vertebrate reproductive aging in killfish

David Colognori Jane Coffin Childs

Department of Molecular and Cell Biology,, University of California, Berkeley

Read more

Developing new CRISPR-Cas system for eukaryotic RNA knockdown and detection

CRISPR-Cas systems provide prokaryotes with an adaptive immune mechanism whereby foreign nucleic acids are recorded and, when re-encountered, destroyed. Foreign DNA fragments are incorporated into the host’s CRISPR array and later transcribed and processed into crRNAs. crRNAs then assemble with Cas effector proteins and guide them to complementary nucleic acid sequences for destruction. The well-known Cas9 cleaves DNA site-specifically, and thus has been widely adopted as a programmable tool for gene editing. Analogous tools for cleaving RNA are lacking, with the exception of Cas13 which exhibits non-site-specific cleavage and toxic off-target effects. My research aims to discover and characterize new Cas effectors for precise RNA-cleavage in prokaryotes, and further develop them into tools for detection and cleavage of RNA sequences in eukaryotes.

Thomas Cooke HHMI Fellow

Whithead Institute for Biomedical Research

Read more

The origin and evolution of cell types

One of the special features of animal and plant cells is their differentiation into hundreds of specialized types. How these diverse cells originated is a fundamental question in evolution. To approach this question, I am using single-cell RNA sequencing to characterize hundreds of cell types across diverse species of planarians and their distant relatives. This will enable a search for key regulatory factors in an unprecedented range of differentiation pathways, guided by the fact that conserved expression is a common feature of such genes. Planarians are particularly well-suited for testing the function of fate-specifying genes because cell differentiation is an ongoing process in all tissues in the adult stage, and during regeneration. Through this approach, I propose to learn general principles concerning the molecular basis of cell type homology across diverse animal taxa.

Alicia Darnell Merck & Co., Fellow

Koch Institute, Massachusetts Institute of Technology

Read more

Understanding cellular and organismal amino acid homeostasis

Kristen DeMeester Jane Coffin Childs

Department of Chemistry, Scripps Research Center

Read more

Chemoproteomic discovery of small-molecule probes for autophagy proteins

Seth Donoughe

Department of Molecular Genetics and Cell Biology, University of Chicago

Read more

Dissecting mechanical feedback in the Drosophila egg chamber

Priscilla Erickson

Department of Biology, University of Virginia

Read more

Genetics and evolution of photoperiodism in Drosophila melanogaster

Organisms exhibit diverse strategies to survive environments that vary in space and time. In temperate climates, environmental cues are used to anticipate the onset of unfavorable seasons. One of the most reliable indicators of season is photoperiod: the length of light and dark periods within a 24-hour day. Insects exhibit a spectacular array of responses to changes in season. For example, aphids develop sexually reproducing morphs in the fall, moths and lacewings develop unique seasonal patterns and colors, monarch butterflies undergo seasonal migrations, and hundreds of species, including the fruit fly Drosophila melanogaster, are able to suspend development or reproduction until more favorable conditions return. Despite nearly a century of research on insect seasonality and photoperiodism, the genetic pathways used to make these ecologically crucial transitions remain unknown. The abundance of genetic and genomic resources for Drosophila makes it an ideal study system for this question.

My research uses custom-built environmental chambers, field studies in an experimental orchard, and novel genetic mapping techniques to dissect the genetic basis of photoperiodism and seasonal responses in Drosophila. Understanding how insects detect photoperiod will inform our understanding of economically and biomedically important insects and offer predictions about how insects may adapt to ongoing anthropogenic climate warming in which temperature, but not photoperiod, is changing.

Monifa Fahie

Department of Biology, Brandeis University

Read more

Translation regulation and viral exploitation in innate immunity

Anthony Flamier

Whitehead Institute for Biomedical Research

Read more

Formation of phase separated condensated in fragile X-linked syndromes

Fragile X syndrome (FXS) is a genetic neurodevelopmental disease causing the most common form of mental retardation after trisomy 21 and includes pathological features ranging from impaired cognition to intellectual disabilities. While FXS pathology starts at the early childhood, Fragile X-linked tremor/ataxia syndrome (FXTAS) occurs around age 60 with tremor, ataxia and parkinsonism. Both diseases are caused by an extension of CGG triplet repeats at the five prime (5’) untranslated region (UTR) of FMR1. Individuals with more than 200 repeats are predisposed to get FXS while individuals carrying between 55 and 200 repeats will develop FXTAS over time. The key question addressed in this project is to understand how the number of repeats in the FMR1 gene impacts protein translation and causes the clinical manifestation of either FXS or FXTAS.

Ninghai Gan HHMI Fellow

Department of Physiology, UT Southwestern

Read more

Role of two pore channels in NAADP-induced Ca2+ signaling

Christina Gladkova HHMI Fellow

Department of Cellular and Molecular Pharmacology, University of California, San Francisco

Read more

Understanding mitochondrial trafficking: linking mitochondria to motors

Yogesh Goyal

Department of Bioengineering, University of Pennsylvania

Read more

Cellular states guiding plasticity and reprogramming paradigms in cancer

Resistance to therapy is a hallmark of many cancers (e.g. melanoma). Advancements in quantitative single-cell biology has allowed characterization of pre- and post-therapy melanoma cells with unprecedented resolution. Specifically, recent studies have demonstrated that rare populations of preresistant melanoma cells exhibit non-genetic plasticity such that they occupy a transient state capable of withstanding drug treatment, but can be reprogrammed into a stable drug-resistant state upon drug addition. While this provides novel opportunities to tackle resistance, we still lack information on different cellular states and the underlying molecular mechanisms of transition between states. The first aim of this proposal is to develop a theoretical and conceptual understanding on the origins of transient, rare preresistant populations. The second aim focusses on developing an experimental data-driven computational framework to dissect the genetic networks in the pre- and post-resistant states. The last aim proposes developing stochastic population dynamics models to track cells at multiple timescales, and inform on rational drug dosing strategies. The eventual goal is to integrate the network models with the population level model, thus allowing multiscale analysis of regulation in melanoma. Together, my work will develop quantitative frameworks to systematically characterize the cellular landscapes guiding plasticity and reprogramming paradigms for therapy resistance.

Thomas Graham Merck Fellow

Department of Molecular and Cell Biology, University of California, Berkeley

Read more

In-Vivo single-molecule imaging of enhancer-promoter communication

The different cell types in our body have an incredible variety of sizes, shapes, and functions, despite having the same genome. Differences between cell types arise from differences in which genes are transcribed into RNA. Transcription is regulated by DNA sequences called enhancers, which in some cases are located hundreds of thousands of basepairs away from their target genes. While we know the identities of many of these enhancers, and the proteins that bind to them, we lack a coherent model of how enhancers regulate transcription. Various lines of evidence suggest that large protein complexes form a bridge between enhancers and their target promoters. However, we lack a basic understanding of the composition, size, and internal organization of these enhancer-promoter complexes. Important questions are: 1) How many copies of different proteins assemble at enhancers and promoters? 2) What protein-protein and protein-DNA interactions are important for assembling enhancer-promoter complexes? 3) How dynamic are these complexes? 4) How do enhancer-promoter complexes ultimately regulate transcription? To address these questions, I am working to develop new fluorescence imaging approaches in live cells, which will combine fluorescent labeling of DNA, RNA, and protein with new technologies such as single-molecule tracking and lattice light sheet microscopy.

Abigail Groff

Whitehead Institute for Biomedical Research

Read more

Sexually dimorphic gene expression in human preimplantation development

Abbie Groff studies sex differences at the earliest stages of development in Dr David Page’s laboratory at the Whitehead Institute.

Differences between the sexes start only a few cell divisions after conception. XY (‘male’) embryos tend to develop more quickly than XX (‘female’) embryos, reaching the blastocyst stage faster and with more cells. Prior studies have also reported various metabolic differences between the sexes in preimplantation development across multiple mammalian species. Since these cells have never been exposed to sex hormones, and the conditions of their culture are highly controlled, these differences must be due to the gene content and regulatory influence of the sex chromosomes. However, the transcriptional underpinnings of these differences are unclear.

Abbie’s work focuses on characterizing gene expression differences between 46,XX and 46,XY cells in preimplantation human development at single-cell resolution. Using this system, Abbie seeks to understand the specific contributions of the sex chromosomes to gene expression during the first cell divisions, and also chart the influence of nascent X chromosome inactivation on genome-wide expression changes.

Beyond explaining current “known” physiological sex differences at this developmental stage, she anticipates this work may provide insight into the development of sex biased phenotypes at later developmental stages, such as the predominance of disorders of placental dysfunction, including pre-eclampsia, in pregnancies with a male fetus.

 

Alexandra Grote Jane Coffin Childs Fellow

Department of Infectious Disease and Microbiome, Broad Institute, MIT, Harvard

Read more

Pioneering comparative regulomics to probe mechanisms of chroic salmonella

Advancements in vaccine design and immunotherapy have helped us gain insights into how to promote immunity against infections or cancers. However, excessive inflammation associated with immunotherapies, autoimmune diseases, non-healing wounds and even COVID19 is currently at the center of healthcare challenges. Following an inflammatory insult, such as an injury or pathogen invasion, immune cells in the tissues are crucial to resolve inflammation and regain healthy tissue function. Damaging inflammatory signals also activate nearby high threshold sensory neurons– the nociceptors – which are responsible for initiating pain and guarding/withdrawal responses which is believed to prevent further tissue damage. While it is conceivable that nociceptors can cooperate with immune to promote healing, the role of these neurons in shaping the healthy immune landscape of barrier tissues is currently unexplored. In the Woolf lab, I aim to determine the role of nociceptor sensory neurons in restoring the healthy immune profile of barrier tissues following an adverse and painful inflammatory event and develop novel strategies to manipulate neuroimmune interactions using genetic and pharmacological methods. Traditionally, inflammatory conditions are treated with broad immunosuppressants that put the patients at risk for further infections. The ability to fine tune immune function by controlling specific neuronal signals will offer a safer and effective therapeutic strategy for various inflammatory diseases as well as malignancies.

Joshua Gruber

Department of Genetics, Stanford University, Stanford, California

Read more

Integrated omics of malignant transformation by breast cancer genes, with Michael Snyder

Through my clinical work with oncology patients I became acutely aware of how few interventions we are able to offer patients to prevent cancer.  Even patients with inherited syndromes that confer a near-certainty of developing cancer have few, often unappealing, options to actually prevent cancer.  This motivated me to investigate molecular mechanisms of the earliest steps of malignant transformation.  I chose to study the genes causing inherited breast cancer because each one constrains the malignant phenotype of breast cells, an effect that can be modeled in vitro.

These ideas led me to team up with my advisor Dr. Michael Snyder at Stanford who has pioneered multiple high-throughput omics technologies to densely profile biological systems.  These tools allow for an unprecedented window into cellular dynamics driving malignant transformation.  I am particularly interested in how genomic aberrations in non-coding DNA elements can unlock transcriptional programs that drive malignancy.  The hope is to uncover molecular switches that can be targeted to prevent cancer onset.

Jennifer Hamilton

Department of Molecular and Cell Biology, University of California, Berkeley

Read more

Redesigning lentiviruses to achieve CRISPR-Cas9 genome engineering in vivo

CRISPR-Cas genome editing enables control of gene expression in cells, tissues and whole organisms. Although invaluable for experimental studies, translation of these advances into clinical therapeutics requires delivery of CRISPR-Cas proteins and guide RNA to disease-relevant organs in the body. Current in vivo delivery strategies have drawbacks including ineffective delivery to target tissue, prolonged nuclease expression leading to off-target damage, and clearance of edited cells by adaptive immune responses.

My research leverages viral infection strategies to overcome the challenges faced by the in vivo delivery of genome editing tools. In the Doudna laboratory, I am applying my background in engineering enveloped viruses to create the next-generation of CRISPR-Cas delivery vehicles and translate these technologies into therapeutics. By merging virology with bioengineering, I aim to both better understand the cellular response to genome editing and, ultimately, to make genome-based treatments accessible to all people who can benefit.

Annie Handler HHMI Fellow

Department of Neurobiology, Harvard Medical School

Read more

The physical and molecular determinants of touch

Our sense of touch emerges from a wide array of low-threshold mechanoreceptor neurons (LTMRs) that innervate the skin. Across our bodies, anatomically, molecularly and neurophysiologically distinct regions of skin house unique combinations of physiologically distinct LTMRs, which form unique 3-dimensional end organ structures as a result of their close association with local, terminal Schwann cells and other cell types. Distinct LTMRs and their end organ complexes, which are unique both in structure and mechanical sensitivity, allow us to perceive the slightest deflection of a hair follicle from a slight breeze, the low-frequency vibrations from the slip of your phone through your fingertips, or the high-frequency vibrations of a passing train. As such, our ability to perceive a wide array of mechanical stimuli in our environment emerges from the concerted activity of distinct end organ structures and the diverse LTMR endings embedded within. While the heterogeneity in both end organ structure and LTMR mechanical tuning has been appreciated for nearly 50 years, we understand very little of how the 3-dimensional structure of these end organs informs the tuning preference of their associated LTMRs and where the obligate mechanically sensitive ion channel, Piezo2, resides within them. As a postdoctoral fellow in the Ginty lab, I am using modern electron microscopy methods to create full-volume reconstructions of the distinct sensory end organs that enable our sense of touch. This 3-dimensional perspective, coupled with the genetic tools of the mouse and electrophysiological approaches, is allowing me to define molecular underpinnings of end organ function and to isolate the sites and mechanisms of mechanotransduction within the diverse sensory neurons of touch.”

Kiah Hardastle Jane Coffin Childs

Department of Organismal and Evolutionary Biology, Harvard University

Read more

Investigating how striatum selects and modifies actions across contexts

Understanding how the brain drives natural behavior is a central question in neuroscience. This quest is made particularly difficult by the fact that animal behavior is highly adaptable, thus requiring underlying neural circuits to alter the information they compute or represent depending on the task at hand. In my research, I examine how neurons in the motor pathway represent natural behaviors, and how these representations may change depending on the task the animal must perform. I investigate these questions using a combination of in vivo electrophysiology, machine vision, and computational models.

Theodore Ho HHMI Fellow

Department of Bioengineering, Stanford University

Read more

The role of altered neural activity in brain aging and cognitive decline

Both neural activity in different brain regions and behavior change over time and in disease states in both humans and animals, but how exactly activity of single neurons and their associated network dynamics change and directly affect such altered behavior is largely unknown. I am using single-cell optical and electrophysiological neural recording and perturbation techniques to study changes in neural circuit dynamics that control changes in animal behavior.
Previously, I completed a four-year joint bachelor’s/master’s degree program at Harvard University in Human Developmental and Regenerative Biology/Bioengineering, and then I received my PhD in Biophysics from UCSF studying stem cell aging in the lab of Dr. Emmanuelle Passegue.

Melissa Hoyer

Department of Cell Biology, Harvard Medical School

Read more

Spatial and temporal organelle quality control during changes in cell state

I have always been fascinated by the individual machines of the cell called organelles. In undergrad, I tagged yeast cells with a fluorescent mitochondria reporter. When I looked under the microscope, I was fully hooked. The microscopic world inside the cell was much more elaborate that I could have ever imagined. Subsequently, I decided to continue on to graduate school and study the endoplasmic reticulum (ER) in mammalian cultured cells. The ER is often pictured as this static platform for protein synthesis, but using live cell fluorescence microscopy, you can see how the ER dynamically rearranges its structure: tubules grow out or retract, sheets shrink or expand. This drives a constant remodeling process. For my PhD thesis, I focused on why and how the ER remodels its structure to contact other organelles.

In my current work, I now get to study organelles in neurons. A specialized cell like a neuron maintains a certain shape and structure to properly function. Cells can clear away damaged organelles through the “self eating” process of autophagy. Interestingly, prior evidence indicates that autophagy machinery is needed for human embryonic stem cell differentiation to different cell states. However, to date, there is no established systematic map of organelle-phagy for stem cell conversion to a neuron. Additionally, in human patients with neurodegenerative diseases, including Parkinson’s disease, many identified gene variants are in autophagy-regulating genes. In my work, I genetically edit and tag stem cells using CRISPR and then convert these cells to neurons. With these engineered induced neurons, I study organelle structure, dynamics, and turnover in order to reveal the underlying mechanisms sustaining the architecture required for healthy and efficient neuronal function.

Bessie P-H Huang Jane Coffin Childs Fellow

Read more

Isolation and characterization of conditions mutations affecting cellular neurotubules

Aakanksha Jain Jane Coffin Childs Fellow

Department of Neurobiology, Boston Childrens Hosptial

Read more

Somatosensory control of barrier tissue immunity

Advancements in vaccine design and immunotherapy have helped us gain insights into how to promote immunity against infections or cancers. However, excessive inflammation associated with immunotherapies, autoimmune diseases, non-healing wounds and even COVID19 is currently at the center of healthcare challenges. Following an inflammatory insult, such as an injury or pathogen invasion, immune cells in the tissues are crucial to resolve inflammation and regain healthy tissue function. Damaging inflammatory signals also activate nearby high threshold sensory neurons– the nociceptors – which are responsible for initiating pain and guarding/withdrawal responses which is believed to prevent further tissue damage. While it is conceivable that nociceptors can cooperate with immune to promote healing, the role of these neurons in shaping the healthy immune landscape of barrier tissues is currently unexplored. In the Woolf lab, I aim to determine the role of nociceptor sensory neurons in restoring the healthy immune profile of barrier tissues following an adverse and painful inflammatory event and develop novel strategies to manipulate neuroimmune interactions using genetic and pharmacological methods. Traditionally, inflammatory conditions are treated with broad immunosuppressants that put the patients at risk for further infections. The ability to fine tune immune function by controlling specific neuronal signals will offer a safer and effective therapeutic strategy for various inflammatory diseases as well as malignancies.

Nicholas Jourjine

Department of Molecular and Cellular Biology, Harvard University

Read more

Genetic and neural basis of natural variation in infant vocalization

Infant vocalization is a pervasive mammalian social behavior that elicits parental care essential for infant health. Features of infant vocalization are innate, heritable, and vary between species, but we know little about the genetic or neural mechanisms underlying this variation. To better understand these mechanisms, I study the cries of infant Peromyscus mice (also known as deer mice), a group of closely related rodents that have recently diversified across North America and evolved a range of heritable behaviors. Deer mice are attractive systems to understand natural variation in infant vocal behaviors because interfertile species exhibit infant cries that differ in their spectral and temporal features, opening the possibility to map the genetic basis of natural variation in these features. Using approaches from neuroscience, genetics, and ethology, my work aims to make explicit mechanistic links between genes, neurons and a conserved mammalian behavior essential for early life health in rodents and humans alike.

Alisa K Kabcenell Jane Coffin Childs Fellow

Department of Cell Biology, Yale University

Read more

Role of a Ras-like protein in yeast secretion

Harris Kaplan HHMI Fellow

Department of Molecular and Cellular Biology

Read more

Functional development of social behavior circuits

Mammalian social behaviors change dramatically over the lifespan: infants rely on their mothers for food and warmth, adolescents engage each other in social play, and adults mate and parent. This highly conserved social niche trajectory consists of dynamic motivational drives and behavioral repertoires and co-occurs alongside rapid changes in brain organization. However, it remains unclear how developmental changes in behavior result from transformations of the underlying brain circuits.
As a postdoctoral fellow in Catherine Dulac’s lab, I am dissecting these developmental transitions in mammalian brain and behavior. Focusing on the mouse hypothalamus, I am charting the coordinated emergence of transcriptional cell-type identities, spontaneous and stimulus-evoked neuronal activity patterns, and corresponding changes in behavior. Further, I am exploring the robustness and plasticity of these trajectories by manipulating the animal’s sensory and social rearing environment. This work will provide novel insights into the developmental processes that build animal behavior.

Lawrence M Kauvar Jane Coffin Child Fellow

Read more

Justus Kebschull

Department of Biology, Stanford University

Read more

Investigating cell type and brain circuit evolution in the cerebellum

Brain circuits and the neuronal cell types that form them are not static over evolutionary time. Rather, they cause and reflect the changing repertoire of animal behavior. How circuits and cell types change from their ancestral state to support novel behaviors during evolution, therefore, gives us important clues as to their current function. In my project, I will investigate the interaction between the cerebellum and the rest of the brain from this evolutionary angle by studying the progressive expansion and elaboration of the deep cerebellar nuclei, the output pathway of the cerebellum. I will profile transcriptional and projectional cell types of the DCN across species to probe changes in the DCN over deep evolutionary time. I will then integrate this dataset with developmental trajectories of the identified cell types in mouse, to provide mechanistic insight into how brain regions specialize on the level of single cells and circuit wiring to support new functions over the course of evolution.

Mina Kojima

Department of Genetics, Yale University

Read more

Dissecting the molecular mechanisms that trigger zygotic genome activation

Naina Kurup

Department of Chemistry and Chemical Biology, Harvard University

Read more

Superresolution imaging of age related changes to the neuronal cytoskeleton

​With global increases in average lifespan, understanding the neurological changes associated with normal aging has become increasingly relevant. Changes in neuronal architecture and synapse function have been proposed to underlie age related cognitive decline in healthy individuals, although the precise mechanisms remain unclear. The neuronal cytoskeleton is essential to the formation of unique neuronal architectures. Advances in superresolution microscopy have enabled the identification of an evolutionarily conserved Membrane-associated Periodic Skeleton (MPS) that forms an integral part of the neuronal cytoskeleton. Mutations in components of the MPS cause neurodegenerative disorders, suggesting that the presence of this network is also important for the maintenance of neuronal function. My project will focus on dissecting the functional role of age related changes to the MPS, providing us with a better understanding of the progressive loss in cognitive ability widespread in the aging population.

Benjamin Larson Merck Fellow

Department of Biochamistry and Biophysics, University of California, SF

Read more

Principles of cellular behavior: gait coordination in unicellular walker

I am interested in understanding how cells control shape and movement to thrive in different environments. Although often regarded as simple building blocks, single cells frequently execute surprisingly complex, even animal-like behaviors, which are necessary for proper cellular function. In cells, these behaviors emerge from the joint action of myriad molecular components and interactions between the cell and its environment. How this occurs is poorly understood. To better understand and predict cell behavior, I am working to uncover general principles by studying the coordination of walking in a unicellular organism, the ciliate Euplotes.
How can a single cell, lacking a nervous system, coordinate a gait? While unusual in some ways, Euplotes locomotion is amenable to rigorous behavioral analysis, and many underlying cellular processes and molecular components are deeply conserved among eukaryotes. My work combines theory from computer science and non-equilibrium statistical physics with quantitative microscopy experiments to uncover the mechanisms by which Euplotes coordinates its gait and will develop new theoretical and experimental tools for interrogating the control of complex cellular behaviors.

Rosalie Lawrence HHMI Fellow

Department of Biochemistry and Biophysics, University of California, San Francisco

Read more

Dynamic control of the integrated stress response by elF2B

All cells and organisms mount stress response programs in response to external insults; some recover to baseline after stress, while others suffer from side-effects such as chronically altered proteomes that can reduce cellular and organismal fitness. I study the cellular machinery that executes the Integrative Stress Response (ISR), a highly conserved cellular program that rewires translation in the wake of stresses such as nutrient deprivation, viral infection, or redox imbalance. I seek to understand how the ISR machinery remains flexible enough to both respond to diverse stresses and return to baseline, and how dysregulation of the ISR leads to chronic inflammation and memory disorders in higher organisms. I am particularly excited to leverage recent advances in structural biology to go beyond a static understanding and toward uncovering dynamic conformational transitions in cellular ISR machinery that enable nuanced decision-making. To this end, I use hydrogen deuterium exchange, biochemical and cellular assays, and live imaging to study the key ISR actuator eIF2B both in vitro and in cells.

Chip Le Jane Coffin Childs

Department of Chemistry and Chemical Biology, Harvard University

Read more

Characertization of catechol dehydroxyglases in the gut microbiome

Catechol dehydroxylation is a highly relevant metabolism in the human gut microbiota with a significant impact on human health. A wide range of neurotransmitters, dietary compounds, and drug molecules have been identified as substrates for this uniquely microbial transformation. However, the ability to predict and manipulate such an important process has been hindered by the limited understanding of enzymes that facilitate the transformation. The Balskus group recently identified dopamine dehydroxylase (Dadh) as the enzyme responsible for the conversion of dopamine to m-tyramine in the gut microbiota. Phylogenetic analysis showed that Dadh and its homologs form a unique DMSO-reductase subfamily. These proteins have not been characterized, and the mechanism has not been deciphered. Moreover, a survey of the human gut microbiome revealed a large number of molybdopterin-dependent enzymes with unknown chemical capability. The main focus of my work is to investigate human gut catechol dehydroxylases via a substrate-guided approach. This work will be accomplished by (1) deciphering the structure and mechanism of dopamine dehydroxylase, (2) biochemically characterizing and comparing reactivity of catechol dehydroxylase homologs, and (3) exploring additional molecular scaffolds that could be susceptible to dehydroxylation by unknown molybdopterin dehydroxylases.

Jiefu Li HHMI Fellow

Institute for Immunity, Transplantation and Infection, Stanford University

Read more

Mapping Global and TCR-Vicinity proteomic states of T Lymphocyte Surface

T lymphocytes are central players of our adaptive immune system for fighting against pathogens as well as aberrant self cells. The recognition, action, and modulation of T cells rely on diverse molecules on their surface, including T cell antigen receptors (TCRs) and numerous signaling modulators, such as CTLA-4 and PD-1. Using systems approaches, I study cell-surface signaling of human T cells, with two focuses: 1) I combine TCR repertoire profiling, computational analysis, and scalable antigen screen to quantify TCR repertoire dynamics in infectious diseases and search for population-shared antigens to inspire vaccine development; 2) I build novel tools for spatiotemporally-resolved quantitative proteomics to determine how the T cell surface proteome evolves under distinct cellular states and look for molecular targets for invigorating or modulating T cell activities.

Jaechul Lim

Department of Immunobiology, Yale University

Read more

Deciphering the mechanism and significance of stress tolerance

Cells continually encounter a variety of suboptimal conditions which restrict growth and proliferation. In response to such stressors, proper adaptive mechanisms are typically activated, which can be categorized into two groups, specific and general. The stress-specific responses, such as DNA repair or unfolded protein response, directly deal with the primary cause. By contrast, a common response is assumed to inhibit growth and render cells highly tolerant to the stress as a dormant state of an organism. While most studies have focused on the stress-specific responses, little is understood about how cells initiate and maintain the common program of stress tolerance. By analyzing sequencing data on various stress conditions, I have found several genes that are commonly regulated in mammalian cells. I hypothesize those genes may modulate stress tolerance which may protect cells from stressors. To understand the role of those candidates, I will 1) determine their targets to unveil regulatory networks and 2) perform in vivo experiments with various stresses to confirm whether the candidates function in the physiological context. By understanding the core stress response, this research will address an important but often overlooked as standing of cell survival and maintenance.

Zachery Lonergan Jane Coffin Childs

Department of Biology & Biological Engineering, California Institute of Technology

Read more

Bacterial nitric oxide metabolism at the host-pathogen interface

Energy conservation is an organizing principle for microbial communities. This conservation becomes challenging for bacterial pathogens that must overcome the host immune response. Nonetheless, bacterial infections are major sources of morbidity and mortality, demonstrating that mechanisms exist for pathogens to persist within hosts. Within the lungs of immunocompromised individuals, immune cells are recruited to eliminate pathogens, but this recruitment is unable to clear the infection. Extreme oxygen gradients exist within the lung environment that require metabolic flexibility for bacterial pathogens to survive. While the unique metabolic sources and requirements for microbes within the lungs is not well-defined, we predict that nitrogen oxides serve an important role in supporting bacterial lung persistence. To test this hypothesis, we are implementing geochemical-based strategies to track bacterial nitrogen oxide metabolism, which will provide new conceptual and technical handles on pathogen activities within the human host.

Elija Mena HHMI Fellow

Department of Genetics, Brigham & Women's Hospital

Read more

Defining nuclear-specific degradation pathways

Ubiquitylation is a post-translational modification that regulates the stability of thousands of proteins in our cells. The specificity for ubiquitylation is typically conferred by E3 ubiquitin ligases that attach ubiquitin onto substrate proteins. Despite the critical role that ubiquitylation plays in regulating the abundance and activity of many proteins, most ubiquitylation pathways are still poorly understood and many of the estimated ~600 E3 ubiquitin ligases have no known protein substrates.

Our lab has developed the Global Protein Stability (GPS) assay, which is a way to rapidly monitor protein stability using fluorescent proteins. We have recently been adapting this approach for library-on-library genetic screens in order to map, in parallel, dozens of ubiquitylation substrates to their cognate E3 ubiquitin ligases. We have also been using GPS screens to find degradation pathways specific to particular intracellular compartments. Together, these approaches will shed light on ubiquitylation pathways that are important for human health.

Jeffrey Morgan HHMI Fellow

Department of Biochemistry, University of Utah

Read more

The eukaryotic RNA-metabolite interactome and its role in gene regulation

The ability of cells and organisms to sense and respond to change is fundamentally driven by dynamic interactions between many different types of molecules. Although we understand some of these interactions, there are many to be uncovered.

I am investigating the landscape of RNA-metabolite interactions and their role in gene regulation. Although RNAs and small molecules can form specific and high-affinity interactions, we know effectively nothing of the RNA-metabolite interactome that might be present in eukaryotic cells. Using RNA-structure probing technologies coupled with high-throughput sequencing, I am studying a broad pool of human RNAs in various metabolic contexts, which will uncover the scope of interactions between human RNAs and human metabolites, identify the specific RNA-metabolite interactions that do occur, and allow us to test the role of these interactions in gene regulation. In complement to this approach, we have developed a screening platform to simultaneously measure the affinity between specific RNAs and 450+ human metabolites. This platform has allowed for rapid, targeted screening of viral RNAs that might sense host metabolism via RNA-metabolite interactions and can be applied to any RNA of interest.

 

Youcef Ouadah

Department of Biology & Biological Engineering

Read more

A genetic approach to the logic and evolution of aggression circuitry

Samuel Pontes

Biological Sciences, Columbia University

Read more

Behavioral function of pattern completion in the cortex

Stephanie Ragland

Department of Pedicatrics, Boston Children's Hospital, Harvard Medical School

Read more

Mechanisms of transport for bacterial molecules across phagosomal membranes

A cornerstone concept of mammalian innate immunity is that our cells can detect bacteria and subsequently produce appropriate antibacterial responses. Bacterial detection is achieved through the action of protein receptors, called pattern recognition receptors (PRRs), that sense conserved bacterial molecules, termed pathogen-associated molecular patterns (PAMPs). Since the cellular localization of PRRs varies (e.g., cell surface, phagosomal lumen, cytosol), PRR and PAMP co-compartmentalization is required for bacterial detection. It therefore stands to reason that only bacteria that escape phagosomal confinement should have the capacity to stimulate cytosol-localized PRRs. In contrast, bacteria that cannot damage phagosomes will be confined (along with their PAMPs) to the phagosomal lumen, where they are only sensed by phagosome-localized PRRs. Despite this rationale, bacteria that are unable to escape from the phagosome (which is true for most bacteria studied to date) are somehow detected by cytosolic PRRs. I am studying how cytosolic PRRs gain access to phagosomal PAMPs, how phagosomal dynamics influence detection, how bacteria manipulate host-derived processes, and the consequences of bacterial detection on innate control of infection.

Taehyun Ryu Jane Coffin Childs

Department of Genetics, Harvard Medical School

Read more

Novel roles of ultraconserved elements in genome integrity

Ultraconserved elements (UCEs) are a set of DNA sequences that exhibit perfect conservation across the genomes. I learned of UCEs and their putative role in maintaining genome integrity at a seminar by Dr. Chao-ting Wu. Scattered across genomes, unique, and 200bps or greater in length, UCEs have remained unchanged for over 300 million years. Yet, their extreme sequence conservation is still a mystery. Although my Ph.D. training is in the DNA repair field, I decided to join Dr. Chao-ting’s lab as a postdoctoral researcher and explore the biology of UCEs. Previous studies have demonstrated that UCEs can contain transcription factor binding motifs an function as enhancers to regulate tissue-specific transcription. However, no regulatory or proteincoding functions can explain such extreme sequence conservation. My research will focus on testing a model that can explicitly address such an explanation. I hypothesize that homologous UCEs compare their sequences via pairing and any detected discrepancies in sequence or copy number will lead to cell death and/or disease onset. As a result, genome integrity would be maintained by culling out cells carrying deleterious rearrangements. I will assay this model with different approaches – a) computational analyses, b) CRISPR-based genome editing, and c) imaging techniques. Ultimately, the potential of UCEs to sense and cull deleterious rearrangements genome-wide offers a unique yet intriguing and still largely unexplored potential general strategy for treating diseases derived from rearrangements, regardless of the etiology of diseases.

Gavin Schlissel Jane Coffin Childs

Department of Biology, Whitehead Institute for Biomedical Research

Read more

Understanding extracellular modifiers of morphogen signaling

Animals rely on effective coordination of cell behavior in all phases of their development and lifespan. Cells communicate to coordinate their activity using several physical or chemical communication strategies, which are often interdependent. One communication strategy central in development and in adult animals relies on secreted signaling proteins that bind membrane-tethered receptors in diverse target tissues to affect cell identity or behavior. Whereas we understand in great detail how signals are synthesized, secreted, received and processed, we understand comparatively very little about how signals travel from their origin to their destination. I use molecular genetic and synthetic biology tools in cultured mammalian cells to reconstitute cell signaling events, and I use these reconstituted signaling pathways to understand how secreted protein signals navigate the extracellular environment in developing or adult tissues.

Madeline Sherlock Jane Coffin Childs Fellow

Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus,

Read more

Structural Basis for Noncanonical Translation Initiation in Viruses

My postdoctoral research is focused on structured viral RNAs involved in enhancing translation of viral proteins. Some of the RNAs I’m studying are able to induce a reinitiation event within the viral RNA genome through specific interactions with the ribosome. My research focuses on the determining the molecular interactions that enable this RNA structure to promote translation activity at downstream open reading frames following a translation termination event. Another set of RNAs I’m studying are found primarily in plant viruses and mimic cellular tRNAs. Previous and ongoing studies in the Kieft lab aim to determine how different examples of these tRNA-like structures fold, the structural and functional differences between different classes and subtypes, and how these RNAs enhance viral translation.

Frederick Varn Merck & Co. Fellow

Department of Genomic Medicine, The Jackson Laboratory

Read more

Glioma evolution in the presence of local immune activity

Diffuse glioma is the most common primary brain tumor in adults and is characterized by a poor prognosis and near universal recurrence following therapy. Given the poor response rate to the current standard-of-care, there is an active interest in applying immunotherapy to treat this disease. However, progress on this front has been limited, due in part to limited knowledge of how the immune system interacts with glioma to influence the tumor’s evolution. My work focuses on how cells of the immune system and accompanying microenvironment interact with malignant cells to influence the developmental trajectory of diffuse glioma. By integrating multi-omic bulk and single-cell datasets from pre- and post-treatment tumors, I aim to develop a better understanding of how gliomas evade the immune response and how the standard-of-care alters these processes. Results from this work can provide insights into how to shape disease progression and enable the sensitization of the gliomas to subsequent treatment approaches.

Caleb Weinreb Jane Coffin Childs

Department of Neurobiology, Harvard Medical School

Read more

Unified model of social processing in prefrontal cortex

I study the deep statistical structure of behavior to learn how it is shaped by ongoing brain activity. The purpose of the central nervous system is to coordinate an animal’s actions in space and time. The power of mammalian brains is evident in the variety and expressiveness of their behavior, yet it is precisely these qualities that make the behavior difficult to annotate and record – steps that are prerequisite for modern data analysis. As a consequence, neuroscience has mostly been limited to a narrow set of behaviors and well-defined tasks. This limitation is especially severe for the study of social behavior, in which the spontaneous actions and reactions of two interacting animals created an added level of complexity.

Recently, the advent of new tools in machine learning have made it possible to quantify behavior with much greater precision and richness. My research focuses on creating new tools for behavior measurement and applying them to rodent social behavior, with the specific goal of understanding how social interaction is shaped by the prefrontal cortex.

Gregory Wyant HHMI Fellow

Department of Medical Oncology, Dana-Farber Cancer Institute

Read more

Unbiased analysis of the mitochondrial permeability transition pore

Heart failure is a common and lethal condition, yet the mechanisms by which the heart fails remains a mystery. Over the past decade, heart failure etiology has shifted from valvular heart disease and hypertension to coronary artery disease. As a result, ischemic cardiomyopathy-symptomatic left ventricular (LV) dysfunction in the setting of coronary artery disease- now accounts for nearly 70% of all heart failure causes in the United States. The exact basis of ischemic cardiomyopathy is unknown; however, identifying molecular changes in the ischemic myocardium and the generation of animal models by which these processes can be studied are an absolute necessity.

Hypoxia-inducible factor (HIF), which consists of a labile  subunit and stable  subunit, is master transcription factor that accumulates during hypoxia and activates genes whose products promote cellular survival under ischemic conditions. The HIFsubunit is regulated through prolyl hydroxylation by -ketoglutarate (KG) dependent dioxygenases known as EGLNs (also called PHDs). Acute PHD inactivation in the heart has been shown to be protective during acute cardiac ischemia in rodents, and several PHD inhibitory drugs are now in development as tissue protectant molecules. Conversely, chronic PHD inactivation or HIF stabilization itself, both predictable consequences of chronic ischemia, is sufficient to induce the hallmarks of ischemic cardiomyopathy. My work in William Kaelin’s lab has identified a new mechanism contributing to the pathogenesis of HIF-driven ischemic cardiomyopathy.

Katherine Xue Jane Coffin Childs

Department of Biology - Medicine, Stanford University

Read more

Adaptation and dispersal in the evolution of microbial communities

The trillions of microbes that live in and on the human body play key roles in health and disease. However, little is known about how microbes evolve in complex communities, even though this evolution can have important consequences for human health. I will study how adaptation and dispersal drive the evolution of antibiotic resistance in microbial communities, both in the human gut microbiome (in vivo) and in experimental, gut-derived microbial communities (ex vivo). First, I will track evolution in the human gut microbiome in a cohort of healthy individuals treated with ciprofloxacin. Using strain-resolved metagenomic sequencing, I will identify selective sweeps and strain replacements to determine how natural microbial communities evolve in response to a disturbance. Next, I will examine how adaptation and dispersal shape the evolution of gut-derived microbial metacommunities. These experimental metacommunities allow me to test how dispersal shapes the rates and mechanisms of adaptation in more controlled, laboratory contexts. Finally, I will study adaptation and transmission in the human gut microbiome by tracking strain transmission in cohabiting individuals before and after antibiotic treatment. This work will combine new computational and experimental approaches to shed light on how microbial communities evolve in the context of human health.

Nathan Yoder Merck Fellow

Department of Physiology, University of California, SF

Read more

Elucidating thermal gating mechanisms of an ion channel involved in pain

The ability to sense and respond to our external environment is a trait fundamental to the survival of all organisms. One such sense modality, the detection of noxious heat, is accomplished by way of transient receptor potential V1 (TRPV1) ion channels, integral membrane proteins that are also activated by capsaicin and other pungent vanilloid compounds from chili peppers. TRPV1 channels are expressed by afferent neurons of the sensory ganglia and, when exposed to noxious heat, undergo a conformational rearrangement that opens a non-selective pathway for cations across the cell membrane, triggering downstream signaling pathways. By employing a combination of cryo-electron microscopy and electrophysiological techniques, the long-term goal of my research is to define the molecular mechanisms that govern heat detection by TRPV1 and other related ion channels.

Bingjie Zhang Jane Coffin Childs

New York Genome Center

Read more

Functional interactions bewtween the neuronal and immune cells