Current Fellows

Mohammad Abedi HHMI Fellow

Department of Biochemistry, University of Washington

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Lauren Aguado Jane Coffin Child Fellow

Laboratory of Virology and Infectious Disease, The Rockefeller University

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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.

Juan Barajas Jane Coffin Childs

Department of Pathology, St Jude Children's Hospital

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Karl Barber Jane Coffin Childs

Department of Genetics, Brigham and Women's Hospital

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Emily Bayer Jane Coffin Childs

Department of Biozentrum, University of Basel

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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

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Tessa Bertozzi HHMI Fellow

Weissman Lab, Whitehead Institute of Biomedical Research

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Chemical modifications to DNA and histones are implicated in the establishment of heritable cell type-specific transcriptional networks. The emergence of molecular epigenetic editors creates new opportunities to mechanistically probe these relationships and understand the functional repercussions of epigenetic dysregulation in cancer and aging. The CRISPRoff editor was developed in a collaboration between the Weissman and Gilbert labs as a single fusion protein containing the catalytically inactive dCas9, a repressive KRAB domain, and DNA methyltransferase domains. Transient expression of RNA-guided CRISPRoff achieves robust and heritable gene silencing in human cells, likely as a product of the synergistic spatiotemporal relationship between the coupled domains. Using a CRISPR-based screening approach, I plan to uncover and mechanistically characterize additional cooperative protein interactions which facilitate the establishment and maintenance of long-term transcriptional memory.

John Blair Jane Coffin Childs Fund

New York Genome Center, New York Univrsity

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Protein phosphorylation is a fundamental, dynamic process that can have drastic effects on cellular physiology. Mutations in kinases, the enzymes that phosphorylate other proteins, are often implicated in neurological disease. Understanding the context and consequences of protein phosphorylation in different cell types throughout neurodevelopment is imperative to developing new treatments as well as our basic understanding of cell biology. Recent technological developments permit the simultaneous quantification of protein levels, chromatin accessibility and gene expression from single cells (DOGMA-Seq). I am extending this technology to quantify both phosphorylated proteins and total proteins as well as chromatin accessibility and gene expression. I am applying this assay at discrete timepoints throughout in vitro neurodevelopment to reveal previously uncharacterized cell-type specific signaling patterns affecting gene expression and ultimately, cell fate decisions.

Julianna Bozler Jane Coffin Childs

Department of Cell and Developmental Biology, University of Pennsylvania

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Joshua Brickner Jane Coffin Childs

Department of Chemical and Systems Biology, Stanford University

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Paula Bucko Jane Coffin Childs Fund

Department of Systems Biology, Harvard Medical School

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In response to DNA damage, the tumor suppressor protein p53 induces expression of stress-responsive genes to inhibit proliferation of cells with damaged DNA. Changes in p53 protein levels over time (p53 dynamics) impact cellular outcomes: p53 oscillations facilitate repair of DNA-damaged cells, whereas sustained levels of p53 promote senescence and cell death. While it is now established that p53 dynamics contribute to these competing cell-autonomous processes, how p53 dynamics regulate genes involved in non-cell-autonomous events, such as those involved in immune signaling, is not known. I propose to develop new tools and approaches to study the role of p53 in regulating immune gene expression in cancer cells and in mediating the killing of cancer cells by immune cells. This research will provide fundamental insights into the mechanisms that govern of cancer cell-immune cell interactions and pave the way for developing effective combination therapies to treat cancer

Cori Cahoon Jane Coffin Childs

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

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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.

Vikram Chandra Jane Coffin Childs Fund Fellow

Department of Organismic and Evolutionary Biology, Harvard University

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How animal brains evolved the capacity for sophisticated computation is not well understood. One major facet of this problem is the evolution of chemosensation. Chemosensation is the primary sense of most animals, and involves complex neural computations. We do not know how this sense evolved, or how most animals – which are aquatic invertebrates – perform chemosensation. I am studying chemosensation in an acoel worm, an aquatic invertebrate that by virtue of its phylogenetic position as the likely outgroup to all other animals with central nervous systems, retains some primitive features of early central nervous systems. Acoels nonetheless perform sophisticated behavior that requires complex chemosensory processing, but how their brains and chemosensors work is unknown. Using a combination of automated behavioral tracking, transgenics, and neural activity imaging, I aim to understand the logic of chemosensory processing in a tractable acoel worm. Through comparisons with known chemosensory mechanisms of other animals, this will shed light on how complex chemosensory systems evolved. This project will also establish experimental approaches for the future study of neural computations and behavior in acoel worms and other aquatic invertebrates.

Jingxun Chen Jane Coffin Childs

Department of Gennetics, Stanford University

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Reproductive aging is a global challenge. Older men and women face fertility loss and a higher chance of having children with genetic disorders. Currently, we lack a detailed molecular understanding of what causes reproductive aging in vertebrates. I am developing an emerging short-lived model system, the African killifish, to study vertebrate reproductive aging. The lifespan of this organism is 4 times shorter than mice and 7 times shorter than zebrafish. I will combine my graduate training (gamete biology) with the expertise of the Brunet Lab (killifish and aging) to probe the molecular basis of age-dependent fertility decline in the killifish and identify potential targets for therapeutic intervention. These studies will shed light on methods to protect or rejuvenate the germline from aging, which can have a profound impact on human fertility.

James Chen Jane Coffin Childs Fund Fellow

Department of Cell Biology, New York University, Grossman School of Medicine

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Antibiotic treatment of Mycobacterium tuberculosis (Mtb) is hindered by the inability of small molecules to cross the complex mycobacterial outer membrane (MOM). To understand the architecture of the MOM, I am using a combination of biophysical and microbiological approaches to study the MCE (Mammalian Cell Entry) proteins, which are critical virulence factors located on the Mtb cell envelope. These proteins are thought to transport hydrophobic molecules by assembling into large, multiplex structures that span the cell envelope and may have implications in MOM biogenesis and nutrient acquisition. However, the molecular bases for these functions are not known and the MCE proteins could play additional roles in the cell that have yet to be characterized. This work will provide mechanistic insights into these essential virulence factors that will be critical to understanding pathogenesis and to developing new antibiotics to counter emerging multi-drug resistant strains of Mtb.

David Colognori Jane Coffin Childs

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

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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.

Alicia Darnell Merck & Co., Fellow

Koch Institute, Massachusetts Institute of Technology

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Kristen DeMeester Jane Coffin Childs

Department of Chemistry, Scripps Research Center

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Seth Donoughe Jane Coffin Childs

Department of Molecular Genetics and Cell Biology, University of Chicago

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Priscilla Erickson Jane Coffin Childs

Department of Biology, University of Virginia

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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 Jane Coffin Childs

Department of Biology, Brandeis University

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Abraham (Avi) Flamholz, Jr Jane Coffin Childs Fellow

Department of Biology and Biological Engineering, California Institute of Technology

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While cells are often studied in suspension or monolayers, more structured forms like tissues and biofilms dominate natural environments. In such settings, the concentrations of critical nutrients like sugars and O2 vary in space and time because cells produce and consume them locally, leading to measurable differences in physiology and gene expression between nearby cells. Spatially structured environments therefore represent many-body systems interacting on multiple timescales through a rich collection of chemical and physical processes. My overriding goal is to determine whether metabolism in mixed biofilms can be predicted quantitatively from simple models with intelligible and measurable parameters. I am currently developing Pseudomonas aeruginosa, a model bacterium that grows in suspension and as a biofilm, as a model for studying metabolic heterogeneity in spatially structured environments. It is commonly assumed that variation in the local O2 concentration is a primary determinant of metabolic heterogeneity in biofilms. As such, I am developing optical approaches to measure local O2 concentrations in real time to test whether a mathematical model can explain O2 dynamics, cell growth, and metabolic rates in biofilms.

Anthony Flamier Jane Coffin Childs

Whitehead Institute for Biomedical Research

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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.

Nadezda Fursova Jane Coffin Childs Fund Fellow

Center for Cancer Research, National Cancer Institute/NIH

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Enhancers are distal cis-regulatory elements that control precise execution of transcriptional programs during development and in response to external stimuli. How enhancers find and activate their target genes, and what molecular activities are required for enhancer function remains a central outstanding question in the field. Recent advances in nascent RNA-sequencing uncovered widespread transcription from enhancers, which has become widely recognized as a robust signature of enhancer activity. However, mechanistic understanding of enhancer transcription, its regulation and, most importantly, functional role in gene activation is currently missing.
In my work, I aim to address these fundamental questions by using single-molecule and live-cell imaging approaches to characterize the intrinsic dynamics of enhancer transcription in single cells. To generalize my conclusions from individual enhancers to a genome scale, my ultimate goal is to develop high-throughput single-molecule approaches for systematic characterization of enhancer transcription. Using these new tools, I will investigate how transcription at enhancers and their target gene promoters is coordinated at the single-cell level to discover if these processes are functionally linked. Together, this work will be an essential step towards a deeper mechanistic understanding of enhancer function in gene activation and how enhancer perturbations can lead to severe developmental disorders and cancer.

Ninghai Gan HHMI Fellow

Department of Physiology, UT Southwestern

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XinXin Ge Jane Coffin Childs Fund Fellow

Department of Phsiology, University of California, San Francisco

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George Ghanim Jane Coffin Childs Fellow

Laboratory of Molecular Biology, MRC

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Christina Gladkova HHMI Fellow

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

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Nicola Guzzi HHMI Fellow

Laboratory of Mammalian Cell Biology and Development, The Rockefeller University

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Tumor initiating cells (TIC) have a remarkable ability to evade the immune system, hindering the effect of immunotherapies and fostering tumor relapse. Hence, it is critical to understand the intrinsic mechanisms underlying TIC capacity to escape immune recognition.
My research focuses on squamous cell carcinoma (SCC), an aggressive cancer harboring TIC uniquely equipped to escape immunotherapy. Notably, SCC-TIC maintain low protein synthesis and dysregulated metabolism, implicating translational control as a key player in therapy resistance. However, how aberrant translation contributes to tumor progression and immune-evasion remains poorly understood.
Using unique mouse models, and a combination of ribosomal tagging and ribosome profiling I aim to delineate the translational dynamics promoting TIC ability to evade the immune system. If successful, my unbiased approach will delineate new mechanisms driving altered translational control and promoting immune evasion and tumor relapse

Annie Handler HHMI Fellow

Department of Neurobiology, Harvard Medical School

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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

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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

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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 Jane Coffin Childs

Department of Cell Biology, Harvard Medical School

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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.

Sarah Innes-Gold Merck and Company Fellow

Department of Chemistry and Chemical Biology, Harvard University

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Cancer metastasis and immune cell migration require motile movement, meaning the cell membrane must slip relative to the cytoskeleton. Thus, membrane-cytoskeleton attachments in motile cells likely rearrange, allowing tension to propagate across the membrane. In the current literature, there are ~106-fold discrepancies in reported timescales of membrane tension propagation. I hypothesize these discrepancies reflect variability between cell types, arising from differences in membrane microstructure. I specifically hypothesize that in motile cells, transmembrane proteins are arranged to allow membrane flow, enabling rapid tension equilibration, while non-motile cell membranes are structured to impede tension propagation.

I will directly measure tension propagation timescales in motile and non-motile cells and simultaneously characterize the arrangement of cytoskeleton-anchored transmembrane proteins. I will use optical tweezers to stretch membrane tethers, perturbing and measuring tension. I will visualize immobile transmembrane proteins with targeted photochemical labeling and high-resolution fluorescence imaging, revealing how transmembrane protein arrangement regulates membrane fluidity, and how cancer cells might exploit this to metastasize

Aakanksha Jain Jane Coffin Childs Fellow

Department of Neurobiology, Boston Childrens Hosptial

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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 Jane Coffin Childs

Department of Molecular and Cellular Biology, Harvard University

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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.

Harris Kaplan HHMI Fellow

Department of Molecular and Cellular Biology, Harvard University

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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.

Justus Kebschull Jane Coffin Childs

Department of Biology, Stanford University

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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 Jane Coffin Childs

Department of Genetics, Yale University

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Anna Kotrys HHMI Fellow

Department of Molecular Biology, Massachusetts General Hospital

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Description: Mitochondria are present in nearly all human cells where they play key roles in energy metabolism, biosynthesis, signaling, and cell death. Mitochondrial homeostasis depends on the proper maintenance and expression of the mitochondrial genome (mtDNA). Germline mtDNA mutations can lead to severe, maternally inherited disorders with limited treatment possibilities. Moreover, somatic mtDNA mutations accumulate in neurodegeneration, cancer and aging. mtDNA is a high copy number genome and a mixture of wild-type and mutant mtDNA molecules can co-exist within one cell resulting in “heteroplasmy”. Heteroplasmy dynamics are governed by a complex mix of random drift and selection, but the underlying molecular mechanisms remain unknown. The aim of my post-doctoral research is to uncover the molecular mechanisms that govern mtDNA heteroplasmy. Mechanistic studies of heteroplasmy dynamics will shed the light on the mitochondrial contribution to human health and disease and possibly inspire novel therapeutic approaches to mtDNA disease.

Benjamin Larson Merck Fellow

Department of Biochamistry and Biophysics, University of California, SF

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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

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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

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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.

Hannah Ledvina Jane Coffin Childs Fund Fellow

Department of Biochemistry, University of Colorado, Boulder

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Jiefu Li HHMI Fellow

Institute for Immunity, Transplantation and Infection, Stanford University

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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.

Chi-Yun Lin Jane Coffin Childs Fellow

Department of Chemistry, Pennsylvania State University

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Protein-based radicals participate in biological processes and natural product biosynthesis that link to life and death in organisms. One remarkable example is class I ribonucleotide reductases (RNRs), which catalyze DNA synthesis with tyrosyl radical relays. To compete for available resources, particularly in pathogens that live in the context of a host, RNRs have evolved distinct cofactors, assembly strategies, and radical translocation mechanisms. Understanding these distinctions from human counterparts is a key step in developing successful anticancer, antimicrobial, and antiviral drugs that inhibit RNRs. However, tyrosines are abundant and form highly cooperative networks, presenting difficulties in isolating their contribution to vectorial redox. I aim to dissect these tyrosines in the newly discovered class I RNRs to probe the free energy landscape of their one-electron oxidation and determine the active state structures. To further advance the field of redox enzyme design for difficult chemical reactions, I will elucidate the crucial protein environmental factors that modulate productive tyrosyl radical relays and prevent detrimental side reactions.

John Lin-King Merck and Company Fellow

Depatment of Biology, Stanford University

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Zachery Lonergan Jane Coffin Childs

Department of Biology & Biological Engineering, California Institute of Technology

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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.

Venkata S Mandala HHMI Fellow

Laboratory o Molecular Neurobiology and Biophysics, The Rockefeller Universtiy

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Many transmembrane proteins reside in functionally important clusters on cell membranes. Fluorescence microscopy of membrane proteins in cells has revealed ‘hot spots’ of co-localized proteins such as a2A-adreneregic G-protein coupled receptors and G proteins participating in signaling complexes. Yet the functional significance of these signaling clusters in cells is not well established. Developing tools to induce controlled clustering of membrane proteins in the lab would thus provide valuable insight into the function of these signaling complexes in cells.


My project proposes three complementary strategies to induce controlled protein clustering in lipid bilayers. The approaches span raft-forming lipid mixtures, tetraspanin and MARVEL domain 4-TM proteins, and membrane-anchored scaffolding proteins with multiple PDZ domains. These tools will be applied to a signaling pathway comprised of G protein-gated K+ channels (GIRK) and their activator, the βγ complex of G proteins (Gβγ). The extent of protein clustering and the subsequent effect on activity will be assessed using fluorescence microscopy and electrophysiology

Elija Mena HHMI Fellow

Department of Genetics, Brigham & Women's Hospital

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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.

Carlos Mendez-Dorantez Jane Coffin Childs Fellow

Department of Oncologic Pathology, Dana Farber Cancer Institute

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Long interspersed element-1 (LINE-1) is the only active, protein-coding transposon in humans. LINE-1 overexpression and LINE-1 retrotransposition are hallmarks of human cancers, although the impact of LINE-1 activity on cancer genomes and cancer cell growth remains poorly understood. My research focuses on addressing the hypothesis that LINE-1 retrotransposition causes substantial gross genome instability in cancers. Supporting this hypothesis, a recent pan-cancer analysis demonstrated associations between somatically-acquired LINE-1 insertions and segmental copy-number changes. Moreover, our lab recently identified that the Fanconi anemia/ BRCA pathway is required for growth of LINE-1(+) cells, suggesting that this DNA repair pathway might limit genotoxic effects of LINE-1. I am developing several approaches to assess the impact of LINE-1 on genome integrity, and I am evaluating the contribution of the FA/ BRCA pathway to LINE-1-associated DNA damage. These studies will be the first to evaluate the scope of LINE-1-mediated genome instability and should inform efforts to exploit LINE-1 genotoxicity as a cancer therapeutic strategy.

Jeffrey Morgan HHMI Fellow

Department of Biochemistry, University of Utah

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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

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Samuel Pontes

Biological Sciences, Columbia University

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Stephanie Ragland

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

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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.

Eric D Roche Jane Coffin Childs Funds

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

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Taehyun Ryu Jane Coffin Childs

Department of Genetics, Harvard Medical School

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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

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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.

Sally S Seaver Jane Coffin Childs Fellow

Institut de Chimie Biologique, France

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Changwoo Seo Jane Coffin Childs Fund Fellow

Department of Molecular and Cellular Biology, Harvard University

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Madeline Sherlock Jane Coffin Childs Fellow

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

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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.

Justin Silpe Jane Coffin Childs Fund Fellow

Department of Molecular Biology, Princeton University

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Marla Tharp HHMI Fellow

Page Laboratory, Whitehead Institute of Biomedical Research

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Cancer affects men and women differently. For example, glioblastoma, the most aggressive form of brain cancer, has a male-biased incidence rate and poorer response to standard treatments in men versus women. My research investigates the genetic and molecular basis of sex differences in glioblastoma from the perspective of microglia, the resident immune cells of the brain. Microglia are a major player in the brain tumor microenvironment and promote tumor growth and metastasis. Using XX and XY human microglia isolated from healthy brain regions and brain tumors, I am identifying sex-biased genes and biological pathways that are responsible for establishing sexually dimorphic brain tumor microenvironments. Further, I am testing how possessing an XX or XY sex chromosome complement drives the observed genome-wide sex-biased gene expression patterns in microglia, in particular, through X-linked genes that aberrantly escape X chromosome inactivation or homologous X-Y gene pairs with imbalanced expression or function. I anticipate that my research will lay the groundwork for more effective and sex-specific treatments for glioblastoma.

Frederick Varn Merck & Co. Fellow

Department of Genomic Medicine, The Jackson Laboratory

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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.

Jenelle Wallace Jane Coffin Childs Fund Fellows

Department of Neurobiology, University of California, San Francisco

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Over the last six million years, the human brain has evolved in remarkable ways. The story of human brain evolution is written in our genome, but determining which genetic changes are responsible for cognitive differences between humans and other primates is challenging. Differences in gene expression are likely controlled by regions of the genome that were once considered “junk DNA” but are in fact crucial regulators. Utilizing stem cell-derived neurons from humans and other primates, I will investigate how alterations in the genetic sequences of these regulatory elements have driven human brain evolution.

Caleb Weinreb Jane Coffin Childs

Department of Neurobiology, Harvard Medical School

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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

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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

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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

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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

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