Directory

Margaret (Meghan) McDaniel, Ph.D. Jane Coffin Childs Fellow

University of Washington

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The innate immune system is paramount in recognizing foreign or mutated material and initiating proper immune responses to combat them. Recognition of allergens and parasitic worms (helminths) elicit a socalled “type 2” immune response focused on expulsion of stimuli and tissue repair. Type 2 immune responses impact the prognosis of many cancers and the success of immunotherapies, but how these responses are established remains poorly understood. Group 2 innate lymphoid cells (ILC2s) initiate and propagate type 2 immune responses, but do not sense immune agonists directly. The origin and regulation of host-derived signals leading to ILC2 activation is therefore an area of immense interest. Recent work identified a specialized population of epithelial tuft cells responsible for sensing helminths and activating ILC2s by secreting interleukin(IL)-25 and cysteinyl leukotrienes in the small intestine. Airway ILC2s are similarly important for type 2 immune responses in the lung, but tuft cells are dispensable in this context. My proposal seeks to identify the signals that activate intestinal tuft cells and a novel cell subset responsible for airway ILC2 activation. Examining the initiation of type 2 immunity in multiple organs will uncover both convergent and divergent mechanisms by which type 2 responses can be further manipulated.

Carlos Mendez-Dorantez, Ph.D. Jane Coffin Childs Fellow

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.

Phi Nguyen, Ph.D. Jane Coffin Childs Fellow

Columbia University /
New York State Psychiatric

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Major depressive disorder (MDD) is a psychiatric disorder with a lifetime prevalence of ~15% and is the leading cause of disability worldwide1. The societal burden of MDD is immense, causing profound personal suffering and economic loss, which has recently been intensified by the Covid-19 pandemic2. The most effective treatments for MDD, a class of antidepressants called the selective serotonin reuptake inhibitors (SSRIs), are successful in achieving remission, but only in ~40% of patients3. Despite being in use for over 50 years, it remains unknown how SSRIs modulate neural circuit function in patients that achieve remission and where these mechanisms are disrupted in those that do not. Thus, a fundamental question remains: What are cellular and molecular mechanisms that mediate antidepressant response and resistance? Defining the answers to this question could provide fundamental insights into the pathophysiology of MDD and uncover novel substrates for future precision medicine approaches.

 

Yitzhak Norman, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

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Speech is a defining characteristic of human cognition. It provides humans with the flexibility to convey an unlimited range of thoughts and feelings using a limited number of basic elements. Over the past decade, intracranial electrocorticography (ECOG) recordings in patients have provided invaluable insights into the neural mechanisms underlying speech perception and production. While significant progress has been made, basic questions still remain regarding the functional architecture of the neuronal circuits involved. Particularly, we do not know how the brain assembles phonemes into words, and words into meaningful goal-directed utterances. Such phonemic-to-semantic transformation relies on real-time interactions between the speech cortex and distributed memory networks that encode, store, and retrieve our lexical and semantic knowledge quickly and efficiently. The hippocampus, as a critical node in this declarative memory system, is believed to play a key role in coordinating such processes in real time.

My research seeks to elucidate the cortical-hippocampal interaction during speech perception and production, and more broadly, to unravel the interface between speech representations and long-term memory. To accomplish this, I combine ECOG recordings with 7T fMRI to measure neuronal activity simultaneously from the hippocampus and speech cortex during perception and production of speech.

 

Jose Orozco, M.D.,Ph.D. Jane Coffin Childs Fellow

Dana-Farber Cancer Institute

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Organisms adapt to scarce and bountiful nutrient environments by employing nutrient signaling pathways. Sugar is a rich source of energy and carbon for organisms, Dr. Jose Orozco will explore sugar-sensing pathways using biochemical and genetic approaches to discover sugar-regulated kinases and their roles in metabolic adaptation. Dr. Orozco will conduct his work in Dr. Lewis Cantley’s lab at Dana-Farber Cancer Institute. These studies may reveal a new therapeutic target to alleviate metabolic maladaptive responses to the chronic overconsumption of sugars and carbohydrates.

As a graduate student in Dr. David Sabatini’s lab at Massachusetts Institute of Technology, Orozco investigated the nutrient-regulated pathway that controls the target of rapamycin complex 1 (mTORC1) kinase. Specifically, Dr. Orozco discovered a new amino acid sensor that integrates S-adenosylmethionine levels, identified a metabolic product of glycolysis that communicates with mTORC1, and discovered new genes in the mTORC1 pathway. Dr. Orozco will continue pursuing his interests in the link between metabolism and signal transduction pathways in his investigations of MondoA.

Xingjie Pan, Ph.D. Jane Coffin Childs - HHMI Fellow

Harvard University

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During mammalian development, coordinated cell differentiation and migration convert a simple neural tube into a brain with more than a hundred anatomical regions and probably more than a thousand cell types. How do these cell types emerge? How do cells migrate to their destined locations? How do cells communicate with each other? These are some fundamental problems in brain development.

 

As a postdoctoral fellow in Xiaowei Zhuang’s lab at Harvard, I develop new methods to systematically study these problems in mouse brain development. I develop new computational methods to connect cells from MERFISH spatial transcriptomics measurements into trajectories and determine cell-cell communication pathways activated in each cell. The reconstructed trajectories will allow me to comprehensively map the differentiation, maturation, and migration of individual cells. I will identify which cell-cell communication pathways are functionally crucial for generating each cell type. Then I will develop high throughput imaging-based screen methods to validate the discoveries.

Mark Plitt, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley

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As we learn new behaviors, we still have to remember old behaviors as well. Thus there is a tension between the flexibility in learning and the stability of maintaining behaviors. Dr. Mark Plitt proposes that neural circuits resolve this tension by using neuromodulation to adaptively switch between stable and labile states. He will investigate these questions in Dr. Yvette Fisher’s lab at the University of California, Berkeley. There, Dr. Plitt will use a fly’s head direction circuit – a neuronal representation of the fly’s orientation in space – to investigate the tradeoffs between flexibility and stability. Dr. Plitt predicts that different neurotransmitters will reinforce learning and maintenance of memory. By developing this powerful model system, Dr. Plitt hopes to uncover physiological and computational principles that govern flexible learning.

As a graduate student in Dr. Lisa Giocomo’s lab at Stanford University, Plitt investigated hippocampal “place” cell remapping – a cellular process that encodes an animal’s memory-guided navigation. Specifically, Dr. Plitt demonstrated that hippocampal remapping patterns are predictably driven by an animal’s prior experience. This expertise in memory establishment will assist Dr. Plitt in investigating the tradeoff between stability and flexibility during adaptive learning.

Chinmay Purandare, Ph.D. Jane Coffin Childs - HHMI Fellow

University of California, San Francisco

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The hippocampus is a mental GPS that uses visual information to determine relative location. However, the neural pathways that convey visual information to the hippocampus are unknown. Dr. Chinmay Purandare will investigate this information transmission in Dr. Massimo Scanziani’s lab at the University of California, San Francisco. Dr. Purandare will use a novel set of visual cues, developed during his graduate studies, to directly activate hippocampal neurons and determine which visual brain regions are informing the hippocampus. Furthermore, Purandare would probe if the visual information conveyed is different depending on whether the subject is moving versus externally generated visual motion. Dr. Purandare’s research will further our understanding of circuit level connections between visual pathways and the hippocampus.

As a graduate student in Dr. Mayank Mehta’s lab at the University of California, Los Angeles, Purandare explored the minimal set of cues necessary for driving hippocampal responses. He developed novel visual stimuli and found that the hippocampus responds like sensory cortices when presented with these cues. This research led Dr. Purandare to the question of how these visual cues reach the hippocampus, which he will now explore in Dr. Scanziani’s lab.

Sahana Rao, Ph.D. Jane Coffin Childs - HHMI Fellow

Broad Institute

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Oxidative phosphorylation is a central metabolic pathway that occurs within mitochondria. Decline in oxidative phosphorylation capacity is observed during aging and in many diseases. Dr. Sahana Rao aims to investigate how a tumor suppressor gene also suppresses mitochondrial biogenesis. Dr. Rao will also use a genome-wide screen to identify novel regulators of mitochondrial biogenesis. Rao will conduct these studies in Dr. Vamsi Mootha’s lab at the Broad Institute. Collectively, these studies will provide insight into the regulation of mitochondrial biogenesis. They may also inform on mitochondrial dysregulation in aged or diseased states.

As a graduate student in Dr. Daniel Bachovchin’s lab at Memorial Sloan Kettering Cancer Center, Rao investigated inflammasomes – innate immune sensors that detect pathogenic signals and form large signaling complexes to alert immune cells. Dr. Rao’s studies elucidated molecular mechanisms of the activation of two inflammasome proteins, NLRP1 and CARD8, and established new tools to activate inflammasomes. With her extensive training as a chemical biologist, Rao will now study cellular metabolism and mitochondrial biogenesis in her postdoc.

Julia Rogers, Ph.D. Jane Coffin Childs Fellow

Columbia University

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Cells efficiently convert environmental information into specific functional responses through cascades of biochemical reactions and biomolecular interactions. High fidelity signal transduction requires spatiotemporal regulation of these molecular events. This can be accomplished through phase separation. Many signaling condensates dynamically assemble through multivalent protein–protein interactions mediated by modular interaction domains. How the molecular factors that drive phase separation enable coordinated and precise flow of information among myriad signaling pathways remains a mystery. To answer such questions that encompass molecular- and systems-level phenomena, my research focuses on developing integrative data- and physics-based modeling frameworks using the tools of machine learning and statistical mechanics. Using these approaches, I aim to decipher the modular grammar of signaling proteins that governs phase separation and, more broadly, the biophysical principles that underlie cell homeostasis.

Alexandra Schnell, Ph.D. Jane Coffin Childs - HHMI Fellow

Whitehead Institute for Biomedical Research

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Tumor-associated macrophages (TAMs) are the most abundant innate immune cell type in tumors. TAMs can either inhibit or support tumor progression, though it is unclear how their dichotomous functions are regulated. Dr. Alexandra Schnell predicts that the functional heterogeneity of TAMs may be due to distinct lineage origins and cell plasticity. To investigate these hypotheses, Dr. Schnell is developing a myeloid-specific lineage tracing tool to track TAM heterogeneity in tumors, and in response to immunotherapies. Schnell will conduct these experiments in Dr. Jonathan Weissman’s and Dr. Kipp Weiskopf’s labs at the Whitehead Institute. By better understanding TAM heterogeneity, Schnell hopes to enable the development of TAM-targeted cancer immunotherapies that specifically target tumor-promoting macrophages.

During her PhD, Schnell studied the fundamental mechanisms of the immune system in Dr. Vijay Kuchroo’s lab at Harvard Medical School. There, Dr. Schnell performed lineage tracing of immune cells during autoimmune inflammation. Her studies provided a mechanism for how homeostatic intestinal immune cells act as a reservoir for pathogenic inflammation elsewhere in the body. With this background in immunity and lineage tracing, Dr. Schnell will now investigate how the heterogeneity of tumor immune cells can be leveraged to generate new cancer immunotherapies.

Changwoo Seo, Ph.D. Jane Coffin Childs Fellow

Harvard University

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The periaqueductal grey (PAG) plays a critical role in the generation of complex social and defensive behaviors. However, the mechanisms by which transcriptionally distinct cell types and their neural dynamics within the PAG are organized to produce these behaviors are poorly understood. In this study, we used miniaturized 2-photon microscopy to record the neural activity of the PAG in behaving mice as they engaged in social and defensive behaviors. We aim to combine this information with imaging-based spatial transcriptomics, to better understand how the gene expression patterns of different neurons contribute to the functional organization of the PAG, and the regulation of social and defensive behaviors.

 

Honglue Shi, Ph.D. Jane Coffin Childs - HHMI Fellow

University of California, Berkeley

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CRISPR-Cas enzymes are versatile tools for gene editing and research applications such as transcriptional regulation and imaging. The speed and accuracy of CRISPR-Cas enzymes are crucial, yet how they identify a unique ~ 20-base-pair target within billions of base pairs in the genome is still unclear. Dr. Honglue Shi aims to obtain a more quantitative and predictive understanding of how natural and engineered CRISPR-Cas enzymes rapidly and accurately target specific DNA sequences in Dr. Jennifer Doudna’s lab at the University of California, Berkeley. Shi will use structure-guided biochemistry to develop a kinetic model for CRISPR-Cas9 search speed and accuracy. He will then test the generality of the model on additional CRISPR enzymes and ancestral RNA-guided TnpB enzymes. This research is fundamental to understanding both the evolutionary history of RNA-guided enzymes and the utility of these systems for genome editing. In the future, these results will enable predictions and design of genome editing functions that are not possible or practical today and will greatly accelerate the field as well as the precision and outcomes of next-generation genome editing tools.

As a Ph.D. student in Dr. Hashim Al-Hashimi’s lab at Duke University, Shi focused on the development of biophysical approaches such as NMR spectroscopy to extend the description of nucleic acids from static structures to dynamic ensembles, which results in a deeper and more predictive understanding of how nucleic acids are being recognized by other biomolecules. Having developed this expertise in nucleic acid biophysics and perspectives in dynamic ensembles, Dr. Shi is ready to elucidate the properties that define the best genome editors in Dr. Doudna’s lab.

Justin Silpe, Ph.D. Jane Coffin Childs - HHMI Fellow

Princeton University

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DNA-damaging agents are the pervasive inducers of temperate phages in model bacteria. Most bacteria in the biosphere are polylysogens, harboring multiple prophages. Thus, how co-residing prophages compete for cell resources if they all respond to an identical trigger is unknown. My project in the Bassler Lab is focused on the discovery of regulatory modules that control prophage induction independently of the DNA damage cue. The modules I uncovered lack sequence similarity but share regulatory logic by having a transcription factor that activates the expression of a neighboring gene encoding a small protein. The small protein inactivates the master repressor of lysis, leading to induction. Polylysogens harboring two prophages exposed to DNA damage release mixed populations of phages. Single-cell analyses reveal that this blend is a consequence of discrete subsets of cells producing one, the other, or both phages. By contrast, induction via the DNA-damage-independent module results in cells producing only the phage sensitive to that specific cue. Thus, in the polylysogens tested, the cue used to induce lysis determines phage productivity. Considering the lack of potent DNA-damaging agents in natural habitats, additional phage-encoded sensory pathways to lysis could play fundamental roles in phage-host biology and inter-prophage competition.

 

Adam Wei Jian Soh, Ph.D. Jane Coffin Childs Fellow

Duke University

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Dr. Adam Wei Jian Soh will investigate how the basement membrane (BM), a sheet-like extracellular matrix that encloses tissues, stretches in mechanically-active tissues in Dr. David Sherwood’s lab at Duke University. Dr. Soh will use C elegans ovulation as a novel model system for examining BM stretching and recovery. Soh has performed a localization screen and identified candidate proteins that are likely important for BM dynamics. He will follow up on these findings by determining which proteins are functionally important for the stretching and recovery of BMs. Soh hypothesizes that type IV collagen is critical for stretching tissues as genetic defects in this gene lead to vasculature hemorrhaging and muscle dysfunction. This research may also identify novel genes that are critical for tissue support and are mutated in human disease.

Previously, Dr. Soh investigated the mechanics of motile cilia beating as a PhD student in Dr. Chad Pearson‘s lab at the University of Colorado Anschutz Medical Campus. Specifically, he discovered a novel intracellular mechanism involving the cortical cytoskeleton network that regulates cilia beating synchronization. Through this research Soh developed expertise in imaging techniques and cellular biophysics. This experience has prepared Dr. Soh for his current project dissecting basement membrane dynamics.

Jiarui Song, Ph.D. Jane Coffin Childs - HHMI Fellow

University of Colorado, Boulder

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Histone methyltransferase PRC2 (Polycomb Repressive Complex 2) silences genes via successively attaching three methyl groups to lysine 27 of histone H3 (H3K27me3). Several research groups including ours demonstrated that PRC2 associates with numerous pre-mRNA and lncRNA transcripts with a strong binding preference for G-quadruplex forming RNA. However, the structural details of their interactions have so far been unclear. My research provides a 3.3Å-resolution cryo-EM structure of a PRC2-RNA ribonucleoprotein complex. Notably, G-quadruplex RNA bridges the dimerization of PRC2 with a symmetric interface comprised of two copies of the PRC2 catalytic subunit EZH2. Especially, EZH2 SET domain is indicated to directly facilitate the RNA-mediated dimerization of PRC2. Interestingly, those residues were previously characterized in the PRC2-nucleosome cryo-EM structure to physically interact with the histone H3 tail and nucleosome DNA. Therefore, I hypothesize that in the dimerized PRC2-RNA complex, RNA inhibits PRC2 activity by limiting H3 tail accessibility to the active site. Overall, my study provides a new perspective of RNA regulation of chromatin modifiers.

Elizabeth Stone, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley

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The discovery of novel antitumor drugs requires the development of new methods to synthesize molecules of increasing diversity and complexity to meet the challenges of drug efficacy and safety. Biocatalysis provides an attractive strategy to perform chemical reactions under mild and sustainable conditions. The Chang Lab has recently discovered a family of radical halogenases that perform the regio- and stereoselective chlorination of unactivated, aliphatic C–H bonds within several amino acid substrates. Despite the synthetic utility of organohalides, there are limited biosynthetic and chemical methods for the selective chlorination of unfunctionalized alkanes beyond this example.

 

Using mechanistically-guided protein engineering, my research aims to expand the substrate and reaction scope of these enzymes to produce noncanonical amino acids bearing versatile functional group handles, including halogens or azide. These synthetic residues will then be incorporate into biological molecules of interest, such as known anticancer peptides, and can be further functionalized to access diverse, cyclic structures. Overall, this strategy provides a fully biosynthetic method for producing novel analogs of anticancer peptides with the goal of discovering improved drugs.

 

Xiaochen Sun, Ph.D. Jane Coffin Childs Fellow

Stanford University

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The ability to learn and memorize is essential for all living organisms to adapt to the ever-changing environment, and it serves as the foundation for higher-order cognitive processes such as reasoning, planning, and decision-making. However, the neuronal basis of memory remains unclear — it is largely unknown how memory-related information is represented by populations of neurons in the brain, and how that representation is formed as a result of learning-induced plasticity. By studying the activity of neurons underlying long-term memory using in vivo imaging and opto/chemogenetics, I hope to understand the neural mechanisms by which new information is learned and processed in neuronal populations. This work will provide insights into the computational principles that govern learning in biological and artificial neural networks.

 

Xulu Sun, Ph.D. Jane Coffin Childs - HHMI Fellow

University of California, San Francisco

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When planning or troubleshooting, we often contemplate possible actions and imagine their outcomes based on prior knowledge. The hippocampus has been implicated in our ability to imagine possible futures, yet it is unclear how future representations are regulated and what functions they subserve. Dr. Xulu Sun will explore the anatomical underpinnings, mechanistic control, and functional significance of hippocampal future representations in Dr. Loren Frank’s lab at the University of California, San Francisco. Dr. Sun will use behavioral tasks and multiregional electrophysiology to explore how the hippocampus interacts with other brain regions to enable future representations and how these representations may support flexible planning. This process is impaired in many neuropsychiatric disorders such as schizophrenia. Thus, Dr. Sun’s research of the underlying neuroscience may reveal new strategies for treating such disorders.

As a PhD student in Dr. Krishna Shenoy‘s lab at Stanford University, Sun investigated dexterous movement control. There she used behavioral tasks and large-scale neural recordings to show how the cortical motor system implements a behavior-organizing map in rhesus monkeys. Dr. Sun will now use her strong foundation in neural computations to explore the neural basis of future representations.

Jeffrey Swan, Ph.D. Jane Coffin Childs Fellow

St. Jude Children's Research Hospital

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CRISPR-associated transposons (CASTS) enable programmable DNA insertion, yet there is a limited understanding of how they recognize specific DNA sequences and activate DNA insertion. Dr. Jeffery Swan will conduct structural and kinetic studies of CASTs in Dr. Elizabeth Kellogg’s lab at St. Jude Children’s Research Hospital. Dr. Swan will investigate the AAA+ (ATPases Associated with diverse cellular Activities) regulator TnsC which influences both ATP hydrolysis and DNA deformation. He will use cryo-electron microscopy to structurally characterize the fully assembled integration complex, and single-molecule and ensemble kinetic experiments to better understand transpososome assembly and activation. Swan anticipates that these studies will guide future attempts to rationally engineer CASTs for gene-editing and therapeutic applications.

As a Ph.D. student in Dr. Carrie Partch‘s lab at the University of California at Santa Cruz, Swan investigated the role of the KaiC, an AAA+ protein that effectuates circadian timing. Dr. Swan demonstrated that the ATPase activity in KaiC imparts cooperativity to the transition between autophosphorylation and autodephosphorylation, which is an important feature of the circadian clock. With his expertise in AAA+ proteins, Dr. Swan is ready to investigate how TnsC enables the programmable DNA insertion of CASTs.

Mabel Tettey, Ph.D. Jane Coffin Childs Fellow

National Institute of Allergy and Infectious Diseases

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In disease-causing organisms, hybridization allows for the transfer of traits such as virulence and drug resistance. Dr. Mabel Tettey will investigate how hybridization impacts African trypanosomiasis outbreaks caused by the parasite Trypanosoma brucei. Dr. Tettey will assess the degree of hybridization occurring in African trypanosome endemic areas, explore the impact of hybridization on virulence, and identify the key molecules involved in this process. She will conduct these experiments in Dr. Michael Grigg’s lab at the National Institute of Allergy and Infectious Diseases. These studies may enable the development of effective disease control strategies against African trypanosomes.

As a graduate student in Dr. Keith Matthews’ lab at the University of Edinburgh, Tettey examined the function of released peptidases in the transmission of African trypanosomes. Specifically, Dr. Tettey identified the genes that dominate quorum sensing signal in African trypanosomes. With her extensive background in trypanosome biology, Dr. Tettey will now examine the role of hybridization in trypanosome virulence.

Marla Tharp, Ph.D. Jane Coffin Childs - HHMI Fellow

Whitehead Institute for 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.

Margaret Torrence, Ph.D. Jane Coffin Childs Fellow

Massachusetts Institute of Technology

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Pancreatic cancer represents 3% of all new cancer cases in the United States, yet it has the worst 5-year survival rate of all cancer types. While many cancer types display durable responses to cancer immunotherapy, which harnesses the cytotoxic activity of the immune system to treat malignancies, immunotherapy has largely failed to treat pancreatic ductal adenocarcinoma (PDAC). The complex tumor microenvironment of PDAC likely underlies the refractory response of PDAC to immunotherapy, including immune checkpoint blockade (ICB). One example of a known mechanism that aids immune evasion by PDAC is the presence of desmoplastic stroma that hinders the infiltration of cytotoxic T cells. In addition to exclusion of immune infiltrate, the cytotoxic T cells that are present within the microenvironment are dysfunctional. Nutrient availability within the tumor environment likely impacts the function of cytotoxic T cells and research in immunometabolism is of growing interest. Understanding cell-specific metabolic changes within GEMMs has been hindered by a lack of mouse models that properly recapitulate the tumor microenvironment and lack of tools able to properly isolate cells in a way that preserves the integrity of the metabolites. My project will use a GEMM of PDAC, congenic markers, and cancer cell-specific surface tags in order to rapidly purify and perform metabolomics of both cancer cells and T-cells. Using this technique, I hope to identify metabolic pathways that are hindering immune cell proliferation and cytotoxic capabilities to reinvigorate the immune microenvironment for tumor control and in response to ICB.

Petra Vande Zande, Ph.D. Jane Coffin Childs Fellow

University of Minnesota

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The human pathogen Candida albicans’ genome varies substantially between clinical isolates, yet it is currently unknown how this variation affects infection. Since many genetic variants are located in gene regulatory sequences, Dr. Petra Vande Zande predicts that there is substantial divergence in gene-regulatory networks between different C. albicans isolates that modifies their fitness. Dr. Vande Zande will use gene expression data from different isolates to model gene regulatory networks and identify key differences that impact fitness. Vande Zande will conduct these experiments in Dr. Anna Selmecki’s lab at the University of Minnesota. This research will provide direct insight into genetic differences that impact C. albicans infections. It may also provide clues into other genetically diverse systems with differences in gene-regulatory networks, including human cancers.

As a graduate student in Dr. Patricia Wittkopp’s lab at the University of Michigan, Vande Zande studied gene expression in the context of adaptive evolution. In particular, Dr. Vande Zande discovered that mutations affecting a gene’s expression from a distance are more pleiotropic and more detrimental to fitness than mutations occurring proximally to the gene of interest. With her experience in the evolution of gene expression, Dr. Vande Zande is now interested in understanding divergence in gene-regulatory networks between different clinical isolates of yeast infections.

Pablo Villar, Ph.D. Jane Coffin Childs Fellow

Harvard University

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Cells detect and transform specific external stimuli into precise biochemical functions in a process termed signal transduction. Sensory systems are one example of signal transduction. Dr. Pablo Villar will investigate a unique sensory system: octopus chemotactile receptors that mediate contact-dependent aquatic chemosensation. Dr. Villar will use single-cell sequencing, cryo-EM, and physiology to investigate the molecular logic of receptor expression, complex formation, and physiological function in cephalopods. These experiments will be conducted in Dr. Nicholas Bellono’s lab at Harvard University. Villar’s studies will reveal general principles for the evolutionary fine tuning of signal transduction and help connect adaptations in protein structure with octopus behavior.

As a graduate student in Dr. Ricardo Araneda’s lab at the University of Maryland, Villar examined how neuromodulatory brain regions regulate circuits that process sensory information. Specifically, Dr. Villar showed that the basal forebrain activates shortly after the onset of a sensory stimuli, and in a stimulus-specific manner. With this experience in neuroscience and sensory stimuli, Villar will now examine the signal transduction of stimuli at a molecular level in cephalopods.

Jenelle Wallace, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

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New experiences elicit novel patterns of neural activity, prompting changes in gene expression that underlie learning. However, most studies of human brain evolution focus on species differences in baseline gene expression. Activity-dependent enhancers that control neuronal gene expression could represent an unexplored substrate for the evolution of human cognitive specializations. To examine the evolution of the activity-regulated genome in the human lineage, I will utilize primary neurons from human and macaque as well as induced pluripotent stem cell-derived neurons from human and chimpanzee to create cortical circuits in vitro and stimulate activity with physiological paradigms. I will measure coordinated changes in chromatin accessibility and gene expression in single cells to discover human-divergent neuronal activity-regulated elements (hDAREs). A CRISPRi screen will allow me to test hDARES to determine which are human-specific activity-dependent enhancers. To begin to investigate the consequences of evolutionary alterations for brain plasticity, I will model a human-specific deletion of a candidate activity-dependent enhancer regulating a gene with known roles in restricting spine growth in mice. Utilizing in vivo imaging to measure synapse formation during motor learning, I will test the hypothesis that activity-dependent expression of this gene, conserved between mice and chimpanzee, may inhibit learning-induced synapse formation and that the human-specific deletion may relieve this plasticity brake. Combining evolutionary genetics and systems neuroscience approaches will lay the groundwork for exploring this new dimension of human brain evolution.

Hannah Wayment-Steele, Ph.D. Jane Coffin Childs Fellow

Brandeis University

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Deep learning methods have revolutionized structural biology by accurately predicting single structures of proteins and protein-protein complexes. However, biological function is rooted in a protein’s ability to sample different conformational substates, and disease-causing point mutations are often due to population changes of these substates. This has sparked immense interest in expanding the capability of algorithms such as AlphaFold2 (AF2) to predict conformational substates. We demonstrate that clustering an input multiple sequence alignment (MSA) by sequence similarity enables AF2 to sample alternate states of known metamorphic proteins, including the circadian rhythm protein KaiB, the transcription factor RfaH, and the spindle checkpoint protein Mad2, and score these states with high confidence. Moreover, we use AF2 to identify a minimal set of two point mutations predicted to switch KaiB between its two states. Finally, we used our clustering method, AF-cluster, to screen for alternate states in protein families without known fold-switching, and identified a putative alternate state for the oxidoreductase DsbE. Similarly to KaiB, DsbE is predicted to switch between a thioredoxin-like fold and a novel fold. This prediction is the subject of ongoing experimental testing. Further development of such bioinformatic methods in tandem with experiments will likely have profound impact on predicting protein energy landscapes, essential for shedding light into biological function.

Kevin Wu, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley

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The endoplasmic reticulum (ER) is a critical organelle for maintaining protein quality control in cells; misfolded proteins are targeted for degradation through the ER-associate degradation (ERAD) pathway. Dr. Kevin Wu will study the ER-membrane bound E3 ubiquitin ligase Doa10 in Dr. Eunyong Park’s lab at the University of California, Berkeley. Doa10 is conserved from yeast to humans and identifies and targets many misfolded proteins for degradation. However, it is unclear how Doa10 recognizes a wide range of client proteins. Dr. Wu will use biochemical and structural approaches to reveal how Doa10 recognizes and processes a range of substrates, and how Doa10 cooperates with other quality control factors to maintain protein homeostasis. Protein misfolding and aggregation are associated with aging and diseases such as neurodegeneration. Thus, Wu’s studies may have implications for developing future therapies to improve protein homeostasis in human disease.

As a graduate student in Dr. James Bardwell’s lab at the University of Michigan, Wu investigated chaperone-mediated protein folding. There, he discovered that weak binding between ATP-independent chaperones enable the refolding of client proteins, whereas stronger binding hinders refolding. Dr. Wu’s background in protein refolding set him up for exploring how Doa10 E3 ubiquitin ligase recognizes unfolded protein targets.

Shiyu Xia, Ph.D. Jane Coffin Childs Fellow

California Institute of Technology

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By detecting molecular signatures of cancer cells, synthetic protein circuits delivered as mRNA could specifically kill cancer cells. However, a major hurdle is the inability to deliver circuits to all cancer cells in a tumor. An ideal therapy would both selectively eliminate cancer cells to which circuits are successfully delivered and trigger a broader killing effect on the surrounding tumor. Inflammatory cell death that releases immunostimulatory signals provides an ideal mechanism to achieve these two goals by directly killing on-target cancer cells, as well as indirectly killing off-target cancer cells by activating lymphocyte-mediated anti-tumor immunity. Our goal is to design protein-level circuits capable of identifying cancer cells, executing cell death, and eliciting anti-tumor immunity. We will engineer an input module that senses and amplifies oncogenic signals, design an output module that thresholds these signals and actuates inflammatory cell death, and validate the full input-output circuit using cellular and mouse cancer models. Our research will offer a novel immunotherapy concept that combines synthetic biology approaches with the immunotherapy.

Liewei Yan, Ph.D. Jane Coffin Childs Fellow

Carnegie Institution of Washington

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Ribosomes are complex molecular machines that translate mRNAs into proteins and are essential for sustaining life. While the ribosome functions in cellular environments that are markedly diverse, its composition has traditionally been seen as static after assembly. Exciting new studies challenge this concept and provide evidence that organisms assemble different types of ribosomes during development, stress response, or disease. For example, during embryogenesis, zebrafish assemble two types of ribosomes with distinct structures: maternal and somatic. Although this ribosome heterogeneity is predicted to alter protein synthesis, no experimental evidence yet exists to demonstrate this. I will use a multidisciplinary approach to test how changes in ribosome composition affect translation during zebrafish development.

Yumei Zheng, Ph.D. Jane Coffin Childs Fellow

Boston Children's Hospital

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