Harnessing long-range hormone signaling for therapeutic delivery

What do poisonous frog toxins have to do with drug delivery? More than you might think, according to Jane Coffin Childs Fellow Dr. Aurora Alvarez-Buylla.

During her thesis research in Dr. Lauren O’Connell’s lab at Stanford, Alvarez-Buylla identified the first toxin binding protein in poison frogs. This protein, a serine protease inhibitor, or serpin, binds to toxins in the blood, and delivers them to skin glands for bioaccumulation. Interestingly, Alvarez-Buylla found that this frog protein is very similar to mammalian hormone carrier proteins that facilitate the transport of lipid-soluble hormones in the bloodstream and their delivery to target cells.

For the fellowship in Alanna Schepartz’s lab, Dr. Alvarez-Buylla plans to reconstruct the evolutionary trajectory of mammalian hormone carrier proteins. Like frog poison, many therapeutics are toxic when delivered systemically, therefore it is desirable to sequester these therapeutics until delivered to a particular organ. By understanding the range of small molecules that these proteins could possibly bind to, and how their release can be triggered, Alvarez-Buylla’s research will establish a framework for rationally engineering proteins to serve as novel drug delivery agents for many therapeutic molecules.

Unlocking the Bacterial Vault: Novel Organelles Involved in RNA Repair

It has been said that RNA is the central molecule in genetic transfer and cellular processes; Dr. Nathan Bullen’s past and planned future research certainly support that sentiment.

During his thesis research in Dr. John Whitney’s lab at McMaster University, Bullen discovered the role of an RNA-modifying enzyme in microbial warfare. Bacteria compete with one another in a microscopic turf war of sorts. One of the ways they combat their foes is by injecting toxins into nearby bacterial cells. Bullen demonstrated that one of these toxins is an enzyme called RhsP2 which works to inhibit protein synthesis or translation in neighboring cells.

As a Fellow in Aaron Whiteley’s lab at the University of Colorado, Dr. Bullen is going on the defensive—asking: how do organisms survive when their RNA is under attack? Intriguingly, the proteins that repair RNA are conserved from bacteria to humans, and Bullen has reason to believe that these systems operate in remarkably similar ways, despite billions of years of evolution. By studying these pathways in bacteria—whose genes are easier to manipulate—his cutting-edge research is shedding light on fundamental processes of RNA metabolism across the tree of life, with far-reaching implications for health, disease, and beyond.

Uncovering oligodendrocyte lineage dynamics in the human brain using somatic mutations

Human brain development is challenging to study for many reasons. Dr. Emre Caglayan’s project as an HHMI-JCC Fellow aims to overcome experimental limitations related to studying brain development and provide unprecedented insight into how a brain develops over the human lifespan.

As a Ph.D. student in Dr. Genevieve Konopka’s lab at UT Southwestern Medical Center, Caglayan investigated human brain evolution. Using advanced genomics technologies, he found that human brains have unique functionalities used for the development and maturation of specialized cells relative to other closely related species.

Dr. Caglayan notes that the absence of non-invasive molecular tools has prevented further exploration of the human brain, and was captivated by the approach of Christopher Walsh’s lab to use somatic mutations as a “barcode” to trace cell lineages. This approach will enable Caglayan’s investigation into brain dynamics so that they can investigate how new mature oligodendrocytes are generated throughout a human lifespan. This research will provide fundamental insight into neurodevelopment and may reveal novel clues about how these processes go awry during neurodegeneration.

Recording cell states and signaling events to reveal cell fate decisions during pancreatic islet differentiation

Gene transcription, the process of copying DNA into RNA for gene expression, is a complicated process that relies on sequences of DNA known as enhancers to help regulate the process. Enhancers are non-coding stretches of DNA that regulate the expression of a subset of genes.

Dr. Brendan Camellato made crucial insights into enhancer-mediated regulation during his thesis research in Dr. Jef Boeke’s lab at NYU Langone Health. In one of his projects, Camellato investigated transcriptional regulation across various species. In addition to being an impressive technical advance, this approach provided insight into a plausible mechanism for how genetic information is transferred and regulated in yeast and mouse embryonic stem cells.

Now, as a Fellow in Junhong Choi, Ph.D.’s lab at Memorial Sloan Kettering Cancer Center, Dr. Camellato will use enhancers as a tool to record cellular histories during normal development, and in diseased states. Using the recently developed ENhancer-based Genomic Recording of transcriptional Activity in Multiplex (ENGRAM), Camellato will investigate how cell signaling drives stem cell differentiation with single-cell resolution. His research promises to advance these important technologies, as well as provide unprecedented insight into human development.

Evolution of receptor-ligand selectivity to evade bacterial ligand mimicry

Dr. Lews Caro is fascinated with the molecular arms race that occurs between a host and pathogen and how it shapes their evolution. Caro hypothesizes “that by understanding the molecular mechanisms of evolutionary phenomena, we can actually gain more insight into the evolutionary process itself.”

Caro’s graduate research in Michael Ailion’s lab at the University of Washington uncovered the mechanism of a toxin-antidote system in C. elegans. While such systems are widespread in bacteria and fungi, relatively few examples have been discovered in animals, and those few examples remain poorly characterized.

As a Fellow in Nels Elde’s lab at the University of Utah, Dr. Caro will explore the relationship between a special type of transmembrane protein, called ligand receptors, and the ligand itself. Pathogens secrete toxic ligand imitators which bind to host receptors and hijack normal host signaling. This exerts an evolutionary pressure on the receptor to escape activation by pathogen toxic ligands while retaining responsiveness to host ligands. Caro will use a combination of evolutionary analyses, functional and binding assays, and structural biology approaches to determine how receptors resolve this evolutionary conflict.

Deciphering the Role of EBV-Infected B Cells and Autoimmunity in Post-Infectious Syndromes and Developing a Targeted Elimination Strategy

Illness can interfere with the brain’s ability to function properly, affecting much more than just clear thinking. Dr. Ya’el Courtney’s fellowship research is uncovering how immune responses to illness contribute to neurological dysfunction and may even trigger neurodegenerative processes, revealing new connections between the immune system and the brain.

During her thesis research in Dr. Maria Lehtinen’s lab at Harvard University, Courtney revealed how the choroid plexus, a specialized brain structure that produces cerebrospinal fluid is regulated. She found that secreted factors stimulate the development of specialized neural cells and alter their developmental trajectory. Interestingly, environmental factors such as maternal exposure to certain drugs or immune activation in response to illness also trigger secretion of factors and, eventually, can influence offspring behavior.

Dr. Courtney will examine immune-neurological interplay in Dr. William Robinson’s lab at Stanford University in a different context. There, she’ll examine how autoimmune responses in chronic post-infectious syndromes, such as post-treatment Lyme disease or long COVID, drive neurological manifestations. Courtney’s research has the potential to uncover novel immune-neurological connections and may elucidate novel and therapeutically tractable targets for patients with these long-lasting post-infection syndromes.

Engineering CAR T cells for Enhanced Cancer Immunotherapy via Protein Interaction Network Analysis

Cancer immunotherapies, such as chimeric antigen receptor (CAR) T cell therapies, have shown great promise against malignancies of the blood but have struggled to effectively treat solid tumors. During his fellowship, Dr. Pascal Devant will focus on understanding how T cells work in an effort to engineer CAR T cell therapies that can better attack solid cancers.

Devant developed his expertise in immunology during his graduate research in Dr. Jonathan Kagan’s lab at Harvard Medical School. There, he focused on caspases, key enzymes that work as the body’s early warning system of invaders. Devant discovered that inflammatory caspases are key enzymes in mammalian innate immunity, providing an alternative activation route to what was previously described. He structurally characterized a caspase complex, providing novel insights into substrate capture and processing.

Now, in Dr. Alex Marson’s lab at Gladstone Institutes, Dr. Devant will generate quantitative protein-protein interaction networks to identify key interactions that regulate T cell function. Devant will leverage this information, using gene editing and preclinical CAR T cell models, to engineer the next generation of CAR T cell therapies for the treatment of solid tumors. In addition to providing fundamental insight into how T cells work, Devant’s work holds great promise in clinical translation for cancer patients.

“Healthy aneuploidy”: Discovering strategies from the placenta to regulate aneuploidy tolerance

Most human cells have two copies of each chromosome, and the loss or gain of entire chromosomes, known as aneuploidy, can often be a characteristic of cancer cells. However, in the placenta, many cells exhibit a high degree of aneuploidy and chromosomal instability. For her fellowship, Dr. Meagan Esbin will study how the cells of the placenta tolerate such high levels of aneuploidy.

During her thesis research, Dr. Esbin studied transcriptional regulation in the joint lab of Drs. Robert Tjian and Xavier Darzacq at UC Berkeley. First, she helped solve the structure of a regulatory hub involved in gene regulation, the human SAGA complex. Then, motivated in part by her passion to improve women’s health and make pregnancy safer, Esbin  demonstrated that a human transcription factor (TFEB) plays an essential role in placental cell-cell fusion. This finding reveals new possibilities for rescuing defective cell fusion that can occur in preeclampsia.

In Dr. Min Yang’s lab at the University of Washington, Esbin will take a new angle on understanding placental biology. Using novel cell models, genetic screening, and live imaging she will attempt to define the rules of aneuploidy development and tolerance in the placenta. Her research will provide insight into this life-giving, yet understudied organ. Ultimately, she aims for her research to reveal how we can improve pregnancy outcomes and manage aneuploid cancer cells.

Illuminating the cell envelope architecture and assembly of a tick-borne pathogen

The bacterial cell surface plays a critical role in bacterial physiology and represents a key target for many antibiotics. However, the properties of many bacterial cell surfaces are not well characterized. Dr. Elayne Fivenson’s fellowship project aims to learn more about the cell surface of Rickettsia parkeri, a tick-transmitted bacteria that is a model system for the more pathogenic species Rickettsia rickettsii that causes the deadly Rocky Mountain Spotted Fever (RMSF).

Fivenson developed her expertise in bacterial cell surfaces in Dr. Thomas Bernhardt’s lab at Harvard Medical School. There, Fivenson demonstrated how an inner membrane protein functions to regulate the synthesis of the outer layer of many Gram-negative bacteria. Next, she investigated how the synthesis of the outer membrane and cell wall are coordinated. While it has long been appreciated that the cell wall impacts cell morphology, Fivenson’s results indicate that the outer membrane also contributes to cell shape.

Now in Dr. Rebecca Lamason’s lab at Massachusetts Institute of Technology, Fivenson will study R. parkeri, a model system for  the more pathogenic rickettsial species that cause RMSF. She will use structural and proteomic approaches to reveal the composition of the R. parkeri cell envelope. Then, she will use genetic approaches to dissect cell envelope synthesis pathways with the goal of identifying therapeutic targets. As tick range expands due to climate change, RMSF prevalence has increased. Fivenson’s research promises new insights towards the eventual therapeutic inhibition of these deadly bacteria.

From Bacteria to Biotechnology: Harnessing Retrons for Precision Medicine

CRISPR-Cas systems have revolutionized how specific genes can be precisely edited. Dr. Grace Hibshman’s fellowship project is focused on how to develop the next generation of genome editors.

During her graduate work in Dr. David Taylor’s lab at the University of Texas, Austin, Hibshman became an expert in the structural and functional characterization of CRISPR-Cas systems.

First, she engineered a more specific genome editing tool with less off-target effects. Then, in a tour de force, Hibshman determined the precise 3D structures of this tool in real-time to understand how it recognizes specific sequences of DNA. Her studies have provided crucial insight into how to improve CRISPR-Cas systems for genome editing.

Now, during her postdoctoral research in Dr. Eva Nogales’s lab at UC Berkeley, Hibshman will study a different set of genetic editing tools focusing on retrons, bacterial elements that can fuse multiple enzymatic activities into a single protein. She’ll use biochemical, structural, and high-throughput mutagenesis approaches to characterize and optimize one such retron. Hibshman’s research may provide us with the latest and greatest genome editor, and she’s betting on its applications in a wide variety of diseases such as cystic fibrosis, Alzheimer’s, and Duchenne muscular dystrophy.

Defining the targets of the antibody response to natural Oropouche virus infection

Dr. Hannah Itell’s passion for understanding the “ever-evolving virus-host arms race” started during her undergraduate global health studies in India, South Africa, and Brazil. Seeing the impact of viral infection on individuals, families, communities, and entire countries, motivated Itell to dedicate her research career to preventing viral transmission.

In her graduate research in Dr. Julie Overbaugh’s lab at the Fred Hutchinson Cancer Center, Itell focused on identifying human traits that limit HIV severity. She discovered that many virus-fighting genes seen in lab-grown cells function differently than real human immune cells,, demonstrating that common lab models may not reflect what really happens in the body. Next, she identified a gene that regulates a pattern in HIV transmission that was not previously understood. 

Now as a Fellow in Dr. Ivelin Georgiev’s lab at Vanderbilt, Itell has switched her focus to the Oropouche virus which is endemic to Brazil.There are currently no vaccines or specific treatments available to prevent or treat infection. Itell will find out how many virus types can be blocked by antibodies and where on the virus the antibodies attach. Itell’s efforts will provide fundamental knowledge about host response to Oropouche virus and directly inform rational vaccine design in the development of antibody therapeutics.

Uncovering the principles of immune sensing within the central nervous system

Dr. Madeleine Junkins is intrigued by brain-body interactions and how this relationship enables complex behaviors and functions. During her graduate research she investigated thirst suppression in ground squirrels, a hibernating species that can forgo water for months. During her fellowship, Junkins will interrogate collaborative immune-neural responses to illness.

During her thesis research in Dr. Elena Gracheva’s lab at Yale University, Junkins demonstrated that a specialized subset of neurons are activated at low temperatures during hibernation and promotes the release of a hormone that tells the body to hold onto water. Additionally, she found that thirst-sensing neurons in specialized brain areas called the circumventricular organs are functionally suppressed during hibernation. Collectively, Junkins’ research provided a major leap forward for understanding the neural regulation of thirst suppression during hibernation.

As a postdoc in Dr. Ruslan Medzhitov’s lab at Yale, Dr. Junkins will now study how our immune and neural systems collaborate to engage defenses when we’re sick. She will uncover the molecular and cellular components that transform inflammatory signals into neural activity. By manipulating the communication between the immune and neural systems during inflammation, Junkins will provide insight into how these two major body systems interact. This understanding could lead to the identification of novel therapeutic targets for neuroimmune disorders.

Investigation of immune systems in multicellular bacteria

Dr. Shoshanna Kahne is interested in bacterial pathways and determining how they change in response to their environment. From Mycobacterium tuberculosis to cyanobacteria, Kahne’s research is creating powerful insights with implications ranging from human disease to environmental impacts.

Kahne’s Ph.D. research in Dr. Heran Darwin’s lab at NYU  focused on how proteins are marked for breakdown in the bacteria that causes tuberculosis, Mycobacterium tuberculosis. Kahne discovered a protein that regulates marking an important vitamin-making enzyme for degradation in response to the abundance of the vitamin it helps synthesize. Her findings could help identify new ways to treat this deadly disease.

Now, in Dr. Alex Meeske’s lab at the University of Washington, Kahne will study how cyanobacteria defend themselves against infection by viruses. She is investigating species in the order Nostocales and has identified numerous and diverse potential defense systems in their genomes.

Kahne will test Nostocales hosts against diverse viruses to characterize how they succeed or fail to prevent infection. This work may reveal strategies to harness useful qualities of Nostocales, such as their abilities to fix atmospheric carbon and nitrogen, as well as combat their toxic overgrowths which can poison plants, animals, and humans.

Role of neoantigen-nonspecific Passenger T cells in cancer-associated immunity and tumor progression

Dr. Dave Klawon is fascinated with the critical, yet disparate roles that our immune system plays in resolving or mediating different diseases. He hypothesizes that comparing productive immune responses during infections with immune responses that fail to resolve in autoimmunity or become dysfunctional in cancer will “reveal precise therapeutic targets capable of tuning the immune response at will”.

Klawon developed his immunology expertise during his graduate research in Dr. Peter Savage’s lab at the University of Chicago. His research there focused on understanding how the immune system recognizes proteins from invaders like viruses or bacteria but knows not to attack the body’s own proteins. Klawon found that a special type of adaptive immune cell, regulatory T cells, selectively suppress self-reactive immune responses during infection to prevent autoimmune disease, thereby providing crucial mechanistic insight into self/non-self discrimination by the immune system.

During his fellowship in Dr. Tyler Jacks’s lab at MIT, Klawon will adjust his research focus to the immune system’s role in cancer. Immunotherapy is a burgeoning and incredibly promising cancer treatment modality, yet many patients fail to respond to current therapeutic options. Klawon notes that tumor-infiltrating T cells are a heterogeneous population that include subsets that either combat tumor growth or suppress the immune response allowing tumors to flourish. His research aims to identify factors driving tumor-enrichment of these disparate populations and reveal novel therapeutic targets that would both promote anti-tumor T cells and inhibit immunosuppressive T cells.

Organisational logic of the spino-parabrachial pathway for light touch

The way our brain senses a soothing touch differs from how it senses a painful one, but how these signals are processed are not well understood. Dr. Anna Lebedeva’s fellowship will leverage novel tools developed during her graduate work to answer this question in conscious, freely behaving mice.

Lebedeva developed her expertise in neuroscience and tool development in Dr. Kenneth Harris’s lab at University College London. There she helped develop Neuropixels 2.0, an implant that can steadily track brain activity in thousands of neurons for over two months. Importantly, this miniaturized implant does not constrain animal behavior, enabling measurements in conscious, freely moving mice and rats. Lebedeva then applied her new tool to uncover why mice make certain behavioral choices versus others that have a greater reward output. 

During her postdoctoral research in Dr. David Ginty’s lab at Harvard,  Dr. Lebedeva will apply Neuropixels 2.0 to understand how the brain processes signals resulting from touch. The brain region called the parabrachial nucleus (PBN) is thought to be important in this process, yet it is unknown how this information is filtered. Lebedeva will be able to monitor thousands of neurons in the PBN to decipher how touch is communicated in response to different stimuli such as light touch, pinching, and heating or cooling. This research will provide unprecedented detail into neural processing of the light touch pathway.

Neuronal mechanisms of simulations in the brain of sleeping mice

Dr. Amir Levi is interested in understanding the neural mechanisms underlying complex behavior. In his thesis research, Levi used innovative techniques to make keen insights into how we learn. In his fellowship, Levi’s research will provide important insight into how our brains generate “internal models”—mental simulations that allow us to predict and control movements and adapt to changing environments.

During his graduate research in Dr. Eran Stark’s lab at Tel Aviv University, Levi focused on neural mechanisms of learning. Learning is frequently understood as the brain adapting to external cues, yet Levi’s approach involved direct manipulation of neuronal networks and subsequent assessment of behavioral performance. Levi created a visual test where mice choose between two options, and found that they can learn the task in just one session, depending on their past experience and how hard the rule is. He also demonstrated how specific brain circuits can transmit neuronal signals with remarkable accuracy and precision, highlighting the brain’s ability to maintain and even enhance signal integrity during processing. His work suggests that using brain activity to guide learning may help us understand how brain signals lead to behavior.

Now in Dr. Massimo Scanziani’s lab at UC San Francisco, Levi will dissect the neural mechanisms involved in generating internal models. Normally, these internal simulations occur together with actual physical movement, making it challenging to study prediction separately from action. Levi will overcome this limitation by studying mice while they sleep. During sleep, internal models are still generated, but no physical movement occurs. Thus, Levi’s clever approach will enable him to tease apart the neural mechanisms for these distinct functions. His research will help us understand how the brain anticipates events, coordinates movements, and processes experiences during dreams.

The early-life microbiome regulates β-cell function and type-1 diabetes via gamma-aminobutyric acid

Environmental interactions during prenatal development have important implications that often last well into adulthood. Dr. Diego López’s research has shown how infections can alter this developmental trajectory, impacting immune function and influencing the development of asthma. In his fellowship he will investigate how our microbiome impacts developmental trajectories and metabolic outcomes in adulthood.

López’s graduate research began in Dr. Anna Beaudin’s lab at UC Merced focused on how maternal immune activation and inflammation have lasting impacts that continue well into the offspring’s adulthood.

In one project, Lopez found that when a mother’s immune system is activated, it causes an increase in certain early immune cells—and this increase lasts into adulthood. Additionally, he demonstrated that maternal inflammation expands and hyperactivates a specific population of innate immune cells that cause their offspring to have increased risk for developing asthma in adulthood. Collectively, López’ results reveal the long-lasting consequences of maternal immune activation on offspring fitness.

Now in Dr. June Round’s lab at the University of Utah, López will shift his focus to a different type of environmental interaction: our microbiome. This collection of trillions of microorganisms in our gastrointestinal tract plays a key role in the development of numerous diseases, including type-1 diabetes. Recently, the Round lab demonstrated that loss of early-life microbial diversity during a critical developmental window results in lifelong metabolic dysfunction due to reduced beta cell development. López will investigate the molecular crosstalk between specific microbes, immune cells, and pancreatic beta cells. His research will increase our understanding of the development of type-1 diabetes, and may reveal novel therapeutic targets for treating this disease.

A spatial stochasticity theory resolves how host-protective T cell responses emerge amid regulatory T cell immunosuppression

Dr. Tomer Milo appreciates distilling simplicity out of complex biological systems. During his graduate work, Milo developed elegant theories for a variety of human diseases and collaborated with experimentalists to validate them. In his fellowship he will develop his own experimental expertise and combine it with his theoretical expertise to tease apart immune processing of self vs. foreign antigens.

During Dr. Milo’s thesis research in Dr. Uri Alon’s lab at the Weizmann Institute of Science he “studied design principles of physiological systems to better understand complex human diseases.” His work provided groundbreaking insight into the tumor microenvironment, bipolar disorder, and autoimmune disease. In his work, Milo used mathematical modeling to identify molecular players and cellular interactions critical in a host of biological diseases.

As a postdoc in Dr. Harikesh Wong’s lab at the Ragon Institute and Mass General, Dr. Milo will focus on systems immunology. Milo will investigate how a specific immune cell population, regulatory T cells, prevents autoimmune responses to self antigens while allowing appropriate immune responses against pathogenic non-self antigens. He thinks that the spatial segregation of the lymph node is crucial for this discrimination and will use high-resolution imaging and mouse models to tackle this question. Milo’s research will answer critical and fundamental questions in immune biology and provide insight into immune responses at homeostasis, during infection, and in autoimmune disorders.

A genetic approach to study metabolite sensing and regulation in organelles

Dr. Toshitaka Nakamura is interested in understanding protein-chemical interactions that mediate how cells sense stress. During his graduate work he found and characterized new compounds that kill cancer cells by triggering a type of cell death called ferroptosis. In his fellowship, he is interested in understanding how cells handle iron and glutathione, a crucial antioxidant and detoxifying agent, to mitigate stress responses.

In Dr. Nakamura’s graduate research in Dr. Marcus Conrad’s lab at Helmholtz Munich, he investigated the role of the protein ferroptosis suppressor protein (FSP1) in halting ferroptosis, a form of cell death that functions by damaging cell membranes. Nakamura discovered molecules that block FSP1, which induces cancer cell death. He showed that these molecules work by moving FSP1 away from cell membranes, inactivating the inherent enzymatic activity that protects them from damage. Then, by studying FSP1 mutations from cancer patients and lab experiments, he found another inhibitor and identified out how both types work. Collectively, his research provided groundbreaking insight into the role of FSP1 in ferroptosis, and revealed how this protein can be therapeutically targeted in cancer treatments.

Now, as a fellow in Dr. Kıvanç Birsoy’s lab at Rockefeller, Nakamura will study how cells sense metabolites in different cellular compartments. To facilitate his studies Nakamura will develop a CRISPR-Cas9-based genetic screening platform that can target specific organelles. Then, he’ll leverage his platform to investigate iron and glutathione sensing in mitochondria. In addition to providing a novel, widely applicable research tool, Nakamura’s studies may provide new insights and identify tractable therapeutic targets in diseases like cancer and neurodegeneration.

Biochemical basis and function of lipid spatial localization within the brain

Dr. Vanha Pham hypothesizes that there are many molecular examples of the “Goldilocks principle” in cell biology. During her graduate research she demonstrated how the right amount of formaldehyde mediates functional epigenetic signaling, while too much leads to general toxicity. In her fellowship, Pham will investigate how lipids in the brain are organized to maintain homeostasis and the functional and disease implications that result when they are not.

Pham’s thesis research in Dr. Chris Chang’s lab at UC Berkeley, focused on the role of small molecules and metal ions in helping the body’s cells carry out chemical processes. Pham discovered that formaldehyde can block an enzyme needed to make SAM, a key molecule in one-carbon metabolism. Surprisingly, this didn’t cause widespread changes in gene regulation, but instead affected only specific spots on certain genes.

As she transitions to Dr. Joshua Rabinowitz’s lab at Princeton University, Pham will shift her studies to the interplay between proteins and lipids. Using the brain as a model system, she’ll investigate why lipids are spatially enriched in different layers of the brain using a novel approach that maps lipids and gene activity in specific parts of a tissue in combination with genetic screens.

Additionally, she will investigate what happens when certain lipid patterns are disrupted. Pham anticipates that her findings will reveal important insights on how lipids impact membrane protein function, regulate cell morphology, and modulate physiology and disease.

Structural mechanisms for higher-order microtubule assembly function in parasites

Dr. Matthew Reynolds is fascinated with the elegant structures of our cytoskeleton – a large network consisting of protein fibers and associated proteins that gives shape and structure to cells. During his thesis research he developed machine-learning based techniques to enable the structural determination of curved and bundled actin structures. In his fellowship, Reynolds will detail specialized cytoskeleton super-assemblies from parasitic cells.

During Reynolds’ thesis research in Dr. Greg Alushin’s lab at Rockefeller University, he made important contributions to processes involved in cryo-EM structure determination. Reynolds developed computational techniques that were crucial in reconstructing bent F-actin segments and bundled F-actin that help shape and move cells.

Now, in Dr. Rui Zhang’s lab at Washington University in St. Louis, Reynolds will apply his structural biology expertise to more complex cellular systems. He will continue to investigate the cytoskeleton and will use a combination of cryo-EM and cryo-electron tomography (cryo-ET) to examine microscopic single-cell organisms. These studies will provide mechanistic insights into the nanoscale protein-protein interactions that drive micron-scale cytoskeleton organization in single-celled parasites. His research will likely push forward technological development in structural determination via cryo-EM and cryo-ET. Reynolds anticipates that his findings will inform parasitic disease models and may reveal novel therapeutic targets.

Discovery of silencing factors of the unfolded protein response in cancer

Dr. Heegwang Roh recalls how the COVID-19 pandemic hit during a pivotal moment of his graduate training. During the lockdown, he devoted considerable effort to reading literature on basic biology and became interested in the unfolded protein response (UPR), a cellular stress response triggered by the accumulation of unfolded or misfolded proteins in a cell.

Roh’s thesis research in Dr. Alice Ting’s lab at Stanford University involved a number of innovative projects covering a broad swath of chemical biology. In one project, he created a better way to tag nearby proteins using an enzyme called laccase, fixing safety problems seen in older methods. This new system works well for studying proteins and viewing cells under powerful microscopes. In another project, Roh turned a harmless version of botulinum toxin into a tool for delivering proteins inside cells.

As he transitions to Dr. Michael Rape’s lab at UC Berkeley, Roh will utilize his expertise in tool development to interrogate the UPR. This response is important for cells to respond to stress stimuli, yet the molecular mechanisms by which the UPR is suppressed after the stress is resolved is unknown. Roh will use genetic screens to identify novel UPR suppressors and develop chemical inhibitors for the UPR suppressors. In addition to uncovering novel UPR biology, Roh’s studies will provide new tools for studying UPR in cancer cells and perhaps reveal lead molecules for cancer drug development.

The functional role of transposable element-derived transcripts in cancer progression

Dr. Wesley Saintilnord is interested in how transposable elements (TEs), DNA sequences that can move from one location in a genome to another, can exploit epigenetic pathways that then lead to their aberrant reactivation in cancer cells to rewire gene expression programs. In his fellowship, Saintilnord will examine how TEs functionally contribute to cancer progression.

Saintilnord developed his expertise in epigenetic mechanisms during his Ph.D. research at the University of Kentucky in Dr. Yvonne Fondufe-Mittendorf’s lab  now at the Van Andel Institute. In his first project, Saintilnord showed that cadmium exposure changes how many genes are turned on during sperm development by affecting DNA methylation. In another study, he found that certain cancer-associated variants of a histone protein make DNA wrap more tightly, changing how genes are expressed. Collectively, his research demonstrates how environmental exposure, and oncogenic mutations rewire gene expression through epigenetic pathways.

Now, in Dr. Ting Wang’s lab at Washington University in St. Louis, he will dissect why cancer cells take control of TEs for gene regulation and how TE-generated transcripts drive tumorigenesis. He will develop a high-throughput screen to evaluate tumor-enriched TE transcripts in classical cancer phenotypes. Then, Saintilnord will evaluate which of these transcripts encode functional proteins that modulate cell signaling and chromatin dynamics. Saintilnord’s studies will provide fundamental insights into TE biology in cancer cells and may reveal novel therapeutic strategies to combat TE-mediated oncogenic programs.

Decoding the Structural Basis of Immunogenicity

Dr. Ellen Shrock envisions a future where novel therapeutics are not seen as dangerous by the immune system. While studying the immune response to SARS -CoV2 in her graduate work, she recognized that even different individuals responded in the same way to the virus. In her fellowship, Shrock is systematically characterizing immunogenicity, the ability of a substance to provoke an immune response, and training models to predict antibody recognition, with the long-term goal of avoiding such features in protein therapeutics.

During her thesis research in Dr. Stephen Elledge’s lab at Harvard Medical School, Shrock studied antibodies from people who had COVID-19 and found they targeted over 800 parts of the virus. She also showed that some parts of these antibodies are built into our genes and help the immune system recognize viruses quickly. Shrock’s research is a giant step forward in understanding immune recognition, with important implications for viral immunoevasion and the design of immunosilent protein therapeutics.

As a postdoc in Dr. David Baker’s lab at the University of Washington, Shrock is taking a systematic approach to more broadly understand antibody recognition. She will execute a large-scale screen to characterize the antibody response against a diverse array of proteins. Shrock will then characterize the epitopes within these proteins and use her results to train an AI model to predict immunogenicity. In addition to providing fundamental learnings on immune recognition, Shrock’s findings will empower the design of future protein therapeutics that are invisible to our immune systems.

Disrupting neuron-glioma interactions in the thalamus for thalamic pediatric low-grade glioma therapy

Dr. Patrick Steadman is passionate about neuroscience and the interplay between neurons and glial cells (support cells in the brain) in physiology and disease. During his graduate research, he examined the interaction between these cell types in normal memory consolidation. In his fellowship, Steadman will now investigate how this interplay impacts pediatric low-grade gliomas.

Steadman’s thesis research in Dr. Paul Frankland’s lab at the University of Toronto, focused on the importance of a specialized glial cell, myelin-forming oligodendrocytes, in memory consolidation. He showed that oligodendrogenesis and de novo myelination in the cortex are promoted by learning. Importantly, when he prevented learning-induced increases in oligodendrogenesis, this impaired memory consolidation. Steadman’s results emphasize the role of glial cells in fine-tuning neural circuits for memory consolidation and retrieval.

Now in Dr. Michelle Monje’s lab at Stanford University, Dr. Steadman will continue to examine glial-neuronal interactions, but in the pathological context of pediatric low-grade gliomas. Recent work from the Monje lab demonstrated that gliomas increase neuronal excitability which promotes tumor growth and disrupts normal brain function. Steadman will investigate the molecular mechanisms mediating glioma progression, and test targeted therapies’ impacts on glioma progression and brain function. This research will provide new insight into pediatric gliomas while taking into account the cognitive impact of potential treatments on patients – an important consideration since children with this disease are typically quite young.

Understanding energetic and vascular constraints on neurophysiology, encoding and behavior

The brain is a remarkable organ; it shapes our perceptions, memories, and cognitive functions, yet these functions come at a high energetic cost. During Dr. Shivang Sullere’s graduate research he discovered a novel mechanism for pain relief that provides significant insight into the role of endogenous cholinergic circuit, while serving as a potential alternative to opioids. During his fellowship, he will investigate the metabolic, neurophysiological and behavioral consequences of deficient energy supply to active brain regions.

During his Ph.D. research in Dr. Daniel McGehee’s lab at the University of Chicago, Sullere used neurophysiological approaches to explore cholinergic circuits involved in central pain signaling. He identified that activating certain cholinergic centers in the brain helped reduce pain, even in conditions in which opioids no longer worked. He then identified the receptor mechanisms mediating the analgesic effects of this cholinergic circuit.

As he transitions to Dr. Chengua Gu’slab at Harvard University, Sullere will adjust his focus to neurovascular coupling (NVC): a dynamic process that matches local blood flow to areas with high neural activity. He will use genetic mouse models and optical methods to disrupt NVC and evaluate how NVC impacts brain function at metabolic, neurophysiological and behavioral levels. Sullere’s studies will provide foundational insights into NVC and may reveal strategies for correcting metabolic deficits in diseases like Alzheimer’s, dementia, diabetes, and atherosclerosis.

Dynamic interactions of hippocampal-prefrontal circuits for flexible behavior

Dr. Shih-Yi Tseng is interested in how the brain coordinates the many functions we use to navigate our way through the world. During her Ph.D. research she studied a large population of neurons to illustrate that neural coding enables these functions and is distributed throughout the cortex. In her fellowship, Tseng will now decipher how two areas of the brain work together to enable the flexible behavior required for navigation.

Tseng’s thesis research in Dr. Christopher Harvey’s lab at Harvard University examined the functional organization of the cortex in supporting sensing, planning, and action to navigate towards a goal location in dynamically changing environments. By tracking the activity of 90,000 brain cells in mice, Tseng found that information about tasks and behavior is spread out across the cortex. Her work suggests that this part of the brain possesses a vast capacity to integrate complex features of behavior and surroundings to guide decisions.

In Dr. Loren Frank’s lab at UC San Francisco, Tseng will now investigate the dynamic interactions between the hippocampus (HPC) and prefrontal cortex (PFC) to enable flexible behavior. The HPC is important for learning and memory, whereas the PFC is crucial for decision-making. These regions need to coordinate during tasks such as navigation, yet how such coordination occurs is not known. Tseng will use multi-area electrophysiology, optogenetic manipulations, and computational methods to determine the HPC-PFC interactions needed for flexible behavior, and to evaluate how their coupling enables these regions to perform their individual functions. This research will provide fundamental insights into HPC-PFC coupling and may reveal ways in which this process goes awry in neuropsychiatric disorders.

Neural mechanism of behavioral exhaustion

Focusing on a task can often leave us exhausted despite low physical exertion. Dr. Yu Wang is investigating the source of this type of behavioral exhaustion. Building off her thesis research on neural sensing of peripheral metabolic states, she’s primed to make key insights into the brain’s metabolic deficiencies that may lead to our fatigue.

Wang developed her expertise in the neural integration of metabolic states during her Ph.D. research in Dr. Ardem Patapoutian’s and Dr. Li Ye’s labs at The Scripps Research Institute. Specifically, she was interested in how sensory neurons regulate peripheral metabolism, metabolic processes that occur in tissues and organs outside of the central nervous system, and how these neurons coordinate intracellular energy use to sustain activity. Wang demonstrated that somatosensory neurons enervate adipose tissue and modulate adipocyte function by acting as a break on the sympathetic system. Interestingly, she found that the mechanoreceptor PIEZO2 is highly expressed in these neurons, and is required for their brake-like function. Collectively, her research has provided keen insight into the interplay between neural function and peripheral metabolic states.

As a postdoc in Dr. Karl Deisseroth’s lab at Stanford University, Wang will examine the neural mechanisms of behavioral exhaustion. She hypothesizes that repetitive behaviors deplete local energy resources in specific brain regions, ultimately leading to behavioral exhaustion. Wang will combine different mouse models with repetitive behaviors, and assess metabolic and energetic states using metabolomics and imaging. Wang’s studies will provide novel insight into behavioral fatigue, and may inform on better intervention strategies.

Multifunctional RNA-binding transcription factors coordinate cell states in development

Human development at the earliest stages is a complicated process with many intrinsic and extrinsic cell signals. For her fellowship, Dr. Bailey Weatherbee will investigate the molecular mechanisms of lineage-defining transcription factors that enable early embryonic development.

During her Ph.D. research in Dr. Magdalena Zernicka-Goetz’s lab at the University of Cambridge, Weatherbee developed a cellular model of the human post-implantation embryo. By combining various types of stem cells made by turning on certain genes, she created cell clusters that mimic important stages of early embryo development. Furthermore, Weatherbee used cell models and embryos to investigate the requirement of specific signaling pathways for different cell types in early development. These studies are a major step forward in modeling the earliest steps in embryonic development and will enable numerous follow-up studies by the broader scientific community.

Now, in Dr. Aaron Zorn’s lab at Cincinnati Children’s Hospital, Weatherbee will investigate the molecular mechanisms of two critical lineage-defining transcription factors (TFs). She hypothesizes that in addition to their canonical DNA-binding activities, binding to RNA is also crucial for their function. Weatherbee will use cell and animal models to evaluate the developmental significance of TF-RNA interactions and identify partner proteins that mediate their function. Since mutations that impact RNA regulation occur in several congenital diseases and cancers, Weatherbee anticipates that her findings will inform on novel therapeutic strategies to treat these conditions.