Directory - Jane Coffin Childs Memorial Fund

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Saskia B. Neher, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Study of mechanisms ensuring productive SRP targeting

Joseph E. Neigel, Ph.D. Jane Coffin Childs Fellow

University of California, Los Angeles

Project Title: Cell-cell recognition

Keats A. Nelms, Ph.D. Jane Coffin Childs Fellow

National Institute of Allergy and Infectious Diseases

Project Title: Molecular interactions in the IL-4 receptor signaling pathway

James W. Nelson, Ph.D. Jane Coffin Childs - HHMI Fellow

Broad Institute

Project Title: Continual evolution of proteins in eukaryotes

New methodologies are needed to develop the next-generation of macromolecular human therapeutics that have the potential to improve our ability to treat diseases. Continuous directed evolution techniques such as phage-assisted continuous evolution (PACE) have demonstrated a transformative ability to access_x000D_
biomolecules with therapeutically relevant properties that could not have been readily accessed using conventional protein evolution methods, including improved genome editing agents, and proteases reprogrammed to cleave proteins implicated in human disease. However, PACE is greatly constrained by the requirement that it be performed in Escherichia coli, thereby precluding its application to solve important problems that require eukaryotic infrastructure, such as post-translational modification,_x000D_
chaperones that are not found in E. coli, chromatin editing or modification, subcellular localization, or organelles. I propose to design and execute a system for the continuous evolution of biomolecules in yeast, enabling access to many of these important selections. We will use this system to evolve versions of the E3 ligase MDM2 that exclusively target mutant, but not wild-type p53, for ubiquitination and degradation, demonstrating the power of eukaryotic continuous evolution to evolve proteins that are_x000D_
inaccessible to PACE, as well as generating a novel potential research tools and leads for future cancer therapeutic development.

Hillary CM. Nelson, Ph.D., MPH Jane Coffin Childs Fellow

Medical Research Council (MRC),UKRI

Project Title: Mutagenic analysis of nucleosome positioning

Scott W. Nelson, Ph.D. Jane Coffin Childs Fellow

Pennsylvania State University

Project Title: Kinetics and mechanism of lesion bypass

Alexandre Neves, Ph.D. Jane Coffin Childs Fellow

Fred Hutchinson Cancer Center

Project Title: Modeling Myc-induced tumorigenesis in Drosophila

Joseph R. Nevins, Ph.D. Jane Coffin Childs Fellow

Rockefeller University

Project Title: Messenger RNA

Walter Newman, Ph.D. Jane Coffin Childs Fellow

Albert Einstein College of Medicine

Project Title: Properties of products of activated lymphocytes

Berne L. Newton, M.D. Jane Coffin Childs Fellow

Yale University

Project Title: Heterologous transplantation of tumors

KangBo Ng, Ph.D. Robertson Foundation-Jane Coffin Childs Fellow

Whitehead Institute for Biomedical Research

Project Title: Mechanisms and functions of soma-to-germline mitochondrial transfer

KangBo Ng, Ph.D., has long been fascinated by how somatic cells, the non-reproductive cells of the body, and germ cells, the reproductive cells, work together to ensure the proper development of an organism. During his graduate research, Ng studied how these cells organize themselves in space to build the embryo. Now, as a Robertson Foundation – Jane Coffin Childs Fellow, Ng will investigate how somatic and germ cells exchange metabolic resources to help kick-start embryonic development.

Ng’s thesis research in Nathan Goehring’s lab at the Francis Crick Institute addressed how cell polarity shapes animal development. Because polarity systems are used across many different cellular contexts, they must be able to respond sensitively to spatial cues while still producing stable outcomes. Ng demonstrated that oscillatory polarity feedback, coupled to the cell cycle, allows cells to resolve these seemingly contradictory requirements. He also found that mechanical flows generated during cell division can directly transport polarity proteins to organize the embryo. Altering these flows changed division patterns, suggesting a simple mechanism by which embryos could generate different body plans.

In Ruth Lehmann’s lab at the Whitehead Institute, Ng will focus on metabolic communication between somatic and germ cells. Germ cells switch between phases of rest, division, and quality control, and somatic cells appear to help control these transitions, but the underlying mechanism remains unclear. Ng hypothesizes that somatic cells may orchestrate these processes by transferring metabolic resources to germ cells. His work could reveal new principles of embryo development and inform future research into reproductive health.

Jordan Matthew. Ngo, Ph.D. Robertson Foundation-Jane Coffin Childs Fellow

California Institute of Technology

Project Title: Molecular mechanisms of de novo peroxisome biogenesis

Jordan Ngo, Ph.D. is interested in uncovering the mechanistic principles that govern organelle biogenesis and membrane assembly in both normal physiology and human disease. As a graduate student, Ngo provided important insight into how extracellular vesicles are formed and how the plasma membrane is repaired. As a Robertson Foundation – Jane Coffin Childs Fellow, Ngo will continue to study organelle biogenesis, investigating how peroxisomes, membrane-bound organelles that play essential roles in human physiology, form.

During Ngo’s thesis research in Randy Schekman’s lab at UC Berkeley, he made important discoveries around extracellular vesicles and the plasma membrane. First, Ngo discovered that exosomes, a specific subtype of extracellular vesicles, form in response to plasma membrane damage and that the protein Annexin A6 is crucial for this process. Then, he demonstrated that the selective autophagy receptor p62 is important for sorting protein and RNA cargo into exosomes. Finally, he identified sorcin as a scaffold that couples Annexin A11 recruitment to ESCRT-III assembly for plasma membrane repair.

For his Robertson Foundation – Jane Coffin Childs Fellowship in Rebecca Voorhees’s lab at Caltech, he will search for genes that control peroxisome assembly and build a new test to study how early peroxisome-related vesicles form. Because defects in peroxisome formation cause serious disorders, such as Zellweger spectrum disorders, and have been implicated in cancer progression, this work could clarify how peroxisome problems contribute to disease.

Van Q. Nguyen, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Key regulators of pathogenesis in H capsulatum

Phi Nguyen, Ph.D. Jane Coffin Childs Fellow

Columbia University /
New York State Psychiatric

Project Title: Neuronal and

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.

Shiro Nii, M.D. Jane Coffin Childs Fellow

Columbia University

Project Title: Electron microscopy

Maho Rosen. Niwa , Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: RNA function in the signal recognition particle

Steven K. Nordeen, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Gene Expression

Yitzhak Norman, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Uncovering the functional architecture of the human speech cortex

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.

Dominic P. Norris, Ph.D. Jane Coffin Childs Fellow

Harvard University

Project Title: Analysis of the control of nodal expression

Image of Abraham Novogrodsky, M.D., Ph.D.

Abraham Novogrodsky, M.D., Ph.D. Jane Coffin Childs Fellow

Albert Einstein College of Medicine

Project Title: DNA dependent RNA polymerase

Roni Nowarski, Ph.D. Jane Coffin Childs Fellow

Yale University

Project Title: Inflammasome dysregulation in colorectal tumorigenesis

Image of Kathaleen O'Connor-Giles, Ph.D.

Kathaleen O'Connor-Giles, Ph.D. Jane Coffin Childs Fellow

University of Wisconsin, Madison

Project Title: Neurogenetics of synaptic growth and plasticity

Patrick H. O'Farrell, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Segregation of chromosomal proteins

Elizabeth M. O'Neill, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Regulation of the activity of the CDK inhibitor PHO81

Andreas Obers, Ph.D. Jane Coffin Childs Fellow

Icahn School of Medicine at Mount Sinai

Project Title: Uncovering cellular stress programs governing intestinal resilience and aging

Andreas Obers, Ph.D. investigates the biological mechanisms that determine whether tissues recover after injury and inflammation or become trapped in persistent, maladaptive states that contribute to chronic disease and aging. Inspired by his graduate research showing that biological responses are shaped by local tissue environments and prior experiences, Obers now explores how a key regulator of cellular stress responses influences the balance between tissue repair and persistent dysfunction.

Obers conducted his doctoral research in the laboratories of Laura Mackay and Christoph Wilhelm through a joint program between the University of Melbourne and the University of Bonn. In his first-author work, he revealed that retinoic acid, a metabolite derived from vitamin A, shapes the durability and distribution of immune surveillance across tissues. In related work, he contributed to the discovery that immune cells occupying the same tissue can adopt distinct functional identities, allowing them to either promote tissue protection or contribute to disease.

Now in the laboratory of Shruti Naik at Mount Sinai, Obers studies a key regulator of cellular stress responses whose expression is consistently elevated in aged tissues. Although it is widely associated with aging, scientists are only beginning to explore whether it has functions beyond its classical role. By investigating how inflammation reshapes its localization and activity within cells, Obers aims to uncover how tissues transition from successful repair to persistent dysfunction and chronic disease.

Eugene Oh, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley

Project Title: Investigating the ubiquitin-dependent mechanisms that govern human stem cell maintenance and the course of neurogenesis

Ubiquitylation is a versatile post-translational modification required for most cell fate decisions. During neurogenesis, ubiquitin-dependent mechanisms ensure the irreversible transformation of neural stem cells into neurons. By contrast, the misregulation of the ubiquitylation system can set off a wide range of developmental abnormalities, from uncontrolled cell proliferation and tumor formation to neurodegeneration and cell death. Despite its medical relevance, our understanding of how ubiquitylation governs the course of human neurogenesis is far from complete. For my research fellowship, I propose to develop a large-scale screening platform to identify the ubiquitylating enzymes that promote the maintenance of undifferentiated human stem cells as well as those that facilitate the specification of neural cell fates. To better grasp the physiological parameters that underlie the directionality of cellular differentiation, I will define the collection of endogenous substrate proteins modified by the newly identified enzymes. Aside from generating a list of substrates, I aim to study the functional consequences of ubiquitylation by characterizing substrate mutants that are resistant to ubiquitylation in stem cells. Together, my results will shed light on fundamental principles of human development and potential mechanisms that cause neuronal cancers and neurodegenerative disorders.

Charles EY. Oh, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco /
California Institute of Technology

Project Title: Transcriptional regulation of the engrailed gene

Melanie Ohi, Ph.D. Jane Coffin Childs Fellow - Agouron

Harvard Medical School

Project Title: Electron microscopy of spliceosomes

Hiroto Okayama, M.D., Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: Expression of cDNAs in mammalian cells

James T. Olesen, Ph.D. Jane Coffin Childs Fellow

Harvard University

Project Title: Cloning and analysis of trans-acting factors controlling Drosophila adult Adh expression

Brian C. Oliver, Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: Fruit fly splicing mutations

Image of Kassandra M. Ori-McKenney, Ph.D.

Kassandra M. Ori-McKenney, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Modes of microtubule nucleation in Drosophila neurons

Joseph Orly, Ph.D. Jane Coffin Childs Fellow

University of California, San Diego

Project Title: Hormonal regulation of ovarian cell cycle in culture

Stephen L. Oroszlan, Ph.D. Jane Coffin Childs Fellow

National Institutes of Health

Project Title: Viral oncogenesis

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

Dana Farber Cancer Institute

Project Title: Determining the mechanism of sugar sensing in the Mondo pathway

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.

Terry L. Orr-Weaver, Ph.D. Jane Coffin Childs Fellow

Carnegie Institution for Science

Project Title: Amplification of Drosophila chorion genes

Lev Z. Osherovich, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Are protein aggregation and aging related

Jessica A. Osterhout, Ph.D. Jane Coffin Childs - HHMI Fellow

Harvard University

Project Title: Characterizing the thermoregulatory circuits that control animal behavior

Thermoregulation is fundamental for survival; even slight changes in body temperature have a dramatic effect on vital processes such as sleep, appetite, and thirst, and during an immune response, febrile patients often become fatigued, antisocial, and exhibit other sickness-related behaviors. Specific brain areas are thought to control body temperature by triggering various mechanisms that produce or dissipate heat, but how thermoregulatory neurons modulate thermo-adaptive and other behaviors is unknown. I will use recently developed tools for genetic profiling and circuit analysis to molecularly identify thermoregulatory and fever-inducing neurons and map their connectivity patterns, thereby gaining new insight into thermoregulatory circuits and how they are connected to other homeostatic and social functions in the brain.

Paul Ottolenghi, Ph.D. Jane Coffin Childs Fellow

Carlsberg Research Laboratory

Project Title: Genetic transformations in yeast

Youcef Ouadah, Ph.D. Jane Coffin Childs Fellow

California Institute of Technology

Project Title: A genetic approach to the logic and evolution of aggression circuitry

Image of Adegboyega (Yomi) K. Oyelere, Ph.D.

Adegboyega (Yomi) K. Oyelere, Ph.D. Jane Coffin Childs Fellow

Yale University

Project Title: Abiotic model for tRNA mediated polypeptide synthesis

Carl O. Pabo, Ph.D. Jane Coffin Childs Fellow

Harvard University

Project Title: Crystallographic study of bacteriophage repressors

Image of Francis Belén. Pacheco Fiallos, Ph.D.

Francis Belén. Pacheco Fiallos, Ph.D. Jane Coffin Childs Fellow

Massachusetts Institute of Technology

Project Title: Recognition and Attenuation of Pervasive Transcription by the Restrictor Pathway

Belén Pacheco-Fiallos, Ph.D. studies how gene activity is regulated. Although scientists know the structures of many individual parts, a major next step is learning how these molecular “machines” work together. In graduate school, she studied how cells export the right messenger RNAs (mRNAs) from the nucleus out of roughly 20,000 different transcripts. As a Jane Coffin Childs Fellow, she will now study how cells prevent unhelpful (“non-productive”) transcription from happening everywhere in the genome.

In Clemens Plaschka’s lab at the Research Institute of Molecular Pathology in Vienna, Austria, Pacheco-Fiallos studied selective mRNA transport via the Transcription and Export (TREX) complex. She demonstrated that TREX lives up to its name by being an enormous oligomeric complex that’s approximately 2 megadaltons in size. Using cryo-electron microscopy and tomography Pacheco-Fiallos revealed how TREX selectively recognizes mature mRNA-protein complexes for export to the cytosol and eventual translation of the transcript. Her research stresses the importance of studying molecular machines in relevant conditions and at the appropriate level of molecular complexity.

Pacheco-Fiallos will continue this approach to tackle a different selectivity problem in gene expression at Seychelle Vos’s lab at MIT. There she will study a different selectivity problem: RNA polymerase II makes full mRNAs from genes, but it also makes very short, non-coding transcripts at enhancers and promoters. How the cell stops transcription in those regions isn’t well understood. She will test whether a Restrictor complex helps recognize and shut down this inappropriate transcription, using integrative structural biology to figure out how the complex assembles and works.

Jon E . Paczkowski, Ph.D. Jane Coffin Childs Fellow

Princeton University

Project Title: Manipulating pseudomonas aeruginosa quorum-sensing to control pathogenicity

Quorum sensing is a mechanism of cell-cell communication that allows bacteria to synchronously control processes that are only productive when undertaken in unison by the collective. I will focus on Pseudomonas aeruginosa because it has a well-defined quorum sensing network that is essential for biofilm formation and virulence factor production, and because P. aeruginosa is an important pathogen that affects cystic fibrosis sufferers, cancer patients undergoing chemotherapy, burn victims, and patients with implanted medical devices._x000D_
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My work combines structural biology, chemistry, and genetics to define the mechanisms underlying activation and inhibition of quorum-sensing receptors with the aim of understanding how quorum sensing receptors accurately decode the information contained in small molecule signals to drive collective behaviors. These investigations could lead to strategies for controlling quorum sensing, potentially resulting in the development of anti-microbial drugs aimed at bacteria that use quorum sensing to control virulence and biofilm formation.