Directory - Jane Coffin Childs Memorial Fund

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Eric C. Birgbauer, Ph.D. Jane Coffin Childs Fellow

University of California, Irvine

Project Title: Patterning and segmentation in the nervous system

Kivanc Birsoy, Ph.D. Jane Coffin Childs - Anna Fuller Fellow

Whitehead Institute

Project Title: Diet-dependent regulation of tumor growth through stroma metabolism

Amir Bitran, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley

Project Title: An unprecedented atomistic picture of co-translational protein folding

The majority of functions we associate with living thing are made possible thanks to the molecular functions of proteins. Proteins, just like cars and other macroscopic machines, require a specific 3D structure in order to be able to perform their functions and improper protein folding is linked to diseases cut as Alzheimer’s, Parkinson’s, and various cancers. Yet despite decades of research, we still do not understand how proteins fold up into these structures, and what determines whether folding ultimately proceeds correctly—these questions are not addressed by structure-prediction algorithms such as DeepMind’s AlphaFold. It is crucial that we make progress on these issues if we are to rationally design treatments for misfolding diseases, and to predict evolution of organisms, which is often mediated by changes to protein folding and function.

All proteins are made up of one or more chains of amino acids. For some proteins, the physical and chemical interactions between these amino acids are entirely sufficient to drive protein folding into correct native structure. But growing evidence suggests that, for many other proteins, these interactions instead cause the amino acid chain to misfold into non-functional molecular structures. A major goal of my research is to understand how this conundrum is resolved in the complex cellular environment.

One possible resolution to this issue may lie in the fact that, in addition to folding, a protein molecule needs to be synthesized one amino acid at a time by the ribosome. It turns out that many proteins can start folding as they are being synthesized, a process known as co-translational folding which has been shown to significantly increase the odds that certain proteins fold correctly. Indeed, many proteins contain evolutionarily conserved slowdowns in their rate of synthesis at chain lengths corresponding to putative co-translational folding intermediates, indicating it is broadly useful to modulate synthesis rates to give time for co-translational folding. This is akin to how dance (analogous to a chain’s folding) is closely linked to musical rhythm (how quickly amino acids are added)—I may have taken this analogy a bit too far and written a musical piece inspired by it (The Dance of the Nascent Chain).

My research aims to develop a detailed molecular picture of this process, and why it is beneficial to fold co-translationally for many proteins, by combining in vitro and in vivo experimental techniques, physics theory and atomistic simulations. In the future, this interdisciplinary pipeline can also be applied to investigate additional complex processes in the cell including mechanisms of misfolding in disease.

Joshua C. Black, Ph.D. Jane Coffin Childs Fellow

Massachusetts General Hospital

Project Title: Histone lysine tri-demethylases regulate cell cycle progression

I am studying how chromatin structure contributes to transcription, DNA replication, differentiation and maintaining genome stability.¬† My research is focused on how the JMJD2 family of histone tri-demethylases are involved in regulating these processes.

I received BS degrees in biology and chemistry/biochemistry from Worcester Polytechnic Institute, where I became interested in understanding how the expression of genes was controlled to coordinate differentiation and development.¬†¬† I received my PhD at UCLA where, in Michael Carey’s laboratory, I developed a reconstituted chromatin system to begin to elucidate the biochemical events required prior to gene transcription.¬† My research uncovered an interaction between the critically important Mediator co-activator complex and the chromatin regulator p300. In post-doctoral work in the laboratory of Jonathan Whetstine, I am studying how the JMJD2 family of histone tri-demethylases regulates chromatin structure and gene expression.¬† I have uncovered an important role for one of these enzymes, JMJD2A, in DNA replication and cell cycle progression.¬† Since these enzymes are amplified in numerous cancers and important for maintaining genomic stability, this work has potential to lead to new cancer therapies.

Lindsay W. Black, Ph.D. Jane Coffin Childs Fellow

University of Geneva

Project Title: Mechanisms for the assembly of bacteriophage +4

Helen E. Blackwell, Ph.D. Jane Coffin Childs Fellow

Harvard University

Project Title: Explore Fas signaling with a synthetic trimerizer

John Blair, Ph.D. Jane Coffin Childs Fellow

New York Genome Center

Project Title: A novel single-cell phospho-protein and chromatin accessibility assay

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

Laura Blasco-Chamarro, Ph.D. Hope Funds for Cancer Research-Jane Coffin Childs Fellow

Dana-Farber Cancer Institute

Project Title: Targeting Developmental GABAergic Signaling in Diffuse Hemispheric Gliomas with H3G34 Mutations

Pediatric brain tumors arise in the developing brain, yet how they interact and communicate with their neighboring cells to promote tumor growth is not well understood. In Laura Blasco-Chamarro’s previous research she discovered how neural stem cells pause cell division to maintain a quiescent state. Now, as a Hope Funds for Cancer Research – Jane Coffin Childs Fellow, Blasco-Chamarro will study how pediatric brain tumors, called gliomas, misuse normal developmental programs to trigger abnormal cell division.

As a graduate student in Isabel Fariñas’ lab at the University of Valencia, Blasco-Chamarro explored how localized cues support neural stem cell (NSC) quiescence. She found that in response to a specific signal, NSCs secrete a supportive material, called the extracellular matrix (ECM) that induces quiescence. This matrix then activates specific proteins called YAP and TAZ, which move into the nucleus and turn on genes that reinforce the resting state. Her work showed how a cell’s environment can push neural stem cells toward staying inactive.

In Dr. Mariella Filbin’s lab at Dana-Farber Cancer Institute, Blasco-Chamarro will study the opposite process: how pediatric high-grade gliomas activate developmental signaling to keep dividing. She will map how tumor cells interact with surrounding cells in the tumor microenvironment and identify the signals that promote tumor growth. She expects that blocking these support signals could slow or stop tumor growth. This research could lead to new treatments for pediatric high-grade gliomas and offer a broader strategy for targeting similar, lineage-specific signaling pathways in other cancers.

Richard A. Block, Ph.D. Jane Coffin Childs Fellow

University of Colorado, Boulder

Project Title: Characterization of E coli translational mutants

Steven M. Block, Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: Measurement of myosin movement along actin filaments

Kerry S. Bloom, Ph.D. Jane Coffin Childs Fellow

University of California, Santa Barbara

Project Title: Protein binding to yeast centromeric DNA

David E. Boettiger, Ph.D. Jane Coffin Childs Fellow

Cancer Research UK (CRUK)

Project Title: Virions of RNA tumor viruses

Aparna B. Bohil, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: ParM plays a central role in bacterial plasmid segregation

Kenneth Adam A. Bohnert, Ph.D. Jane Coffin Childs Fellow - Calico

University of California, San Francisco

Project Title: Germline rejuvenation in C. elegans

The survival of a species requires that age must be reset with each generation. How germ cells, the reproductive cells of animals, accomplish this feat remains a fundamental, unsolved question in biology.

Utilizing the genetically-tractable nematode¬†Caenorhabditis elegans,¬†my research aims to identify mechanisms that cleanse the germ lineage of cellular damage and thereby allow for trans-generational rejuvenation. As a JCC fellow in Dr. Cynthia Kenyon’s lab, I have uncovered a regulatory switch that links damage elimination to fertilization and establishes a clean slate for the next generation prior to embryogenesis. Currently, I am exploring the molecular underpinnings of this switch in more detail.

Because molecules that ensure the immortality of the germ lineage might be capable of rejuvenating diverse cell types, I am also testing whether these natural age-reversal strategies can be co-opted in somatic tissues. If so, mechanisms important for germline immortality might provide a promising entry point for reversing whole-organism aging.

Alexandre Bolze, Ph.D. Jane Coffin Childs - HHMI Fellow

University of California, San Francisco

Project Title: Regulation of gene expression by ribosomal proteins

Annalise Bond, Ph.D. Jane Coffin Childs Fellow

Salk Institute for Biological Studies

Project Title: Hypothalamic inflammation and metabolism in sepsis outcomes

There are two ways the body survives an infection, the immune system can kill the germ, or the body can reduce harm from the infection even if the germ isn’t eliminated.
Annalise Bond, Ph.D., created a new research tool during her Ph.D. that improved our understanding of how immune cells identify and destroy targets. As a Jane Coffin Childs Fellow, she will now focus on the second strategy—helping the body tolerate infection and limit damage, known as “cooperative defense”.

During Bond’s graduate work in Meghan Morrissey’s lab at UC Santa Barbara, she studied how macrophages (immune cells that act as the first responders) pick out pathogens among many healthy cells. She realized that the field lacked a tool to precisely control the duration and intensity of macrophage signaling, so she designed a synthetic, light-activated switch to turn on the signal. Using it, she showed that earlier activation can “prime” macrophages to engulf more of their target (in her experiments, cancer cells). She also found this priming works through a fast mechanism and a longer-lasting one, making the effect both quick and durable. These insights could help researchers design better ways to regulate immune responses, including against cancer.

Much less is known about the mechanisms of cooperative defense, which also means that this strategy remains essentially untapped in terms of therapeutic interventions. Dr. Bond will shift her studies to cooperative defense in Janelle Ayres, Ph.D.’s lab at the Salk Institute using a mouse model of sepsis. By analyzing neural-system signaling that correlates with survival, Bond is uncovering how the nervous and immune systems communicate to help the host survive an infection. In addition to discovering fundamental principles about cooperative defense, her work may lead to new ideas for improving outcomes for people with sepsis.

David S. Booth , Ph.D. Jane Coffin Childs - Simons Foundation Fellow

University of California, Berkeley

Project Title: Genetic regulation of multicellularity in a close relative to metazoans

The evolution of regulatory mechanisms to coordinate multicellular development was critical to the origin of animals. Fundamental mechanisms that led to animal multicellularity may also be conserved in the closest living relative of animals, the choanoflagellates, since one species, Salpingoeca rosetta, can transition to a multicellular form called a rosette in a process that is reminiscent of early embryogenesis in animals. To uncover how this multicellular transition is controlled in S. rosetta, we are establishing transgenic and genomic methods that will enable investigating how genes coordinate rosette development. These advances will provide essential tools for exploring the molecular biology of these ecologically and evolutionarily important organisms and potentially illuminate the earliest stages of animal evolution and development.

William R. Boram, Ph.D. Jane Coffin Childs Fellow

University of Washington

Project Title: Molecular analysis of yeast DNA

Image of Marcus W. Bosenberg, M.D.,Ph.D.

Marcus W. Bosenberg, M.D.,Ph.D. Jane Coffin Childs Fellow

University of Wisconsin, Madison

Project Title: Characterization of signal transductions

Alfred LM. Bothwell, Ph.D. Jane Coffin Childs Fellow

Cold Spring Harbor Laboratory

Project Title: kPost-transcriptional controls of animal viruses

Margot Bowen, Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: Consequences of P53 activation during development

The p53 protein is a transcription factor that becomes activated in response to various cellular stress cues. Once activated, p53 induces target genes involved in apoptosis, cell cycle arrest, senescence and differentiation. Maintaining the correct levels of p53 is critical, since loss of p53 promotes cancer, while increased p53 activity promotes developmental defects and premature aging. To further define the consequences of increased p53 activity, the Attardi lab created a novel mouse model in which p53 is activated during embryogenesis. Intriguingly, this led to a variety of craniofacial and cardiovascular defects. This unique constellation of phenotypes is reminiscent of human CHARGE syndrome, which is caused by mutations in CHD7. I am now using our p53 mouse models to study the cellular and molecular mechanisms by which p53 promotes features of CHARGE syndrome. These studies will further our understanding of p53 as a mediator of developmental disease in addition to its role as a tumor suppressor.

Bruce A. Bowerman, Ph.D. Jane Coffin Childs Fellow

Fred Hutchinson Cancer Center

Project Title: Early determinants of neuronal fate in the nematode

Julianna Bozler, Ph.D. Jane Coffin Childs Fellow

University of Pennsylvania

Project Title: Molecular regulation of behavioral and reproductive plasticity in ants

Image of Thomas J. Braciale, M.D., Ph.D.

Thomas J. Braciale, M.D., Ph.D. Jane Coffin Childs Fellow

Australian National University

Project Title: Cell-mediated cytotoxicity to influenza virus

Robert W. Brackenbury, Ph.D. Jane Coffin Childs Fellow

Rockefeller University

Project Title: Molecular mechanisms of cell-cell interactions

J. Michael Bradshaw, Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: Calmodulin binding and trapping by CaM kinase II

Colleen Brady, Ph.D. Jane Coffin Childs - HHMI Fellow

Massachusetts General Hospital

Project Title: Driving differentiation of retinal glia

William A. Braell, Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: ATP-dependent clathrin disassembly

Julian R. Braxton, Ph.D. Jane Coffin Childs Fellow

California Institute of Technology

Project Title: Defining the role of protein homeostasis in spermatogenesis

Traditionally, structural biology efforts have been limited to studying purified samples in isolation. While we have learned a great deal via these efforts, such approaches unfortunately strip away much of the biological context from the sample of interest.

Dr. Julian Braxton will overcome these limitations by using cryo-electron tomography (cryo-ET) to examine proteostasis, or the process by which cells maintain the proper balance, folding, and function of proteins, within sperm cells in Dr. Zhen Chen’s lab at the California Institute of Technology. Proteostasis plays important yet understudied roles in cellular development processes, as the proteome must be reprogrammed to enable new functions. Braxton will apply cellular cryo-ET to analyze such developmental processes in mammalian sperm, where highly specialized functional compartments are assembled. This research will provide foundational understanding into the posttranslational regulation of sperm maturation and expand the frontier of cryo-ET development and analysis.

Braxton’s expertise in proteostasis stems from his graduate studies in Dr. Daniel Southworth’s lab at the University of California, San Francisco. There, Braxton used the related structural technique cryo-EM to reveal the intricate details of how the autophagy-related adapter UBXD1 regulates the hexameric AAA+ chaperone p97. His findings revealed that UBXD1 separates two adjacent p97 protomers to open the p97 ring, allowing for a new mode of substrate entry and/or exit into the p97 central pore. In a related project, Braxton revealed a novel asymmetric state of the mitochondrial chaperone Hsp60 that enables client refolding. In his postdoctoral work, Braxton will expand his structural biology toolkit to include cryo-ET and use this technique to provide unprecedented insight into the role of nuclear proteasomes in spermatogenesis.

David G. Breckenridge, Ph.D. Jane Coffin Childs Fellow

University of Colorado, Boulder

Project Title: Role of mitochondria during apoptosis in C elegans

Mark SC. Bretscher, Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: Nucleic acid metabolism and protein synthesis

Joshua Brickner, Ph.D. Jane Coffin Childs Fellow

Stanford University

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

Eve B. Briles, Ph.D. Jane Coffin Childs Fellow

Washington University in St. Louis

Project Title: Mitogenic effects of certain lectins

Hugh W. Brock, Ph.D. Jane Coffin Childs Fellow

University of Washington

Project Title: Dosage compensation in Drosophila LSPI-alpha genes

Danielle Brotto, Ph.D. Jane Coffin Childs Fellow

University of Minnesota, Twin Cities

Project Title: The role of the

Human chordoma is a locally aggressive and invasive type of cancer that occurs in the bones of the skull base and spine, and it is part of a group of malignant bone and soft tissue tumors called sarcomas. It is characterized by high recurrence rates and a lack of chemotherapy response. Although studies using exome sequencing identified a few genetic alterations, the vast majority of chordomas do not appear to have a causal genetic mutation, given that the overall somatic mutation burden in chordoma is modest. Recently, the Chordoma Genome Project provided essential clues about novel genes implicated in chordoma tumorigenesis. DNA sequencing revealed that mutations in the gene encoding the lysosomal trafficking regulator protein (LYST) have a role in chordoma biology, as recurrent truncating mutations were found in 10% of tumors. Our lab has preliminary data suggesting that epigenetic regulation of LYST leads to a clinically aggressive chordoma variant, marked by reduced survival and a high rate of metastasis. Herein, this research focuses on elucidating the mechanisms of epigenetic regulation of chordoma-related genes, like LYST, by applying chromosome conformation capture and protein-DNA interaction techniques. Initial findings have shown differences in chromatin accessibility and conformation between tumor subtypes, suggesting an association with the patient’s prognosis.

Nicholas G. Brown, Ph.D. Jane Coffin Childs - HHMI Fellow

St. Jude Children's Research Hospital

Project Title: Anaphase-promoting complex ubiquitination mechanisms

Breann L. Brown, Ph.D. Jane Coffin Childs - Frederic M. Richards Fellow

Massachusetts Institute of Technology

Project Title: Elucidating the role of the E. coli Lon protease N-domain in substrate recognition and discrimination

My primary research interest is studying the molecular basis of the diverse protein-protein interactions that underlie bacterial cell signaling. I am currently focusing on determining the various types of substrate interactions mediated by the E. coli Lon protease to understand how this critical regulator degrades certain proteins during cellular stress. Lon is one of the major proteases that mediates protein quality control via degradation of over half of the unfolded or misfolded proteins in the cell. Additionally, Lon degrades stably-folded regulatory proteins involved in response to several stresses such as DNA damage, heat shock, and oxidation. Using a combination of biophysical and biochemical assays, including electron microscopy, X- ray crystallography, analytical ultracentrifugation, and enzyme kinetics, my current goal is to identify the molecular interactions critical for Lon self-assembly and substrate recognition. With this detailed information, we can begin to understand in greater detail how Lon discriminates among various substrates to regulate critical cellular stress responses and survival.

Kathryn A. Brozek, Ph.D. Jane Coffin Childs Fellow

University of Oregon

Project Title: Receptor-mediated signal transduction in yeast

Peter Bruno, Ph.D. Jane Coffin Childs - HHMI Fellow

Brigham and Women's Hospital

Project Title: The role of ZNF292 in senescence and tumorigenesis

Senescence is an irreversible cell state characterized by permanent exit from the cell cycle that occurs in response to cellular stresses such as shortened telomeres and DNA damage. Thus, senescent cells accumulate as an organism ages and are thought to contribute to the gradual decline in tissue function as we age. Importantly, elimination of senescent cells in old mice extends healthy lifespan. Therefore, achieving a better understanding of the genetic underpinnings of senescence can lead to improved prevention and treatment of aging-related diseases._x000D_
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It is currently thought that senescence is mediated by three distinct pathways, characterized by their primary facilitators: p53, p16 and GATA4. However, there are likely many more factors that are critical to senescence induction. Thus, we conducted a whole genome CRISPR screen for genes necessary for replicative senescence in IMR90 primary fibroblasts. One novel gene identified was ZNF292. Thus, the objective of my postdoctoral work is to gain a more thorough understanding of the role of ZNF292 in senescence and tumorigenesis._x000D_
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James P. Bruzik, Ph.D. Jane Coffin Childs Fellow

Harvard University

Project Title: D. melanogaster tra-2 function in the male germ line

Robert E. Bryant, Ph.D. Jane Coffin Childs Fellow

Yale University

Project Title: Quantitation of chromosomal content in cell fusion hybrids

Elizabeth A. Bucher, Ph.D. Jane Coffin Childs Fellow

Princeton University

Project Title: Genetic and molecular analysis of C. elegans lineages

Paula Bucko, Ph.D. Jane Coffin Childs Fellow

Harvard Medical School

Project Title: The role of p53 dynamics in immune cell regulation

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

Ahmad I I.. Bukhari, Ph.D. Jane Coffin Childs Fellow

Cold Spring Harbor Laboratory

Project Title: Temperate phage Mu-1 in chromosome replication

Ahmad I. Bukhari, Ph.D. Jane Coffin Childs Fellow

Cold Spring Harbor Laboratory

Project Title: Temperate phage Mu-1 in chromosome of E. coli

Nathan P. Bullen, Ph.D. Jane Coffin Childs Fellow

University of Colorado, Boulder

Project Title: 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.