Directory

Yogesh Goyal Jane Coffin Childs Fellow

University of Pennsylvania
Appointed in 2018

Sponsor: Arjun Raj

Resistance to therapy is a hallmark of many cancers (e.g. melanoma). Advancements in quantitative single-cell biology has allowed characterization of pre- and post-therapy melanoma cells with unprecedented resolution. Specifically, recent studies have demonstrated that rare populations of preresistant melanoma cells exhibit non-genetic plasticity such that they occupy a transient state capable of withstanding drug treatment, but can be reprogrammed into a stable drug-resistant state upon drug addition. While this provides novel opportunities to tackle resistance, we still lack information on different cellular states and the underlying molecular mechanisms of transition between states. The first aim of this proposal is to develop a theoretical and conceptual understanding on the origins of transient, rare preresistant populations. The second aim focusses on developing an experimental data-driven computational framework to dissect the genetic networks in the pre- and post-resistant states. The last aim proposes developing stochastic population dynamics models to track cells at multiple timescales, and inform on rational drug dosing strategies. The eventual goal is to integrate the network models with the population level model, thus allowing multiscale analysis of regulation in melanoma. Together, my work will develop quantitative frameworks to systematically characterize the cellular landscapes guiding plasticity and reprogramming paradigms for therapy resistance.

Thomas Graham Jane Coffin Childs - Merck Fellow

University of California, Berkeley
Appointed in 2018

Sponsor: Xavier Darzacq and Robert Tjian

The different cell types in our body have an incredible variety of sizes, shapes, and functions, despite having the same genome. Differences between cell types arise from differences in which genes are transcribed into RNA. Transcription is regulated by DNA sequences called enhancers, which in some cases are located hundreds of thousands of basepairs away from their target genes. While we know the identities of many of these enhancers, and the proteins that bind to them, we lack a coherent model of how enhancers regulate transcription. Various lines of evidence suggest that large protein complexes form a bridge between enhancers and their target promoters. However, we lack a basic understanding of the composition, size, and internal organization of these enhancer-promoter complexes. Important questions are: 1) How many copies of different proteins assemble at enhancers and promoters? 2) What protein-protein and protein-DNA interactions are important for assembling enhancer-promoter complexes? 3) How dynamic are these complexes? 4) How do enhancer-promoter complexes ultimately regulate transcription? To address these questions, I am working to develop new fluorescence imaging approaches in live cells, which will combine fluorescent labeling of DNA, RNA, and protein with new technologies such as single-molecule tracking and lattice light sheet microscopy.

Adam Granger Jane Coffin Childs - HHMI Fellow

Harvard University Medical School
Appointed in 2014

Sponsor: Bernardo Sabatini

Neurons are typically thought to release a single fast neurotransmitter, though a growing number of examples of neurotransmitter corelease are being discovered. Our lab has found preliminary evidence that the acetycholine (ACh) releasing neurons of the basal forebrain (BF) also release GABA. The BF is the primary source of Ach neurotransmission throughout the central nervous system, and is responsible for modulating attention, arousal, and the cognitive deficits that underlie Alzheimer’s disease. In this proposal, I outline a research plan to characterize the extent of GABA/ACh corelease from BF neurons throughout the cortex. I will then explore the presynaptic mode of ACh/GABA corelease to determine if they are released from the same or separate populations of synaptic vesicles. Finally, I will test the functional importance of this projection in shaping cortical activity by performing in vivo recordings from the cortex awake, behaving mouse during optogenetic activation of ACh-releasing BF neurons. The contribution of GABA will be explored by comparing recordings from wild-type mice with mice that lack GABA release specifically in ACh-releasing BF neurons. The results of these experiments will provide novel insight into the role of GABA/ACh corelease for BF function.

Ethan Greenblatt Jane Coffin Childs Fellow

Carnegie Institute for Science
Appointed in 2013

Sponsor: Allan Spradling

Aging is characterized by a progressive decline in tissue physiology. The reasons for this decline, whether antagonistic pleiotropy, error catastrophe, or developmental programming, have been difficult to pinpoint. Likewise, which cell types and subcellular components are the most important targets of decline remain hotly debated. I have long been interested in aging despite its acknowledged difficulty as a research topic. The submitted proposal describes my strategy for testing ideas and approaches that I believe have the potential to greatly advance this field, and to launch my career as an independent investigator. My approach involves a novel system in which to study aging – the Drosophila follicle stem cell lineage, and a novel hypothesis regarding a primary target of the aging process – the epigenetic system of the cell nucleus.

Abigail Groff Jane Coffin Childs Fellow

Whitehead Institute for Biomedical Research
Appointed in 2019

Sponsor: David C. Page

Abbie Groff studies sex differences at the earliest stages of development in Dr David Page’s laboratory at the Whitehead Institute.

Differences between the sexes start only a few cell divisions after conception. XY (‘male’) embryos tend to develop more quickly than XX (‘female’) embryos, reaching the blastocyst stage faster and with more cells. Prior studies have also reported various metabolic differences between the sexes in preimplantation development across multiple mammalian species. Since these cells have never been exposed to sex hormones, and the conditions of their culture are highly controlled, these differences must be due to the gene content and regulatory influence of the sex chromosomes. However, the transcriptional underpinnings of these differences are unclear.

Abbie’s work focuses on characterizing gene expression differences between 46,XX and 46,XY cells in preimplantation human development at single-cell resolution. Using this system, Abbie seeks to understand the specific contributions of the sex chromosomes to gene expression during the first cell divisions, and also chart the influence of nascent X chromosome inactivation on genome-wide expression changes.

Beyond explaining current “known” physiological sex differences at this developmental stage, she anticipates this work may provide insight into the development of sex biased phenotypes at later developmental stages, such as the predominance of disorders of placental dysfunction, including pre-eclampsia, in pregnancies with a male fetus.

Joshua Gruber Jane Coffin Childs Fellow

Stanford University
Appointed in 2015

Sponsor: Michael Snyder

Through my clinical work with oncology patients I became acutely aware of how few interventions we are able to offer patients to prevent cancer.  Even patients with inherited syndromes that confer a near-certainty of developing cancer have few, often unappealing, options to actually prevent cancer.  This motivated me to investigate molecular mechanisms of the earliest steps of malignant transformation.  I chose to study the genes causing inherited breast cancer because each one constrains the malignant phenotype of breast cells, an effect that can be modeled in vitro._x000D_
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These ideas led me to team up with my advisor Dr. Michael Snyder at Stanford who has pioneered multiple high-throughput omics technologies to densely profile biological systems.  These tools allow for an unprecedented window into cellular dynamics driving malignant transformation.  I am particularly interested in how genomic aberrations in non-coding DNA elements can unlock transcriptional programs that drive malignancy.  The hope is to uncover molecular switches that can be targeted to prevent cancer onset.

Liangcai Gu Jane Coffin Childs - HHMI Fellow

Harvard University Medical School
Appointed in 2009

Sponsor: George Church

Current research: Developing a next-generation protein display technology which allows high-throughput screening of gene functions and protein-protein interactions by coupling the cell-free protein synthesis, high-resolution imaging and next-generation DNA sequencing technologies.

I received my B.S. in chemistry and my M.S. in biochemistry and molecular biology in my home country of China, and my Ph.D. in medicinal chemistry in 2008 from the University of Michigan. Between 2004 and 2009, working with Professor David Sherman, I identified and characterized a whole set of novel enzymes involved in the curacin A biosynthesis. Currently, I am learning DNA tricks in Professor George Church’s lab. I am deeply interested in both technology development and answering fundamental biological questions, and look forward to a synergy between them in my future career.

Chantal Guegler, Ph.D. Jane Coffin Childs - Merck Fellow

Harvard University Medical School
Appointed in 2023

Sponsor: Dr. L. Stirling Churchman

mRNA degradation is an important step in gene expression that is traditionally thought to occur in the cytoplasm. However, a recent genome-wide study uncovered a class of genes whose transcripts are predicted to be primarily degraded in the nucleus. Yet, it is unclear how and why these mRNAs undergo nuclear degradation. Dr. Chantal Guegler will use both candidate- and screening-based approaches to determine which pathways are important for nuclear mRNA degradation, and how this process influences cellular physiology. Dr. Guegler will conduct this research in Dr. Stirling Churchman’s lab at Harvard Medical School. This work will reveal the key determinants of nuclear mRNA degradation and how this process contributes to gene expression regulation.

As a graduate student, Guegler studied bacterial toxin-antitoxin (TA) systems and their role in protecting against bacteriophage infection in Dr. Michael Laub’s lab at the Massachusetts Institute of Technology. There, Dr. Guegler demonstrated that the RNase toxin ToxN cleaves phage mRNAs to disrupt the translation and assembly of viral particles. Interestingly, Guegler also demonstrated that T4 phage can combat ToxN using the phage-encoded antitoxin TifA that sequesters RNA-bound ToxN to prevent it from degrading additional phage mRNAs. With her background in RNA degradation in bacterial TA systems, Dr. Guegler will now investigate nuclear mRNA degradation in eukaryotic cells.

Shawna Guillemette Jane Coffin Childs Fellow

Brigham and Women's Hospital
Appointed in 2015

Sponsor: Stephen Elledge

The majority of cancer therapeutics currently used result in DNA damage that can trigger cell death or senescence in cancer cells and in healthy neighboring cells.   Understanding how transformed cells and otherwise healthy cells induce or evade senescence pathways in response to cancer therapies is the major interest of my research in order to better understand therapeutic resistance mechanisms._x000D_
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I was born and raised in New Hampshire and received my BS in biochemistry from the University of Vermont.  My research career started in Jim Vigoreaux’s lab where I investigated mechanisms of energy transport in Drosophila flight muscle. As a graduate student in Sharon Cantor’s lab at the University of Massachusetts Medical School I studied DNA repair pathways and mechanisms that lead to chemo-resistance in hereditary forms of ovarian cancer.  Currently, I am working with Dr. Stephen Elledge in the Department of Genetics at Harvard Medical School. Here I aim to elucidate the molecular circuitry that controls cellular senescence.

Nicola Guzzi, Ph.D. Jane Coffin Childs - HHMI Fellow

Rockefeller University
Appointed in 2021

Sponsor: Elaine Fuchs

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

Christine Hagan Jane Coffin Childs - Merck Fellow

Harvard University Medical School
Appointed in 2013

Sponsor: Marc Kirschner

Signaling between cells through the Wnt pathway critically affects cell fates during embryonic development and in disease states, such as cancer. Many of the components of the Wnt pathway have been identified, and it is known that activation of the pathway ultimately leads to the cytoplasmic accumulation of beta-catenin, which then promotes transcription of a set of target genes. However, the molecular mechanism of signal transduction that leads to the increase in beta-catenin is not clear. I propose to identify the specific roles of the upstream components of the pathway in regulating its activity by determining the sequence of protein recruitment, phosphorylation, and oligomerization events that occur on the Wnt membrane receptors in vivo by immunoprecipitation and blue native gel assays. This part of the pathway will then be reconstituted in vitro with purified membrane receptors and cell extracts so that the individual protein binding and phosphorylation steps can be separated by removing or mutating components, and their effect on beta-catenin degradation can be directly assessed. These experiments will thereby elucidate how the different proteins contribute to initiating or modulating the Wnt signal and may identify ways of interfering with the pathway that would be therapeutically useful.

Jennifer Hamilton Jane Coffin Childs Fellow

University of California, Berkeley
Appointed in 2019

Sponsor: Jennifer Doudna

CRISPR-Cas genome editing enables control of gene expression in cells, tissues and whole organisms. Although invaluable for experimental studies, translation of these advances into clinical therapeutics requires delivery of CRISPR-Cas proteins and guide RNA to disease-relevant organs in the body. Current in vivo delivery strategies have drawbacks including ineffective delivery to target tissue, prolonged nuclease expression leading to off-target damage, and clearance of edited cells by adaptive immune responses.

My research leverages viral infection strategies to overcome the challenges faced by the in vivo delivery of genome editing tools. In the Doudna laboratory, I am applying my background in engineering enveloped viruses to create the next-generation of CRISPR-Cas delivery vehicles and translate these technologies into therapeutics. By merging virology with bioengineering, I aim to both better understand the cellular response to genome editing and, ultimately, to make genome-based treatments accessible to all people who can benefit.

Tina Han Jane Coffin Childs - Simons Foundation Fellow

University of California, San Francisco
Appointed in 2013

Sponsor: Lily Jan

I study the role played by TMEM16F, a phospholipid scramblase, in the generation of extracellular vesicles. TMEM16F is a transmembrane protein found in a family of calcium-activated chloride channels (CACCs). Mutations in TMEM16F cause a rare bleeding disorder called Scott Syndrome in which patients are deficient in platelet coagulant activity. Interestingly, 16F and four other members in this family have been implicated as phospholipid scramblases by disrupting plasma membrane asymmetry upon calcium activation. This is presumed to be a prerequisite step in the generation of extracellular vesicles, which are believed to deliver RNA and protein cargo as a form of cell-to-cell communication. It is also unclear whether TMEM16 proteins are themselves scramblases or how the protein might achieve bilateral phospholipid transport.