Directory - Jane Coffin Childs Memorial Fund

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Raymond E. Lockard, Ph.D. Jane Coffin Childs Fellow

Massachusetts Institute of Technology

Project Title: Sequencing of hemoglobin mRNA

Brenda S. Loewy, Ph.D. Jane Coffin Childs Fellow

Columbia University

Project Title: Developmental regulation of membrane biogenesis

David M. Logan, Ph.D. Jane Coffin Childs Fellow

National Institutes of Health

Project Title: Degradation of mRNA in E. coli

Michael R. Loken, Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: Physical and functional characteristics of purified populations of lymphocytes from mice

Zachery R. Lonergan, Ph.D. Jane Coffin Childs Fellow

California Institute of Technology

Project Title: Bacterial nitric oxide metabolism at the host-pathogen interface

Energy conservation is an organizing principle for microbial communities. This conservation becomes challenging for bacterial pathogens that must overcome the host immune response. Nonetheless, bacterial infections are major sources of morbidity and mortality, demonstrating that mechanisms exist for pathogens to persist within hosts. Within the lungs of immunocompromised individuals, immune cells are recruited to eliminate pathogens, but this recruitment is unable to clear the infection. Extreme oxygen gradients exist within the lung environment that require metabolic flexibility for bacterial pathogens to survive. While the unique metabolic sources and requirements for microbes within the lungs is not well-defined, we predict that nitrogen oxides serve an important role in supporting bacterial lung persistence. To test this hypothesis, we are implementing geochemical-based strategies to track bacterial nitrogen oxide metabolism, which will provide new conceptual and technical handles on pathogen activities within the human host.

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

Columbia University

Project Title: On demonstrating DNA intercalation

Chin San Loo, Ph.D. Merck-Jane Coffin Childs Fellow

Harvard Medical School

Project Title: In Vivo tracking of G protein-coupled receptors sensing for gut metabolites

The human gastrointestinal tract harbors trillions of microbes that have been coevolving with humans for a long time. Growing evidence suggested that the gut microbiota produces a myriad of metabolites, and some of these small molecules possess bioactivity that can shape host development and fitness, such as modulating gut immune cells and promoting brain development. G protein-coupled receptors (GPCRs) represent the largest class of membrane receptors that relay extracellular cues into a cellular response. Many of these GPCRs including orphan GPCRs may evolutionally be designed for communicating with microbes through microbial metabolites. My research seeks to develop a genetic tool and platform that can characterize ligand-activated GPCRs in vivo and uncover GPCRs that sense microbial metabolites. This work potentially sheds light to understand the underlying mechanisms of host-microbiota interaction.

Joseph J. Loparo, Ph.D. Jane Coffin Childs Fellow

Harvard Medical School

Project Title: Single-molecule enzymology of the replisome

Diego A. Lopez, Ph.D. Jane Coffin Childs Fellow

University of Utah, Huntsman Cancer Institute

Project Title: 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.

Christopher A. Lopez, Ph.D. Simons Foundation-Jane Coffin Childs Fellow

Vanderbilt University Medical Center

Project Title: Defining the clostridium difficile responses to zinc limitation

Clostridium difficile is an anaerobic Gram-positive bacterium responsible for nearly half a million intestinal infections in the U.S. annually leading to approximately 29,000 deaths. C. difficile infections (CDI) are most commonly triggered after disruption of the resident microbiota through antibiotics or chemotherapy, which allows C. difficile to subsequently colonize the intestines. CDI can manifest as a spectrum of disease, from mild diarrhea to pseudomembranous colitis or death. Even in situations where patients are treated, recurrent infections are common. While many of the risk factors for CDI are known, there is a general lack of understanding of why CDI presents as such a wide spectrum of disease and what the predictors are for recurrent CDI. My research is aimed at defining how C. difficile adapts to survive in the intestines to cause disease. By understanding the fundamental biology governing C. difficile interactions with the microbiota and the host in the context of infection, we can determine the predictors for disease severity or recurrence and guide the design of effective therapeutics.

Vicki P. Losick, Ph.D. Jane Coffin Childs Fellow

Carnegie Institution for Science

Project Title: Drosophila melanogaster spermatheca: a new model for the prostate gland

Identifying cellular mechanisms of tissue repair is critical to our understanding of the normal wound healing process. ¬†I am studying the cellular mechanisms tissues use to respond to damage or injury in the adult Drosophila melanogaster.

As a postdoctoral fellow in Allan Spradling¬ís laboratory, I am working to combine my former?¬†research expertise in microbiology and innate immunity with the study of cellular processes of tissue repair in the adult fruit fly. ¬†My interest in biomedical research began in college, with an undergraduate research project on viral protein stability. ¬†A particularly influential moment was seeing first-hand the impacts of infectious diseases like malaria during a semester abroad in Kenya. ¬†This experience led me to pursue graduate thesis work at Tufts University. In the laboratory of Ralph Isberg, my project involved characterizing mammalian host cell signaling pathways required for the growth of Legionella, a human pathogen known to cause severe pneumonia. ¬†As part of my professional life, I enjoy mentoring and teaching young scientists. Outside of the lab, I¬ím an aspiring amateur golfer, jazz enthusiast, and cook.

Adam Lowet, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley

Project Title: Neural Mechanisms of Naturalistic Social Decision-Making

Adam Lowet, Ph.D. is fascinated by the neural and computational basis of social behavior in both health and disease. During his graduate work, Lowet used insights from AI to uncover a novel way in which the brain learns from rewards and punishments. As a Jane Coffin Childs Fellow, Lowet will now investigate the computational and biological mechanisms underlying social decision-making using an unorthodox model system: the Egyptian fruit bat, a highly social animal.

Lowet’s graduate research in Naoshige Uchida’s lab at Harvard University was motivated by the observation that many AI algorithms are significantly improved when considering the entire probability distribution of outcomes rather than just their mean value. Lowet thought this principle might apply to how our brains work and investigated this hypothesis in the context of the mesolimbic dopamine system. Lowet demonstrated that the brain indeed encodes more than just the mean and uses this distributional information to speed up learning. Surprisingly, Lowet discovered that the upper and lower tails of reward distributions are encoded in different types of neurons, suggesting brain information processing is organized in a more detailed way than previously understood.

Now in Michael Yartsev’s lab at UC Berkeley, Lowet will use the Egyptian fruit bat, an ultrasocial mammal, as a model for studying social decision behavior. Lowet will record behavior and neural activity while groups of bats forage collectively and compare these to normative models of social decision-making from machine learning and behavioral ecology. Ultimately, Lowet hopes that this foundational research into how healthy brains coordinate with others will eventually inform approaches to disorders where this ability is compromised.

Yu Lu, Ph.D., J.D. Jane Coffin Childs Fellow

Harvard Medical School

Project Title: Identification of migration genes from breast cancer

Xin Lu, Ph.D. HHMI-Jane Coffin Childs Fellow

Dana-Farber Cancer Institute

Project Title: Genetic and genomic analysis of prostate cancer progression

Martin Lubin, M.D., Ph.D. Jane Coffin Childs Fellow

Massachusetts Institute of Technology

Project Title: Cell membranes

Richard Luduena, Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: Sequencing of chick brain microtubule protein

James P. Lugo, Ph.D., MBA Jane Coffin Childs Fellow

California Institute of Technology

Project Title: Immunological analysis of thymus gland lymphocytes

Bonaventura F. Luisi, Ph.D. Jane Coffin Childs Fellow

University of Chicago /
Yale University

Project Title: trp repressor/operator system: structure and function

Paul K. Lund, M.D. Jane Coffin Childs Fellow

Yale University

Project Title: Heterologous transplantation of human tumors

Liqun Luo, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Genetic dissection of neuronal morphogenesis

Daniel A. Lutterman, Ph.D. Jane Coffin Childs Fellow

Massachusetts Institute of Technology

Project Title: Identification of transient reactive intermediates in RNR's and potential role in therapeutics

John M. Lyle, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Mechanism of microtubule nucleation in the centrosome

Berkeley A. Lynch, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley

Project Title: Transmembrane regions of the E coli aspartate receptor

Daniel Lyons, Ph.D. Jane Coffin Childs Fellow

University of Colorado, Boulder

Project Title: Regulation of telomere binding protein activity

Heankel Lyons, Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: Mechanisms of Transcriptional Dysregulation in Neurodegeneration

Heankel Lyons, Ph.D. became motivated to do biomedical research while growing up due to a family member developing a rare neurodegenerative disease. As a JCC Fellow, she will take her expertise from her graduate work on how biomolecular condensates regulate gene activity to ask how condensates regulate neuronal gene expression, how these processes shape normal cell biology, and how their dysregulation leads to brain disease.

As a graduate student in Ben Sabari’s lab at UT Southwestern, Lyons uncovered fundamental principles into how biomolecular condensates, membrane-less compartments that gather specific molecules, help regulate transcription. She found that condensates formed by a protein called MED1 recruit RNA polymerase II and helpful regulators while keeping out inhibitors. Impressively, Lyons also identified amino-acid “patterns” that determine which proteins get recruited, and showed how cancer fusion proteins exploit similar patterns to drive cancer-related gene programs.

Now as a JCC Fellow in Aaron Gitler’s lab at Stanford University, Lyons returns to the subject that originally spurred her interest in science: neurodegeneration. She’ll focus on a central protein in amyotrophic lateral sclerosis (ALS), named TDP-43. TDP-43 forms condensates, and most research in the neurodegeneration field has focused on TDP-43’s role as an RNA-binding protein, yet this protein was originally discovered as a DNA-binding protein. Lyons will use her expertise in transcription and condensates to define TDP-43’s role in neurons and investigate how transcriptional dysregulation involving TDP-43 contributes to ALS.

Dan Ma, Ph.D. Jane Coffin Childs Fellow

University of Washington

Project Title: Structural study of porcupine, a membrane protein essential to Wnt function

Im trying to investigate three dimensional structures of proteins those play important roles in Wnt signaling pathway. Aberrant regulation of Wnt proteins and their signal-transduction cascades are associated with the development of many diseases including some cancers. The aims of my research are to explain the molecular mechanism for Wnt secretion and downstream regulation._x000D_
_x000D_
Im from China, and I got my PhD degree at Tsinghua University. I used to be a structural biologist, and now Im still a structural biologist, because I think this is a good way for me to understand many biological processes at molecular level. I mainly focus on structural and biochemical studies of important proteins related with human diseases, and I really hope my research will help people better understand and fight with diseases. Now Im working as a postdoc in Seattle, a beautiful and romantic city, and I think I will enjoy my research and enjoy my life!

Chaoyong Ma, Ph.D. Jane Coffin Childs Fellow

Harvard Medical School

Project Title: Genes encoding bHLH proteins in the mouse retina

Renata D. Maas, Ph.D. Jane Coffin Childs Fellow

New York University

Project Title: Nucleic acid synthesis

Russell E. MacDonald, Ph.D. Jane Coffin Childs Fellow

University of Copenhagen

Project Title: Control mechanisms of cell growth

Bernard F. Mach, M.D., Ph.D. Jane Coffin Childs Fellow

Rockefeller University

Project Title: Mechanisms of synthesis of polypeptides in bacteria

John Maciejowski, Ph.D. Merck-Jane Coffin Childs Fellow

Rockefeller University

Project Title: Can telomere attrition initiate chromosome shattering?

Alyson W. MacInnes, Ph.D. Jane Coffin Childs Fellow

Massachusetts Institute of Technology

Project Title: The role of ribosomal proteins in tumorigenesis

Emily Maclary, Ph.D. Merck-Jane Coffin Childs Fellow

University of Utah

Project Title: Uncovering the genetic basis of variation in musculoskeletal patterning

Variation in musculoskeletal patterning has major impacts on biodiversity and health: intraspecies variation permits adaptation to different ecological niches, while variation both within and between species plays key roles in evolutionary fitness. Despite this importance, the genetic basis of morphological diversity is largely unknown and remains a central question in developmental biology. Identifying genetic changes that underlie variation in musculoskeletal patterning will expand our understanding of_x000D_
developmental patterning and help to elucidate the origins of biodiversity and the etiology of developmental disorders. The domestic pigeon, Columba livia, is an exceptional model for genetic analysis of morphological changes, as extensive selective breeding has given rise to hundreds of breeds prized for_x000D_
unique morphological traits, including changes in musculoskeletal patterning. Because developmental programs are often highly conserved among vertebrates, this work will help identify gene networks that control patterning across many species, including humans. Prior work has identified variation in axial skeleton patterning and limb musculoskeletal development among breeds of C. livia; this catalog of intraspecies provides a unique opportunity to identify the genes and regulatory networks that control_x000D_
musculoskeletal patterning and development. I will use variation among C. livia breeds to identify and functionally characterize genes involved in musculoskeletal patterning.

Lindsey J. Macpherson, Ph.D. HHMI-Jane Coffin Childs Fellow

University of California, San Diego

Project Title: Molecular characterization of gustatory labeled lines

I’m investigating how taste information is encoded at the first relay between taste receptor cells and the gustatory neurons which innervate them. As a third-generation San Diegan who went to the University of California, San Diego as an undergrad and The Scripps Research Institute, La Jolla for graduate school, and who started a postdoc at Charles Zuker¬ís lab at UCSD, I thought I might have beaten the odds and would be able to complete my scientific training in my beloved native city. ¬†Although I had been open to the possibility of moving, I considered myself lucky to be able to live so close to friends and family while pursuing my scientific career at such highly regarded research institutes. So you can imagine my shock when Charles announced his intention to move the laboratory to Columbia University in New York City! ¬†It¬ís been a year since the move, and while I¬ím still a San Diegan at heart, New York has given me a fresh perspective on life and science.

Claire S. Magnani, Ph.D. Merck-Jane Coffin Childs Fellow

Broad Institute

Project Title: A DNA-encoded library strategy for molecular glue discovery

There is an urgent need for cancer therapeutics with improved target specificity and novel mechanisms of action. Molecular glues combine the demonstrated capabilities of small molecules as potent drugs with the power of chemically induced proximity. In enabling new protein-protein associations, molecular glues can address many shortcomings of current small molecule cancer therapeutics, which are often limited to protein targets presenting a clear binding pocket. Furthermore, since protein-protein interactions are widely known to facilitate a range of fundamental cellular activities, chemical compounds which intercede on these pathways can provide access to novel mechanisms of action and enhanced target specificity. The wide-ranging therapeutic potential of molecular glue has already been recognized; however, to date the discovery of these compounds has been limited to serendipity or the synthesis of bifunctional molecules. The systematic and generalizable path to molecular glue discovery has not yet been established. In my research, I will leverage the recording and reporting power of DNA encoded libraries to deliver a new path to molecular glue discovery

Rohit K. Mahajan, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco /
Scripps Research Institute

Project Title: Identification of signals for vectorial export of macromolecules from the nucleus

Lara K. Mahal, Ph.D. Jane Coffin Childs Fellow

Memorial Sloan Kettering Cancer Center

Project Title: Identification and characterization of Golgi SNARE complexes

Jan E. Maisel, M.D., Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Mechanism of regulation of gene expression in eukaryotic cells

Nairita Maitra, Ph.D. HHMI-Jane Coffin Childs Fellow

Fred Hutchinson Cancer Center

Project Title: Determining regulation and function of a major microtubule binding pathway

Each time a cell divides, it must ensure equal segregation of chromosomes. Error in this process causes either loss or gain of chromosomes, resulting in aneuploidy, a hallmark of cancer and other diseases. Chromosome segregation is mediated by a megadalton protein complex called kinetochore that assembles at the centromere of each chromosome and serves as the physical linker between chromosomes and the microtubules. Early in mitosis, microtubule-kinetochore attachments are stabilized by tension that distinguishes proper attachment from the improper ones. However, during anaphase, kinetochore-microtubule attachments become vulnerable as tension drops when the chromosomes separate, and the microtubules start shortening. It is major question how kinetochores remain attached to microtubules under low tension. There are two competitive pathways that recruit the major microtubule binding protein, Ndc80c to the kinetochore- Mis12c and CENP-T^Cnn1 pathway. The CENP-T^Cnn1 pathway gets enriched at the kinetochore during anaphase, making it a potential pathway that could stabilize low tension attachments. I hypothesize that the CENP-T^Cnn1 pathway is key to understanding how kinetochores adapt to low tension during anaphase. My goals are to uncover the underlying regulatory mechanism facilitating upregulation of this pathway at the kinetochore during anaphase and how it contributes to kinetochore-microtubule attachments under low tension.

Umadas Maitra, Ph.D. Jane Coffin Childs Fellow

Albert Einstein College of Medicine

Project Title: Initiation and termination of transcription by RNA polymerases

John E. Majors, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Mouse mammary tumor virus DNA from infected HTC cells

Nadja Makki, Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: Untangling the locus coeruleus noradrenergic neural circuit

My current research aims to explore how DNA regulatory elements influence human development and disease. I am particularly interested in identifying novel enhancers that regulate brain development and identifying mutations within them that lead to neurodevelopmental diseases.

I was born in Germany, where I studied Biology at the University of Goettingen and the University of Kiel. I then came to the US to pursue my Ph.D. in Human Genetics at the University of Utah. My graduate research in the lab of Dr. Mario Capecchi involved examining the role of Hoxa1, a homeobox transcription factor, in early brain development. This sparked my interest in the field of neuroscience and especially in development of the nervous system. I performed a postdoc in Dr. Liqun Luo¬ís lab at Stanford to study the connectivity of individual neurons in the brain. For my current postdoc in Dr. Nadav Ahituv¬ís lab at UCSF, I am focusing on identifying gene regulatory elements that are involved in brain development and examining how changes in the genomic regulatory code can lead to specific phenotypes. Outside the lab, I enjoy the various outdoor activities that the Bay Area has to offer.

Michael H. Malamy, Ph.D. Jane Coffin Childs Fellow

Institut Pasteur

Project Title: Genetic control systems

Prerna Malaney, Ph.D. Jane Coffin Childs Fellow

MD Anderson Cancer Center

Project Title: hnRNP K: a putative driver of high risk DLBCL

Aggressive forms of diffuse large B-cell lymphoma (DLBCL) are often marked by genetic alterations at the MYC locus. However, only about 15% of de novo DLBCL cases actually harbor MYC alterations, yet MYC remains overexpressed in many cases alluding to the existence of uncharacterized mechanisms that facilitate its overexpression. Thus, there is a need to identify novel alterations that cause aberrant MYC expression in order to develop effective and targeted therapies. To this end, I have discovered that hnRNP K (Heterogeneous Nuclear Ribonucleoprotein K) is a novel driver of high-risk DLBCL. hnRNP K impacts lymphomagenesis by directly regulating the MYC oncogene via post-transcriptional mechanisms. Elevated MYC levels render hnRNP K-overexpressing cells sensitive to bromodomain inhibitors. Herein, I will determine the mechanistic basis for hnRNP Ks effect on MYC and test the preclinical efficacy of clinically relevant bromodomain inhibitors in hnRNP K-mediated DLBCL. Next, I will interrogate hnRNP K’s impact on therapeutic resistance to bromodomain inhibitors. Lastly, using a high-throughput fluorescence-based assay, I will identify novel compounds that directly disrupt the hnRNP K/MYC transcript interaction.

Thomas Maley , M.D. Jane Coffin Childs Fellow

Lymphoma Treatment Centre

Project Title: Diagnostic and treatment procedures

Eusebio Manchado, Ph.D. HHMI-Jane Coffin Childs Fellow

Memorial Sloan Kettering Cancer Center

Project Title: Biological impact of chromosome deletions on tumorigenesis

Venkata S. Mandala, Ph.D. HHMI-Jane Coffin Childs Fellow

Rockefeller University

Project Title: Formation and function of potassium channel signaling clusters in membranes

Many transmembrane proteins reside in functionally important clusters on cell membranes. Fluorescence microscopy of membrane proteins in cells has revealed ‘hot spots’ of co-localized proteins such as a_2A-adreneregic G-protein coupled receptors and G proteins participating in signaling complexes. Yet the functional significance of these signaling clusters in cells is not well established. Developing tools to induce controlled clustering of membrane proteins in the lab would thus provide valuable insight into the function of these signaling complexes in cells.

My project proposes three complementary strategies to induce controlled protein clustering in lipid bilayers. The approaches span raft-forming lipid mixtures, tetraspanin and MARVEL domain 4-TM proteins, and membrane-anchored scaffolding proteins with multiple PDZ domains. These tools will be applied to a signaling pathway comprised of G protein-gated K⁺ channels (GIRK) and their activator, the βγ complex of G proteins (Gβγ). The extent of protein clustering and the subsequent effect on activity will be assessed using fluorescence microscopy and electrophysiology

Jerry Manning, Ph.D. Jane Coffin Childs Fellow

California Institute of Technology

Project Title: Integration of DNA from SV40

Colin Manoil, Ph.D. Jane Coffin Childs Fellow

Biozentrum University of Basel /
Harvard University

Project Title: Membrane components involved in E coli conjugation

Tianyang Mao, Ph.D. Jane Coffin Childs Fellow

Massachusetts Institute of Technology

Project Title: LIGHTing up tumor-associated tertiary lymphoid structures through cytokine pharmacokinetic engineering

Proper functioning of our immune systems depends on the precise timing of an orchestra of molecular events. One such important event is the release of cytokines, which are signaling molecules, into the extracellular space to mediate intercellular communication. For cytokines to exert appropriate immunomodulatory roles, their bioavailability must be strictly yet dynamically regulated in space and time. However, the mechanisms by which the immune system interprets the timing of cytokine release remain poorly understood.

Dr. Tianyang Mao will investigate the temporal encoding of cytokine signaling in anti-tumor immunity in Dr. Darrell Irvine’s lab at the Massachusetts Institute of Technology. Dr. Mao will use a novel controlled drug release technology which enables programmable control over the duration of cytokine exposure in vivo. This unique approach will allow Mao to make novel insights into how cytokine temporal dynamics shape cancer immunosurveillance. Better understanding of the immunological impact of cytokine release kinetics will guide the development of temporally reprogrammed cytokine therapeutics for cancer treatment.

Mao’s expertise in immunology emerged as a graduate student in Dr. Akiko Iwasaki’s lab at Yale University. There Mao developed an intramuscular prime–intranasal boost vaccine strategy for SARS-CoV-2 termed “prime and spike,” which leverages preexisting immunity generated by primary mRNA-LNP vaccines to elicit mucosal immunity within the respiratory tract using unadjuvanted intranasal spike boosters. In addition, he developed several antiviral strategies that trigger type I interferon-based immune protection against SARS-CoV-2, including a short stem-loop RNA agonist for the innate immune receptor RIG-I and an aminoglycoside antibiotic with unexpected antiviral properties. Collectively, these strategies hold great promise to not only prevent disease, but also viral transmission. Now, Mao will build on this experience, using novel bioengineering techniques in the Irvine Lab, to make new inroads into the importance of timing in immune responses to cytokines.

Shally R. Margolis, Ph.D. Jane Coffin Childs Fellow

University of Washington

Project Title: Mechanisms of

CRISPR systems are the adaptive immune systems of bacteria that are crucial for defense against bacteriophage infection. Immune memory is stored as short DNA sequences in the CRISPR array, called “spacers”, and upon transcription and processing these associate with Cas nucleases to search for matching viral targets and initiate nucleic acid cleavage. Type VI CRISPR systems are unique in that they recognize RNA, and target recognition leads the nuclease Cas13 to indiscriminately cleave cellular RNA. While the targeting steps of this CRISPR type are well-understood, it is still unknown how new spacers are acquired, especially since most type VI CRISPR operons lack the known acquisition machinery. Here, we probe the mechanisms of type VI CRISPR immune memory generation using Listeria seeligeri, a genetically tractable host that endogenously encodes type VI CRISPRs. We show that type VI CRISPR can use the adaptation genes from other CRISPR systems in the genome to integrate new memories into the type VI array, both in vivo and in vitro. In addition, we find no clear bias for acquisition of functional, RNA targeting spacers during growth or infection; however, we do observe some bias for acquisition from highly transcribed regions. In the future, we aim to identify additional factors required for acquisition of new spacers in the type VI CRISPR locus and determine the origin of newly acquired spacers.