Former Fellows

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Jeanine Amacher Frederic M Richards Fellow

Department of Molecular and Cell Biology, University of California, Berkeley, California

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Substrate docking and ubiquitylation in the E3 ligase Cbl , with John Kuriyan

Post-translational modifications regulate key interactions in signaling pathways. In protein tyrosine kinase (PTK) signaling, for example, crosstalk between phosphorylation and ubiquitylation signals is critical to proper cellular function. A phosphorylation cascade is triggered upon PTK activation; in turn, the RING-type E3 ubiquitin ligase Cbl is activated, and attenuates many of these signals via lysosomal degradation. In cancers where there are mutations in PTK signaling, this communication breaks down, leading to uncontrolled cell proliferation and poor patient prognosis.

During my postdoctoral work in Dr. John Kuriyan’s lab at UC Berkeley, I am using biochemical assays and X-ray crystallography to better understand the regulation and selectivity of Cbl with respect to its targets. Cbl has a unique activation mechanism, whereby substrate docking is followed by phosphorylation at a conserved tyrosine residue, turning Cbl “on.” I hypothesize that crosstalk between Cbl’s tyrosine kinase binding and RING domains dictates its selectivity and regulates substrate kinase activity. PTK signaling is a finely tuned product of evolution, and a greater understanding of how Cbl interacts with its substrates will unveil new possibilities for intervention.

Effie Apostolou

Massachusetts General Hospital Center for Regenerative Medicine Harvard Stem Cell Institute, Boston, MA

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Differentiation hierarchy and reprogramming potential in hematopoietic cells with Dr. Konrad Hochedlinger

My current research focuses on the molecular and epigenetic mechanisms governing the process of nuclear reprogramming of somatic cells into induced pluripotent stem cells (iPS cells). More specifically, I study how the differentiation stage of the initial somatic cell affects the efficiency of reprogramming into iPS.

I was born at Naoussa, a small town in northern Greece. I studied biology at Aristotle University of Thessaloniki and pursued my PhD on molecular  biology at the medical school of the National University in Athens. While working at Dr. Dimitris Thanos’ lab for my PhD thesis — “In vivo study of the dynamics of transcriptional   complexes” — I became intrigued by biochemistry and familiar with molecular and cytogenetic techniques.  I also published my first paper, which  opened the door to Harvard University and a new world.  I switched my scientific focus to this new and exciting field. I joined Dr. Konrad Hochedlinger’s lab and am more than happy with my choice. At the beginning of my second year, I feel so much richer in knowledge and research experience. I also enjoy life in Boston, which is an ideal city for tango dancing and hiking.

Jeremy Baskin

Department of Cell Biology Yale School of Medicine / New Haven, CT

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My current research concerns the mechanisms by which cells regulate the biosynthesis of phosphoinositides, a class of lipids found on the cytosolic face of numerous membranes within the cell. In particular, I am interested in studying the metabolic interconnectedness of different classes of lipids.

I was born and raised in Montreal, Canada in a family of artists. My parents are both classical musicians, and my younger sister is a budding actress; to this day I play classical piano as a hobby. I was drawn to chemistry in high school, and my interest in organic chemistry grew in my undergraduate years at MIT, where I received a B.S. in 2004. Midway through MIT, inspired by an advanced biochemistry class, I joined a young chemical biology lab. I continued in this area in my graduate years at UC Berkeley, in the laboratory of Carolyn Bertozzi, where my research concerned the development of chemical tools for imaging cell-surface glycans in living systems. After earning a Ph.D. in chemistry in 2009, I again switched direction, embarking on post-doctoral research in cell biology, under the supervision of Pietro De Camilli.

Brittany Belin Simons Foundation Fellow

Division of Biology: Geological & Planetary Sciences, California Institute of Technology, Pasadena, California

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The role of hopanoids in plant-microbe symbioses, with Dianne Newman

A native of rural Pennsylvania, my interest in biology was sparked by a summer research program for high school students on ribosome biogenesis at Carnegie Mellon University. As an undergraduate, I studied biochemistry and philosophy at the University of Notre Dame, where I researched the molecular evolution of bacterial actin-like proteins with Dr. Holly Goodson. I continued my Westward migration to pursue a PhD at UCSF. In my thesis research with Dr. Dyche Mullins, I developed new tools for in vivo imaging of nuclear actin, which I used to discover a role for nuclear actin filaments in the DNA damage response.

As a postdoc I decided to jump across the branches of the tree of life, and I am currently working in the lab of Dr. Dianne Newman at Caltech to determine how the membrane composition of rhizobia, soil bacteria that engage in symbiotic nitrogen fixation in the roots of legume plants, affects their symbiotic fitness and recognition by plant hosts. I am particularly interested in the role of hopanoid lipids, which may be required for bacterial adaptations to environmental stress.

Andrea Berman

Howard Hughes Medical Institute Department of Chemistry and Biochemistry / University of Colorado / Boulder, CO

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Holding on for dear life: Primer binding and processivity in tetrahymena thermophila telomerase, with Thomas Cech

I am using biochemical and biophysical techniques to understand how the essential protein p65 facilitates the assembly of the Tetrahymena telomerase ribonucleoprotein particle.  I am also interested in studying the mechanism by which telomerase recycles its RNA template sequence, allowing the protein component to copy the template several times without dissociating.

I grew up on Long Island, NY and received my BS in biology with a concentration in biochemistry from Cornell University.  An undergraduate research opportunity in an x-ray crystallography lab at Cornell piqued my interest and I moved to Connecticut to pursue and earn a PhD in molecular biochemistry and biophysics from Yale University, working in the laboratory of Tom Steitz.  Currently living near Boulder, Colorado, I am engaged in the work I’m doing with Tom Cech, in whose lab I am learning new biochemistry techniques and interacting with graduate and undergraduate students.  When not in the lab, I enjoy practicing yoga, baking, eating New York bagels and pizza, and hiking and biking in Boulder with my husband.

Michael T. Bethune

Division of Biology California Institute of Technology, Pasadena, CA

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My research aims to identify prostate cancer-reactive T cell receptors and their cognate antigens, thereby enabling the design of novel TCR gene therapies and dendritic cell-targeted vaccines.  I am also using protein engineering to improve the safety and efficacy of T cell receptors in such therapies and to extend these therapies to other widely-prevalent cancers of epithelial origin.

My training began at the University of California, Davis, where I was introduced to biochemistry by my undergraduate mentor, Robert Fairclough.  After UC Davis, I spent two years in Washington D.C. before joining the Stanford Biochemistry Department as a graduate student.  There, I worked with my advisor, Chaitan Khosla, on celiac sprue, an autoimmune-like disease in which dietary gluten precipitates an inflammatory immune response in susceptible individuals.  This research piqued my interest in how immune responses are shaped by foreign material, and in the potential for using bacterial and viral vectors to augment immunity to pathogens and to mitigate autoimmunity.  As a deleterious self pathogen, cancer is a uniquely challenging target of this engineering immunity approach. When not working, I enjoy discovering new activities in the L.A. area with my wife, Carol San, who is an occupational therapist.

Manasi Bhate HHMI Fellow

Department of Pharmaceutical Chemistry, University of California, San Francisco

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Design of peptides to target protein-protein interfaces of membrane fusogens, with Willam DeGrado

I am broadly interested in the structure, function and dynamics of proteins that mediate signal transduction across the cellular membrane. These include membrane receptors, enzymes, ion channels and transporters. Since signaling is a dynamic process we need to study the ensemble of protein conformations and motions to understand how physical and chemical stimuli are converted into cellular information.

My graduate training was in solid-state NMR of membrane proteins. I currently use a combination of NMR, protein engineering and biophysics to gain quantitative insights into a family of transmembrane kinases that allow bacteria to sense and adapt to antibiotics in their environment.

Email: Manasi.Bhate@ucsf.edu
Personal Website : https://sites.google.com/site/manasibhate/?

Kivanç Birsoy

Whitehead Institute Massachusetts Institute of Technology, Cambridge, MA

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Current research: Cell autonomous and non-autonomous mechanisms of cancer metabolisum regulation and tumor growth.

I grew up in Izmir,Turkey, and received my BS in molecular biology and genetics from Bilkent University and my PhD in molecular genetics from Rockefeller University.  At Rockefeller, I was a graduate student in Jeffrey Friedman’s lab, studying development of fat tissue and regulation of the obesity hormone, leptin. My current post-doctoral work in David Sabatini’s lab at Whitehead Institute involves studying mechanisms of cancer metabolism regulation. Outside of the lab, I am a big soccer fan. I also enjoy the outdoors, and spending time with friends and family.

Joshua Black

Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts

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Histone lysine tridemethylases regulate cell cycle progression with Dr. Johnathan Whetstine

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.

Kenneth Bohnert Honorary Fellow

Department of Biochemistry and Biophysics, University of California, San Francisco

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Germline rejuvenation in C. elegans, with Cynthia Kenyon

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 HHMI Fellow

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California

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Regulation of gene expression by ribosomal proteins, with Jonathan Weissman

I study how cells regulate the translation of RNA into proteins in the lab of Dr. Jonathan Weissman at UCSF. Firstly, I aim to test the hypothesis that mutations in ribosomal proteins can impair the expression of a specific set of genes without impairing the translation of the majority of mRNAs. Secondly, I aim to identify the driving force behind the observed codon-pair bias, which is the over- or under- representation of some pairs of codons in mammalian genomes.

My interest in the mechanism of translation comes from my PhD work with Dr. Jean-Laurent Casanova at the Rockefeller University. I discovered that heterozygous mutations in the gene RPSA caused Isolated Congenital Asplenia in humans, which is characterized by the absence of spleen at birth. RPSA codes ribosomal protein SA. It remains a mystery why mutations impairing the production of a ubiquitous ribosomal protein would lead to the unique absence of the spleen, and consequently predispose children to severe bacterial infections.

Breann Brown Frederic M. Richards Fellow

Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts

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Elucidating the role of E. coli Lon protease N-domain in substrate recognition and discrimination, with Tania Baker

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.

Alejandro Burga- Ramos HHMI Fellow

Department of Human Genetics, University of California, Los Angeles

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A novel bulk segregant method to identify natural genetic variants underlying C. Elegans resistance to chemotherapy drugs, with Leonid Kruglyak

Highly effective and commonly used drugs in cancer therapy fail to elicit a response or cause adverse side effects in a significant number of patients. In order to improve the prognosis and treatment of individual patients, it is fundamental to understand the basis of such differences. Most human diseases and traits are influenced by genetic factors. Yet, little is known about the total number of loci underlying differential drug response and how genetic variants confer resistance. In order to gain insights into the genetic and molecular basis of differential response to chemotherapeutic agents, we propose the development of a novel bulk segregant analysis (BSA) strategy in the model organism Caenorhabditis elegans. This methodology will allow us to map with unprecedented speed the natural genetic variants underlying differences in drug response in the context of a whole-organism. Our approach will likely reveal physiologically relevant genetic variants, since it incorporates pharmacological variables such as drug absorption and distribution that cannot be studied in cell lines. To model the effects genetic variants present in populations, we will make use highly divergent C.

elegans wild isolates, thus making also an important step towards understanding phenotypic variation in natural populations.

Liang Cai

Department of Anatomy / University of California, San Francisco

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Actin cytoskeleton reorganization during tubulogenesis, with Keith Mostov

Current Research: The role of actin cytoskeleton remodeling during epithelial morphogenesis.

Prior to coming to the United States in 2003, I received bachelor’s degree in science from Fudan University in Shanghai, China. My undergraduate thesis topic was “characterization of bacteriophage T3 DNA ligase.” My graduate study was done under Dr. James E. Bear in the Department of Cell and Developmental Biology at the University of North Carolina, Chapel Hill. My dissertation title was “Coronin 1B coordinates actin dynamics in lamellipodia.”  Currently, I am working with Dr. Keith Mostov in the Department of Anatomy at UCSF.  I really enjoy the life of doing research, and am looking forward to continuing my scientific journey. In my free time, I like to hike and ski.

Joseph Castellano Simons Foundation Fellow

Department of Neurology and Neurological Sciences, Stanford University, Stanford, California

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Effects of irradiation injury on systemic-neurogenic communication as targets for limiting cognitive dysfunction, with Tony Wyss-Coray

During my Ph.D. studies at Washington University, I worked with David Holtzman to show that ApoE e4 may increase Alzheimer’s disease risk by impairing Ab clearance from the brain, thus shifting the onset of its accumulation. My interest in neurodegeneration and aging motivated me to understand factors that regulate aging and brain health in unconventional ways. My project as a Jane Coffin Childs fellow in Tony Wyss-Coray’s laboratory has been to elucidate a novel systemic-neurogenic communication mechanism that appears to be disrupted in the context of brain irradiation therapy. Specifically, I am investigating the role of immune signaling molecules in mediating the neurogenic and cognitive dysfunction observed in the post-irradiation syndrome in pediatric brain cancer patients. Additionally, I am actively pursuing whether related blood-borne signaling molecules in young plasma may be sufficient to ameliorate age-related decreases in cognition and synaptic plasticity. To examine these complex mechanisms, I am leveraging various physiological methods, including plasma transfer and parabiosis.

Jia-Yun Chen

Department of Systems Biology, Harvard Medical School, Boston, Massachusetts

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Molecular dynamics of oncogene-induced senescence, with Galit Lahav

My current research focuses on the molecular dynamics of oncogene-induced senescence (OIS). By using a set of fluorescent reporters and single-cell time-lapse microscopy, I am trying to understand how variability in oncogenic activity, protein expression levels, etc. are linked to distinct cell fates, i.e., proliferation, transient cell cycle arrest and senescence.

My training began in my hometown, Taiwan, where I received my M.S. in molecular medicine and worked on programmed cell death in C. elegans. I then received my Ph.D. in Chemical and Systems Biology at Stanford supervised by Tobias Meyer. I combined single-cell image analysis, multi-parameter signal profiling, and high-content siRNA screening to understand how growth factor signals are translated by individual cells into a decision to proliferate or differentiate. I joined Galit Lahav’s lab at Harvard Medical School for postdoctoral training, and continue my long term interests in cell growth regulations. I expect that the knowledge gained from my postdoctoral work will allow us to understand how cell-to-cell variability at various levels contributes to the establishment of OIS, and explains how OIS is escaped in some cells. It can also be exploited for therapeutic utility to activate cellular senescence in cancer cells.

Gheorghe Chistol

Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts

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Probing the dynamics of the eukaryotic replicative helicase, with Johannes Walter

The eukaryotic helicase CMG (Cdc45+MCM2-7+GINS) is the molecular machine that unwinds dsDNA during replication. Although CMG plays a central role in replication, key aspects of its dynamics are poorly understood. It has been proposed that before activation, loaded MCM complexes can slide on dsDNA. However, this phenomenon has not been examined under physiological conditions and its functional significance remains unclear. In addition, how the CMG helicase operates under conditions of replicative stress is not understood.

To address these questions, I will perform single-molecule imaging of MCM2-7 complexes in completely soluble Xenopus egg extracts, which were pioneered in my sponsor’s laboratory.

In Aim 1 I propose to probe the dynamics of individual dsDNA-bound MCM complexes prior to replication initiation. In particular I seek to determine whether dormant MCM complexes can slide on dsDNA in physiological conditions. In Aim 2 I propose to investigate the fate of dormant MCM complexes upon their collision with oncoming replication forks. In Aim 3 I propose to study the dynamics of the helicase after its uncoupling from the replicative polymerase, and seek to determine how the helicase activity is regulated by the activation of the DNA damage checkpoint.

Edward Chuong

Department of Human Genetics, University of Utah, Salt Lake City, Utah

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Co-option of endogenous retroviruses for host immune responses, with Cedric Feschotte and Nels Elde

My current research is focused on the biology and evolution of transposons, which are DNA parasites that constitute over half of the human genome. Specifically,  I am investigating the long-standing hypothesis that transposon activity is a major mechanism underlying the evolution of gene regulatory networks.

I became interested in evolutionary biology as an undergraduate at UC San Diego, where I worked with Hopi Hoekstra studying the volatile history of rodent placental proteins. I continued studying placental evolution as a graduate student at Stanford University with Julie Baker, where we found that transposons may contribute to pregnancy-related adaptations by functioning as species-specific regulatory elements.  Inspired by the potential for transposons to drive rapid evolutionary change, I decided to do my postdoc in the laboratories of Cedric Feschotte and Nels Elde at the University of Utah, where I am studying the role of transposons in shaping the evolution of human innate immune responses. Outside the lab, I enjoy the vast outdoor recreational activities in Utah, including hiking, skiing, and canyoneering.

Damon A. Clark

Department of Neurobiology,  Stanford University Medical School, Stanford, CA

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Visual feedback modulation in behaving Drosophila, with Thomas Clandinin

Current research: I study the neural circuitry and computations involved in fruit fly vision.

I initially became interested in neuroscience by looking at gross brain anatomy and how microscopic computational requirements might influence the relative sizes of different brain regions. From there, I moved on to studying worms, an organism whose entire neural network is known, and examined how this small nervous system could sense and respond to environmental cues to navigate its environment. I now work on visual circuitry and computations in the fruit fly, an ideal model system for its genetics and behavior, and an ideal system to model. When I’m not in the lab, I like to get out hiking or biking, and in general enjoying the California sun.

Robert E. Collins

Department of Molecular Biophysics and Biochemistry Yale University / New Haven, CT

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RabGDI displacement factors: mechanism and function in membrane traffic, with David Lambright

My research involves the engineering of protein binding modules from Tetratricopeptide repeats using both selection from randomized libraries and rational design. Our goal is to design low cost medical diagnostics, for example, a CD4 test practical for the management of HIV+ patients in the developing world. Early in my freshman year of college, I began my career in science working in laboratories, taking on projects ranging from the enzymatic bleaching of paper to the studies of pathogenic nematodes and complex carbohydrates. In graduate school at Emory University, mentored by Xiaodong Cheng, I focused on the structural biology of the “histone code.” At Yale, in the lab of Lynne Regan, I have turned to an engineering approach, using rational structure-based design and library selection to develop new, inexpensive diagnostics, and also to investigate fundamental questions of protein-ligand interaction. Long-term goals involve development of model systems to probe the molecular/structural evolution of novel interactions and their enhanced affinity and selectivity in directed evolution experiments.

Joseph Cotruvo

Department of Chemistry, University of California, Berkeley, California

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Intersection of nitric-oxide and copper-mediated signaling pathways in mammalian cells, with Christopher Chang

Nitric oxide (NO) is a ubiquitous gasotransmitter involved in vasorelaxation, neurodegeneration, apoptosis, and other processes, and linked to numerous pathologies, including cancer. A major mechanism of NO signaling is S-nitrosation, the oxidative modification of cysteine residues, but how this occurs in vivo is poorly understood. Copper ions catalyze Snitrosation in vitro, while recent data point to mobile pools of copper playing unknown roles in signaling pathways. This proposal aims to connect copper- and NO-mediated signaling, using the lipolysis pathway of adipocytes as a model system. Our preliminary data suggest copper and NO modulate the activity of phosphodiesterase (PDE) 3B. We propose that copper, bound to a protein or small molecule, catalyzes S-nitrosation of PDE3B, inhibiting the enzyme. We will test this hypothesis by altering cellular copper and NO levels via gene knockdowns, and assaying PDE3B activity in extracts. We will detect differences in PDE3B S-nitrosation under these conditions and determine the cysteine(s) modified. Finally, we will search for endogenous copper ligands and reconstitute the S-nitrosation system in vitro. These studies will yield insights into NO’s physiology, unravel a novel signaling role of copper, and motivate examination of copper signaling in other mammalian cell types.

Bryan W. Davies

Department of Microbiology and Molecular Genetics / Harvard Medical School, Boston, MA

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Mapping virulence regulatory and signaling networks in vibrio cholera, with Dr. John H. Mekalanos

I am mapping regulatory and signaling networks in Vibrio cholerae to identify factors and pathways that are required for virulence.

Improving the health of our world is a complex problem.  The balancing act between providing food and health care for the masses, protecting the environment,  and improving economies in developed and developing nations is often difficult.  I enjoy science because of the unlimited potential it offers to provide solutions to many of the problems inherent in creating this balance. The basic sciences provide answers to the inner workings of life.  These insights offer the possibility of developing new products to improve health care, decrease our environmental impact and improve food production, while simultaneously fostering the growth of new industries to bring products to those who need them.  And it can all start at the laboratory bench just by asking, “why?”

Sebastian Deindl

Department of Chemistry and Chemical Biology Harvard University, Cambridge, MA

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Current research: With a combination of novel single-molecule imaging approaches and traditional biochemical techniques I am investigating the mechanisms of ATP-dependent chromatin remodelers, a class of enzymes that dynamically alter chromatin structure.

I am intrigued by the notion that virtually all chemical reactions in our bodies are carried out by microscopic yet intricate molecular machines. For this reason, I decided to study the workings of these machines at a molecular level. John Kuriyan’s laboratory at the University of California, Berkeley was the perfect place for this work. There I studied the allosteric control of protein kinases and developed a passion for correlating protein structure with function. For my postdoctoral research I decided to venture into another important area of biology and study dynamic aspects of chromatin remodeling enzyme mechanisms using single-molecule imaging techniques in Xiaowei Zhuang’s laboratory at Harvard. Next to doing science, I enjoy windsurfing and surfing.

Morgan DeSantis HHMI Fellow

Department of Cellular and Molecular Medicine, University of California, San Diego

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Investigating dynein-mediated viral transport, with Samara Reck-Peterson

I am interested in cellular transport, or in other words, how things, like organelles, mRNA, and viruses are shuttled around the cell. In the Reck-Peterson lab, we study the microtubule-associated motor protein, dynein. Dynein is a large, muti-subunit complex that walks towards the center of the cell along microtubule tracks. I am particularly interested in understanding how other proteins, referred to as dynein-adaptors, regulate dynein function and specificity for cellular cargo.  In our lab, we take a two-pronged approach to understanding dynein biology. First, we use techniques like single molecule-fluorescence microscopy and electron microscopy to study dynein function on a mechanistic level. Secondly, we use mass spectrometry to conduct proteomic screens to identify novel proteins that interact with dynein.

Ines Drinnenberg

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington

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Causes and consequences of a non-canonical H2A variant in flies, with Harmit Malik

My research focuses on the evolutionary diversity of centromeric architectures. Faithful chromosome segregation in all eukaryotes relies on centromeres, the chromosomal sites that recruit the kinetochore protein complex to mediate spindle attachment during cell division. Yet, despite this essential function centromeres are remarkably diverse. Most chromosomes are monocentric i.e., kinetochore assembly is restricted to a defined chromosomal region. In contrast, holocentromeres have kinetochores attached along the entire length of chromosomes. Holocentric chromosomes have evolved multiple times independently from monocentric ancestors. Yet, despite their dramatically different centromeric architectures, the transition to holocentric chromosomes has remained enigmatic.

I performed a computational survey for centromere and kinetochore components in mono- and holocentric insect orders. This study revealed the unexpected finding that the centromere specific histone variant, CenH3 – known to be essential for centromere function in most eukaryotes – was lost on all four lineages that are associated with independent transitions from mono- to holocentric chromosomes. Expanding my analyses to other kinetochore components I found that homologs of many inner kinetochore proteins are still present, suggesting that holocentric insects utilize alternative ways of initiating kinetochore assembly on chromatin. Currently I am in the process of determining the CenH3-independent kinetochore assembly pathway as well as the molecular architecture of the insect holocentromere.

Robert Driscoll

Clark Center Stanford University School of Medicine / Stanford, CA

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Molecular dissection of the replication checkpoint, with Karlene Cimprich

My current research involves analysis of the cellular response to replication fork stress.

After finishing my undergraduate degree at the University of Leeds in the UK, still pretty clueless as to what I wanted to study, I worked in the lab of E. Peter Geiduschek at the University of California, San Diego, as a research technician. There, I developed a fascination with DNA metabolism. I continued pursing this interest  by studying DNA repair in the lab of Steve Jackson at Cambridge University for my doctoral studies, and am now studying DNA replication. I greatly enjoy the challenge of independent academic research but also the fact that it is a very social endeavor. When I’m not in the lab, I’m usually hiking and camping in California or enjoying its excellent food and beverages.

Andrew E. H. Elia (HHMI Fellow)

Massachusetts General Hospital Harvard Medical School, Boston, MA

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Study of regulatory protein modifications in the DNA damage response, with Dr. Stephen J. Elledge

The cellular machinery of the DNA damage response (DDR) consists of a dynamic network of multiprotein complexes whose hierarchical assembly relies upon an array of posttranslational modifications. Dr. Elia is studying novel mechanisms by which such post-translational modifications regulate the DDR.

Dr. Elia attained his Bachelor’s degree in Chemistry from Stanford University before entering an MD/PhD program at Harvard Medical School, where he attained his PhD in the laboratory of Lewis Cantley.  He recently completed his residency in Radiation Oncology at Harvard and is now working in the laboratory of Stephen Elledge. Dr. Elia is interested in genomic instability and how it influences the progression and treatment of cancer.  Numerous cancer susceptibility syndromes arise from the mutation of DNA repair genes, whose loss undermines genomic integrity. The modulation of such DNA repair pathways can also affect tumor sensitivity to radiation and chemotherapy.  Dr. Elia is interested in studying how synthetic lethal interactions between such DNA repair pathways might be exploited in the treatment of cancer.

Laura A.B. Elias

Pathology Department / Howard Hughes Medical Institute Stanford University / Stanford, CA

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ATP-dependent chromatin remodeling in dendritic morphogenesis and targeting, with Dr. Gerald R. Crabtree

My work in Gerald Crabtree’s laboratory focuses on elucidating how structural changes in the packaging of DNA, otherwise known as chromatin, contributes to the acquisition of cellular identity. Specifically, I am investigating the mechanism by which subunit switches in an ATP-dependent chromatin remodeling complex promote the development and maturation of neural progenitor cells into fully functional neurons.

I have been driven throughout my training by a passion for discovery and appreciation for a scientific, analytical approach to problem-solving. I majored in biology at Swarthmore College and earned my PhD in the Neuroscience Program at the University of California, San Francisco (UCSF). My thesis in Arnold Kriegstein’s laboratory at the UCSF Institute for Regeneration Medicine focused on elucidating the mechanism by which newborn neurons migrate from their places of origin to specific cortical regions, where they integrate into the brain’s circuitry.  During my postdoctoral fellowship, I have expanded my studies to include genomics, proteomics and biochemistry to probe the role chromatin structure plays during neural development.   I aspire to use my training to have a broad impact on the global scientific community, and influence the incorporation of scientific innovation into society.

Ellen J. Ezratty

Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York

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Stem Cell migration during wound-induced reepithelialization, with Elaine Fuchs

In my research with Elaine Fuchs, I am studying how the primary cilium regulates the function of epidermal stem cells during embryonic development and wound healing.

I was introduced to nature by my grandmother, who instilled in me a sense of awe for living things as we explored the forests near where I grew up in northwestern Pennsylvania, collecting roots, mushrooms and bugs.  My childhood fascination with nature led me to study biology.

I am interested in how cells interact with and respond to their environment.   In my doctoral research, I tried to understand how the microtubule cytoskeleton controlled the ability of cells to regulate focal adhesions, structures that allow a cell to communicate with its environment during cell migration. For my post-doctoral work, I maintained this interest, but also became fascinated with how stem cells in a tissue are able to “sense” the environmental developmental signals that lead to proper differentiation — leading me to study the function of the primary cilium in the epidermis. Primary cilia are evolutionarily conserved sensory organelles which act as a cellular antenna, allowing the cell to sample its extracellular environment and process signals that are essential for proper cell growth, development and differentiation.

Jeffrey Farrell

Department of Molecular and Cellular Biology, Harvard University, Boston, Massachusetts

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Novel signaling peptides in zebrafish development, with Alexander Schier

The goal of my project is to identify and characterize novel signals regulating development. Many of the processes taking place during development are controlled by a handful of well-characterized signaling pathways. This observation has led to the belief that most, if not all, of the major developmental signals are known. However, recent genomics projects have identified numerous uncharacterized genes, several of which encode short secreted peptides. A zebrafish mutant generated in one of these peptides, EndE, has a dramatic developmental phenotype, where the embryo forms little or no heart tissue. This suggests that EndE regulates the specification and/or migration of cardiac precursor cells. I will investigate the role of EndE in cardiac development and identify its receptor (Aim 1). Additionally, I will generate mutants for several other novel secreted peptides and analyze their phenotypes (Aim 2). My project will elucidate the role of a novel regulator of heart formation and identify new developmental signaling molecules.

Jose Gomez

Department of Pathology & Developmental Biology, Stanford University School of Medicine, Stanford, California

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Characterization of a novel 4 MDa oncogenic complex, with Gerald Crabtree

Recent genome-wide sequencing studies have revealed that genes encoding subunits of SWI/SNF-like BAF complexes are among the most frequently mutated in human cancers. Indeed over 20% of all human cancers have mutations in the subunits of these complexes. I have found that oncogenic subunits of this complex also form a much larger 4 MDa assembly that has been unappreciated to date, raising the question of which assembly is mediating tumor suppression by these complexes. I have also found that this larger complex is characterized by the specific assembly of three subunits, which will allow me to specifically characterize this 4 MDa complex at a biochemical and genetic level. One of these subunits is BAF180 (PBRM1) and my initial results indicate oncogenic mutations in this complex dominantly interfere with the oligomerization of the complex, raising the intriguing model that BAF180 is the keystone subunit of this oncogenic complex. The hypothesis that the 4 MDa complex targets a unique repertoire of chromatin-mediated, tumor suppressor processes will be tested by mass spec and genome-wide analyses. The work I propose will lead to a mechanistic understanding of cancer susceptibility genetics in the context chromatin-mediated control of gene expression.

Adam Granger HHMI Fellow

Department of Neurobiology, Harvard Medical School, Boston, Massachusetts

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Multilingual neurons: GABA corelease from cholinergic basal forebrain neurons, with 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

Department of Embryology, Carnegie Institution of Washington, Baltimore, Maryland

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Understanding the nuclear aging in the Drosophila follicle stem lineage, with 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.

Liangcai Gu (HHMI Fellow)

Harvard Medical School, Cambridge, MA

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Developing cell-free platform for biosynthesis and metabolic engineering of cancer therapeutics, with Dr. George M. 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.

Shawna Guillemette

Department of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts

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The role of SASP regulator GATA4 in senescence and cancer, with 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.

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.

Christine Hagan Merck Fellow

Department of Systems Biology, Harvard Medical School, Boston, Massachusetts

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Biochemical studies of the membrane-associated steps in the Wnt signaling pathway, with 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.

Tina Han Simons Foundation Fellow

Department of Physiology, University of California, San Francisco, California

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Dynamics of RNA granule assembly in temperature synchronization of clock rhythms, with 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.

Elizabeth S. Harris

W. James Nelson Laboratory / Stanford University, Stanford, CA

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Role of the APC multi-protein complex in regulating microtubule function at the membrane, with W. James Nelson

My current research focuses on understanding the relationship between the signaling and cytoskeletal functions of adenomatous polyposis coli (APC), a ubiquitously expressed tumor suppressor commonly mutated in cancers.

I developed curiosity and enthusiasm for science at a young age. My father and I spent many hours performing “experiments” at home, such as making soap-powered boats to explore the principals of surface tension, and building potato clocks to learn about redox reactions. These experiences sparked my passion for science and led me to pursue a career in research. I went on to receive my B.S. in biology from the University of New Hampshire, and my Ph.D. in biochemistry from Dartmouth Medical School. In addition to research, I enjoy teaching and mentoring young people. Outside of the laboratory I love to garden, cook, and hike with my dog.

Daisuke Hattori

Department of Neuroscience Columbia University / New York, NY

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Current research: The architecture and function of a neural circuit governing behavioral plasticity.

I became absolutely fascinated when I learned in my high school molecular biology class that I am made up of molecules and that even my thoughts, and behaviors derive from the intricate functioning of these molecules. This notion, rather surprising to me at the time, is at the root of my interest in neuroscience research. As an undergraduate at the University of Tokyo, I studied molecular mechanisms underlying early neural development of Xenopus in Masanori Taira’s lab. I then moved to Los Angeles,  where I did my PhD study on the role of molecular diversity of Drosophila Dscam in wiring neural circuits at Larry Zipursky’s lab at UCLA. Currently I work on the function of neural circuits mediating plastic behaviors in  Richard Axel’s lab at Columbia University.

Hans-Martin Herz

Stowers Institute for Medical Research, Kansas City, Missouri

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Histone H3K79 methylation in development and cancer pathogenesis with Dr. Ali Shilatifard

Current research: Identification of the machinery involved in H3K79 methylation and development of small molecular inhibitors against H3K79 methylation.

My interest in biology was awakened during my childhood, mainly through my grandfather who introduced me, through books, to the animal world. Through hobbies like fishing this interest was enforced and carried over into my adolescence. After high school, I started to study classical biology but realized early that I had a more pronounced interest in molecular biology. Starting to make fly food as an undergrad in a lab at the University of Heidelberg in Germany ultimately got me involved in the field of Drosophila genetics and development, and served as the springboard for my decision to move to Houston for my graduate studies. Part of my PhD work was to perform genetic screens to identify cell death regulators inDrosophila. One of the identified candidates turned out also to play a role in the regulation of chromatin. To further expand my experience in biochemical research I joined the lab of Ali Shilatifard in Kansas City. My work here is focused on better understanding the mechanisms by which certain factors regulate transcription through chromatin modification.

Norbert Hill

Department of Molecular and Cell Biology, University of California, Berkeley, California

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Illuminating novel actin cytoskeletal dynamics through a bacterial pathogen, with Matthew Welch

An array of actin modulators promotes actin filament assembly, disassembly, and organization. However, a detailed understanding how this vast network of factors work in concert to precisely regulate actin dynamics is at best incomplete. Many insights into actin regulation have been derived through examining how microbial pathogens manipulate the actin cytoskeleton during infection. The bacterial pathogen Mycobacterium marinum, a close relative of Mycobacterium tuberculosis, has the rare ability to stimulate actin-based motility in the host cytoplasm. However, the bacterial and host factors that contribute to this phenomenon are largely unknown.

Circumstantial evidence suggests M. marinum recruits the actin nucleation promoting factors WASP and N-WASP through an unusual ability to synthesize phosphorylated phosphoinositol (PIP) lipids. Subsequently, M. marinum activates WASP and N-WASP to nucleate actin filaments through an unfamiliar pathway. The goal of this work is to define M. marinum actin-based motility to further illuminate actin regulation at cellular membranes.

Wei-Hsiang Huang HHMI Fellow

Department of Biology, Stanford University, Stanford, California

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Spatiotemporal dissection of BDNF/TrkB in circuit assembly, with Liqun Luo

My passion in understanding the transcriptional mechanism underlying neurological disorders was inspired by my Ph.D. mentor, Dr. Huda Zoghbi, at Baylor College of Medicine. Currently, I work with Dr. Liqun Luo at Stanford University and focus on exploring the neurobiology of Rai1, a dosage-sensitive gene responsible for most phenotypes in Smith-Magenis syndrome (SMS). SMS is a neurodevelopmental disorder characterized by multiple congenital anomalies and many autistic features. Little is known about how Rai1, a putative transcriptional regulator, causes the neurological symptoms. I will create several mouse models to dissect the function of Rai1 in the mouse brain, and explore the possible therapeutic strategy for SMS.

John R. James

Howard Hughes Medical Institute University of California, San Francisco / San Francisco, CA

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Defining the role of the actin cytoskeleton in plasma membrane organization during T-cell activation, with Ronald D. Vale

My research involves the reconstruction of the T-cell antigen receptor signaling pathway in an orthogonal cell line to piece apart the molecular details of immune cell triggering, and how the system’s specificity and sensitivity can be genetically encoded.

I am originally from England and did both my undergraduate biochemistry degree and doctoral work at the University of Oxford. Throughout this period, my thoughts became increasingly focused on how signals are transmitted across the impermeable cell membrane, especially where the receptor responsible has no enzymatic activity of its own. For me, this area of research combines cell biology, biochemistry and systems analysis into one very exciting topic which, when applied to cells of the immune system, can have clear implications for new points of therapeutic intervention. Relocating to San Francisco for my postdoc has also provided me with great insights into the similarities and differences between approaches to scientific research on opposite sides of the Atlantic. I hope to combine the best of both worlds when starting my independent career in the near future.

Claudia Janda

Departments of Molecular & Cellular Physiology, and Structural Biology Stanford University School of Medicine / Stanford, CA

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Working in the lab of K. Christopher Garcia, I am studying the assembly and three-dimensional structures of Wnt-receptor complexes in order to understand Wnt signaling mechanisms, and facilitate development of new strategies to clinically target Wnt-associated diseases.

I have always enjoyed studying biological problems, particularly using structural and biochemical methods to understand underlying molecular mechanisms.  I am most fascinated by fundamental and hard problems that require creativity, tenacity and dedication to solve.  After having studied fundamental aspects of protein translocation, I now wish to examine receptor-ligand interactions with high relevance to human disease. Wnt signaling is important in many developmental and regenerative processes, and in a variety of human diseases, including many types of cancers. However, due to major technical difficulties, there is a complete lack of extracellular structural information about Wnt signaling activation and inhibition. We are using traditional and novel methodologies to obtain structural information that can ultimately facilitate the development of new strategies to therapeutically target Wnt signaling. Most of my spare time is spent running over the hills behind Stanford to train for a marathon, relax from hard work, and think about new ways to approach scientific problems.

Alyssa Johnson

Department of Biochemistry & Biophysics, University of California, San Francisco, California

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Mechanisms of VCP-mediated cellular degeneration, with Graeme Davis

I am exploring links between the genetic and molecular causes of neurodegenerative diseases, such as ALS, Alzheimer’s and Parkinson’s disease.  A common hallmark of almost all degenerative diseases is the progressive accumulation of protein aggregates.  Autophagy-lysosome mediated degradation is the major pathway that clears aggregates from the cytoplasm and autophagy defects are associated with many degenerative diseases.  Using Drosophila as a model system, I am studying how the autophagy-lysosome pathway functions normally and how this pathway is affected by degenerative disease causing mutations in both neurons and muscles.  Additionally, I am studying how extrinsic factors, such as sleep deprivation, affect the autophagy-lysosome system in the context of neurodegenerative diseases.

Martin Kampmann

Department of Cellular and Molecular Pharmacology University of California, San Francisco / San Francisco, CA

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I am developing a method for comprehensive and quantitative mapping of genetic interactions in human cells. I will use this method to elucidate cellular pathways that are hijacked by pathogenic bacteria and viruses.

I have always both been fascinated by the complexity of the living world, and partial to the precision and elegance of mathematics and physics. Therefore, I am striving to apply a quantitative and systematic approach to biology. As a graduate student with Günter Blobel at Rockefeller University, I characterized the structure and dynamics of components of the nuclear pore complex, the molecular device that controls transport into and out of the nucleus of cells. With Jonathan Weissman at UCSF, I am working on a method for the quantitative mapping of pathways in human cells, which I will use to elucidate how bacterial toxins exploit trafficking pathways in the host cell. Besides my passion for science, I love music. I enjoy going to concerts and the opera, and I have been a singer since high school. I have performed with different ensembles, including an all-biologist a cappella group I co-founded in New York, named “Darwin’s Finches.”

Avnish Kapoor HHMI Fellow

Department of Cancer Biology, MD Anderson Cancer Center, Houston, Texas

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Delineate mechanisms of oncogenic KRAS independent effector pathways of pancreatic cancer, with Ron De Pinho

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers with a 5-year survival rate of ~5%.

Mutational activation of KRAS is the most frequently detected genetic lesion in PDAC but it still remains undruggable.

This has resulted in efforts to identify and target Kras effector or alternate signaling pathways in PDAC. Recently the DePinho laboratory using a novel inducible PDAC mouse model demonstrated a critical role of oncogenic Kras in tumor maintenance. I propose to use this model for identification and characterization of the mechanisms of Kras independent growth and subsequently validate these findings in human cell lines and patient derived xenografts. Preliminary data I have generated shows Kras extinction in established tumors initially results in tumor regression, but subsequently relapse (in the absence of Kras) does occur. A major goal of this proposal is using integrative proteomic and genomic analysis to identify key signaling and genetic alterations that permit these tumors to relapse independently of Kras expression. I propose that this multi-dimensional approach will not only provide novel insights into mechanisms of PDAC progression but also identify therapeutic targets (for more effective cancer therapies) that can be exploited for understanding MEKi/PI3Ki therapy now entering the clinic.

Alexander Katsov

Bargmann Laboratory Rockefeller University, New York, NY

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How do individual cells arrive at cohesive function as an organ in the course of development? We study this question by tracking functional maturation of the nervous system in the nematode C. elegans.

My first steps in research brought me to J.W. Hastings’s lab at Harvard to work on bioluminescence, and subsequently to Michael Greenberg’s lab at Children’s Hospital Boston, where I worked on the signal transduction of apoptosis and wrote an undergraduate thesis.  A seminar on systems neuroscience in my senior year lighted a path of questions that, along with additional training in the labs of Bill Newsome and Krishna Shenoy at Stanford, led to graduate work with Tom Clandinin to initiate a genetic dissection of neural circuits that inform visual behavior.  My current work aims to understand the developmental steps that shape circuit function in a complete, mature nervous system.

Hyun-Eui Kim

Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA

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Study of relationship between metabolism and protein homeostasis in neurodegenerative diseases, with Andrew Dillin

In the lab of Andrew Dillin, I study the mechanism of proteotoxicity in age-onset neurodegenerative diseases such as Alzheimer’s and Huntington’s. To better understand how protein homeostasis plays a role in these diseases, I use animal model systems — such as c. elegans and mice — that express toxic proteins including the amyloid beta peptide (Alzheimer’s) or poly-glutamate protein (Huntington’s).

I was born in Seoul, Korea. My desire to become a  good scientist outweighed anxiety over separating from my family, so I moved to the U.S, obtaining my PhD in biochemistry at the University of Texas Southwest Medical Center. There, I studied the mechanism of cell death and apoptosis, in particularly in various cancer cells. For my postdoc career, I wanted to try new systems to learn more of biology and use my biochemistry expertise. I chose a genetics lab where I can work with live animals and develop a better understanding of pathology in animal model systems, rather than just in groups of cells. I am hopeful that my basic science findings can turn into therapeutic tools. Outside of work, I play piano and paint, and enjoy walking my little dog on the beautiful San Diego beach.

Matthew Phil Klassen

Department of Physiology, University of California, San Francisco / San Francisco, CA

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My research investigates the assembly and functional organization of neural circuits, using neurons innervating the Drosophila heart as a model system.

I am a scientist because doing science allows one to pursue aspirational questions without predilection for particular answers. With perseverance, each discovery opens doors to greater, albeit sometimes unexpected, understanding. Through this process scientists strive to improve the human condition, a pursuit I feel privileged to play a small part in, and in which I hope to inspire others to participate. In my free time I have transitioned from an avid scuba diver, underwater photographer and fancier of tribal art, to a father who is amazed by the richness of life that can be appreciated closer to home.

Suzanne K. L. Komili (HHMI Fellow)

Department of Biochemistry and Biophysics, University of California, San Francisco, California

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Investigation of the role of chromatin dynamics in programming gene expression noise, with Dr. Hiten Madhani

I am studying genetic determinants of non-genetic variability, or “noise,” in gene expression using the yeast Saccharomyces cerevisiae.

I started college fully intending to become a physician. However, an excellent first-year interdisciplinary course exposed me to the excitement of research science, and demonstrated the power/utility of using tools from one discipline to study problems in another. I pursued a degree in physics, with the intention of applying the quantitative tools and techniques that I had learned to study biology.

My graduate studies were supervised by both Pam Silver, a molecular and cellular biologist, and Fritz Roth, a statistician and computational biologist. Their joint tutelage allowed me not only to learn fundamental molecular biology and genomics, but also how to analyze data I generated in high-throughput and computational studies. My post-doctoral research on noise in gene expression provides another opportunity to apply mathematical and computational techniques to high-throughput datasets that I am collecting myself. I hope that these studies will provide new insight into problems as fundamental.

Claus-Dieter Kuhn

W. M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, New York

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Structure and function of Piwi proteins in planarians essential for regeneration and stem cell differentiation, with Leemor Joshua-Tor

I am studying the functional importance of small RNAs in the regeneration of freshwater flatworms. My hope is that dissecting the importance of PIWI proteins in that process by X-ray crystallography and biochemical techniques will lead to a better understanding of regeneration in general and its applicability in human disease.

I grew up in southern Germany, interested in languages, music, and biochemistry. I decided to focus on science in college, studying biochemistry at the University of Regensburg. Drawn mainly by my love for nature, I moved to Sweden to complete my master’s degree at the University of Stockholm.  For my PhD I returned to Germany. At the University of Munich, I worked mainly on protein crystals; however, in case crystals didn’t grow happily, I developed my interest in other structural techniques, like cryo-electron microscopy.

For postdoctoral work I joined the Cold Spring Harbor Laboratory, known for its impact in small RNA biology. After an excursion into biotech industry, where I was working for proteros biostructures in Munich, I am back in the US, working on the involvement of small RNAs in planarian regeneration, employing structural techniques combined with genetic and biochemical tools.

Anita Kulukian

Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY

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I am researching the connection between centrosome function and asymmetric cell division.

Science was always the subject that intrigued me the most. Biology in particular had always captivated me, and so I majored in molecular and cell biology at the University of California, Berkeley as an undergraduate.  However, not until I was a graduate student in Don Cleveland’s lab at the University of California, San Diego did I realize how fascinated I was by the molecular processes regulating cell division, the outcome that division can have on the developing and adult organism, and the connections between aberrant division and human disease. We have so much yet to learn about this essential process, which is why I chose to continue in this area of research for my postdoctoral studies.

Prabhat S. Kunwar

Division of Biology, California Institute of Technology, Pasadena, California

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Genetic dissection of amygdala neuronal circuitry underlying fear and anxiety in mice, with David Anderson

My research in the lab of David J. Anderson focuses on genetic dissection of neuronal circuitry underlying defensive and offensive behaviors in mice. We use the latest genetic techniques of neuronal marking, mapping and manipulation in order to explain the neuronal basis of these behaviors.

I was born into a middle-class family in a small town in southern Nepal. After finishing high school in my hometown, I began my undergraduate studies in the biology program of Tri-Chandra College in Kathmandu, Nepal.

I considered scientific research early on, as I realized its power both to explain the natural world and our existence, and to bring practical benefits to society. Soon, I became captivated by the spectacular progress in genetics and biomedical sciences. Not seeing any further academic opportunities in the biomedical sciences in Nepal, I came to the U.S., obtaining my undergraduate degree in biotechnology at the University of Nebraska at Omaha. I then did my PhD under the supervision of Ruth Lehmann at New York University Medical Center. I enjoy traveling, and am also involved in promoting biomedical research and education in Nepal via a biomedical society formed by a group of Nepali scientists.

Soo Hee Lee

School of Public Health Yale University, New Haven, CT

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Mechanism for translational regulation of HMG CoA reductase, with Russell DeBose-Boyd

I am trying to figure out what an Argonaut-like protein is doing in the mitochondrion of the sleeping sickness parasite, Trypanosoma brucei.

I did my graduate work at the Johns Hopkins School of Medicine, in the Department of Biological Chemistry, where I worked on trypanosome fatty acid synthesis.  Protozoan parasites that cause human disease—i.e. malaria, Chagas disease, leishmaniasis, and sleeping sickness—are not only relevant medically, but often have surprising and unusual biologies that fill pieces of the larger picture of our own evolution.  For example, GPI anchors were first discovered in T. brucei and have a specific role in parasite evasion of the host immune system.  Besides my fascination with the biology of the bizarre, I enjoy living in New Haven with my dog Jack.

Duncan Leitch Simons Foundation Fellow

Department of Physiology, University of California, San Francisco, California

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Using unique crocodilian physiology to probe somatosensation, with David Julius

The somatosensory system transduces physical and chemical stimuli from the periphery to the CNS to mediate the senses of touch, temperature, proprioception, and pain. However, there is little information regarding the molecular signaling mechanisms of various mechanical stimuli. Activation of mechanosensitive fibers by injury represents a major source of pain, and thus a greater understanding of how these fibers are activated under normal (acute) and pathophysiological (chronic) pain states is an important goal at both basic and translational levels.

To address this important problem, I shall exploit an unconventional model system with exceptionally acute mechanosensation: the crocodilians, whose jaws are covered in discrete tactile receptors. Recent physiological work suggests the receptors mediate a sense of touch exceeding that of human fingertips, providing a high-resolution tactile portrait of surrounding environments. Following recent work in the sponsor’s lab identifying novel, highly-sensitive infrared (heat) ion channel subtypes in rattlesnakes and vampire bats, we propose to exploit state-of-the-art transcriptome profiling to uncover molecules that endow crocodilian sensory ganglia with exquisite mechanosensitivity. Identified molecules will be examined in more tractable genetic systems (e.g. mice) for further functional analyses, with the goal of uncovering molecular mechanosensory mechanisms in mammals under normal and/or pathophysiological pain states.

Manuel Leonetti HHMI Fellow

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California

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Understanding sphingolipid homeostasis in human cells: function and regulation of ORMDL proteins, with Jonathan Weissman

Sphingolipids are essential membrane components and signaling messengers central to many cellular processes, in particular apoptosis. Consequently, sphingolipid levels are dysregulated in many diseases, in particular cancer. However, how cells sense and regulate their sphingolipid content is still poorly understood. The ORM membrane protein family, conserved from yeast to humans, is a key sphingolipid homeostatic sensor: the Weissman laboratory established that ORM proteins mediate a feedback response between cellular needs and de novo sphingolipid biosynthesis. While the molecular details of this response have been elucidated in yeast, how sphingolipids regulate the function of the mammalian orthologs (ORMDL) is completely unresolved. I propose to use a combination of biochemical and cellular biological approaches, together with a transformative genetic interaction mapping strategy, to characterize the mechanisms linking ORMDL function to sphingolipid homeostasis in human cells. Combining the expertise of our laboratory with my own background in membrane protein biochemistry, I will elucidate how the functional properties of ORMDL are modified by specific sphingolipid species and how ORMDL activity in turn modulates sphingolipid biosynthesis. My results will give substantial insights into the mechanism of sphingolipid homeostasis in humans and could open the way for new strategies for the therapeutic tuning of sphingolipid metabolism.

Ang Li

Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York

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Dissecting the molecular crosstalk that governs melanocyte stem cells in their niche, with Elaine Fuchs

Elucidating the molecular mechanisms underlying the regulation of stem cells (SCs) is of great importance for their clinical applications in regenerative medicine, cancer therapy, and aging. SCs are regulated by communication with their specialized microenvironment known as the niche. The bulge niche of the mammalian hair follicle holds Epidermal SCs (EpSCs) and melanocyte SCs (McSCs). While their behavior is tightly coordinated, little of the crosstalk involved is known. My objective is to understand how these two SC populations can remain in quiescence and become activated and differentiate synchronously to generate pigmented hair. I have therefore devised a novel and rapid screening strategy, which combines the powers of mouse genetics with in utero lentiviral shRNA delivery to EpSCs. I will identify EpSC factors, including secreted and cell-to-cell interactions, which govern the differentiation, survival and/or quiescence of embryonic and adult McSCs. My strategy should also uncover genes required for EpSC survival and/or melanin uptake by transit-amplifying SC progeny within the hair bulb. Since my strategy is to screen for factors that uncouple McSC from EpSC behavior, the potential targets could be useful in designing drugs for treating melanomas and pigment disorders.

Wanhe Li HHMI Fellow

Laboratory of Genetics, The Rockefeller University, New York, New York

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Decoding neuromodulatory control of sleep and wakefulness in Drosphila, with Michael Young

The application of Drosophila as a model system has led to many fundamental discoveries concerning the regulation of sleep and wakefulness, including conserved molecular pathways and neural circuits that parallel human studies. Superimposed on the neural circuit wiring diagram are the neuromodulators – biogenic amines and neuropeptides, which are key mediators of the opposing states of sleep and wakefulness. Preliminary research has suggested a novel neuromodulatory circuit in Drosophila that signals arousal and antagonizes sleep. In this proposal, a set of circuit tracing experiments is planned to map this circuit and a novel imaging tool will be developed to visualize peptidergic modulation during states of sleep and wakefulness. In addition, whole-genome transcriptional and translational profiling experiments are proposed to investigate the molecular features of brains under neuromodulatory control. The long-term goal of this proposal is to gain a deep understanding of neuromodulatory processes on genetic, circuit and molecular levels that affect sleep/wake regulation. These studies may also shed light on broader principles of brain function, such as consciousness and memory.

Brian Liau

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts

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Activity-based profiling of lysine-specific demethylase 1, with Bradley Bernstein

My research interests lie at the interface of chemical biology with cancer epigenetics and chromatin biology. In Brad Bernstein’s lab, I am currently studying the function of histone demethylases in epigenetic-mediated mechanisms of drug persistence in glioma stem cells. We found that a subpopulation of glioma stem cells indefinitely persist in the presence of potent receptor tyrosine kinase inhibition by entering a slow-cycling state that recapitulates transcriptional and epigenetic features found in primary tumors. In particular, this slow-cycling state is characterized by high histone demethylase expression and widespread chromatin remodeling. We hypothesize that these demethylases may serve as key enablers of epigenetic plasticity in quiescent glioblastoma cells through the removal of chromatin barriers, thus catalyzing the transition to new epigenetic states that promote adaptation, survival, and disease recurrence. We hope to uncover the functions of histone demethylases in glioma and address the potential of attendant therapeutic strategies in neuro-oncology.

Louisa Liberman

Biology Department and Center for Systems Biology Duke University, Durham, NC

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My current research involves investigating cell-type specific growth regulation in response to cross-kingdom communication in Arabidopsis thaliana.  I am interested in learning about the signaling that occurs between plants and microbes in the soil resulting in developmental and physiological changes in the plant.

Raised in Lexington, Massachusetts, I attended Mount Holyoke College, from which I graduated with a double major in biological sciences and Spanish.  I received my PhD working with Angelike Stahopouolos at the California Institute of Technology.

I have always loved puzzles and nature.  Being a scientist means that I have the opportunity to ask questions and learn about how organisms develop and adapt to their environments.  I was drawn to a career in biology because it appeals to my curiosity and provides exciting possibilities to explore what we do not know about nature. When not engaged in my research, I like to spend time outdoors, particularly gardening.  I also enjoy running, biking, skiing, and swimming.

Wen-Hui Lien

Laboratory of Mammalian Cell Biology and Development Rockefeller University, New York, NY

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Current research: Understanding differential roles of Wnt signaling — beta-catenin-Lef/TCF complex in regulation of epidermal homeostasis, hair follicle stem cell maintenance and activation.

My interests in science started in elementary school in my home town of Tapei, Tawain. Later, when my beloved grandfather died of cancer, I was inspired to understand cancer biology.

At Kaohsiung Medical University I did research in molecular biology, for which I received the Undergraduate Innovative Research Award from Taiwan’s National Science Council. During my graduate research at the Institute of Molecular Medicine in National Chung Kung University, I became interested in understanding how tumor cells escape from different cancer therapies.

When I came to the U.S., I spent a year at the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle, where my research was to identify novel genes that inhibit myc-induced apoptosis.   My PhD dissertation research at the University of Washington / FHCRC focused on understanding underlying mechanisms and physiological significance of the cell adhesion protein, aE-catenin. After obtaining my PhD in 2008, I received the 2009 Harold M. Weintraub Graduate Student Award.  In April, 2009 I joined the laboratory of Elaine Fuchs at Rockefeller University.

Oliver W. Liu (HHMI Fellow)

Biology Department, Howard Hughes Medical Institute Stanford University / Stanford, CA

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Immunoglobulin-domain proteins and synaptic specificity, with Dr. Kang Shen

Dendrites of neurons often adopt complex and morphologically diverse branched arbor structures. The development and organization of these arbors fundamentally determine the potential input and connectivity of a given neuron.  My research in the laboratory of Kang Shen has focused on identifying the molecular mechanisms that regulate branching and morphogenesis of neuronal dendrites using the nematode Caenorhabditis elegans as a model system.

Previously, as a graduate student at the University of California, San Francisco,  I worked in the laboratory of Hiten Madhani, where I developed large-scale systematic genetic approaches to identify genes involved in pathogenesis by the human fungal pathogen Cryptococcus neoformans.  As an undergraduate at Harvard University, I worked in the laboratory of Ed Harlow where I studied the mechanisms of transcriptional repression by the tumor suppressor protein pRB.

Xin Liu

Department of Structural Biology Stanford University School of Medicine, Stanford, CA

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Structural and biochemical studies of transcription initiation by RNA polymerase II and its associated transcription factors, with Roger Kornberg

My current research uses a combination of X-ray crystallography, biochemistry, and chemical biology to address the molecular mechanism of transcription preinitiation and initiation by RNA polymerase II. Specific topics include the assembly of the  transcription preinitiation complex, transcription start site selection, and abortive initiation.

My biomedical research training started at Nanjing University, China, where I majored in biochemistry as an undergraduate.  In 2007, I received my PhD in chemistry from the University of Pennsylvania, where I did my thesis study in the laboratory of Ronen Marmorstein at The Wistar Institute. My graduate work centers on the structural and functional studies on the retinoblastoma and p300/CBP tumor suppressor proteins and their regulation by viral oncoproteins. During my graduate study I became fascinated by the broad field of transcription, epigenetics and chromatin, given its enormous impact on human diseases. I joined the laboratory of Roger Kornberg at Stanford University in 2008 and, since then, I have been studying the molecular basis of eukaryotic transcription by RNA polymerase II.

Xing Liu HHMI Fellow

Division of Biology, California Institute of Technology, Pasadena, California

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Regulation of cullin-RING ubiquitin ligases by Cand1, with Raymond Deshaies

Protein function and stability can be modulated by attachment of ubiquitin, which is achieved by three sequentiallyoperating enzymes, of which the last enzyme in the cascade, ubiquitin ligase (E3), confers substrate recognition and ubiquitination. The Skp1–Cul1–F-box (SCF) complex is one type of cullin–RING ubiquitin ligase (CRL), and its substrate specificity is determined by which one of the 69 different F-box–Skp1 substrate adaptors is recruited to the Cul1 scaffold. Cul1 also binds Cand1 in a manner that is mutually exclusive with F-box–Skp1. Current studies have revealed that Cand1 is a novel exchange factor that equilibrates Cul1 with the total cellular pool of free F-box–Skp1 complexes. However, the mechanism and regulation of the Cand1-mediated protein exchange process and the impact of Cand1 on the cellular ubiquitinated proteome remain elusive. This proposal aims to provide insights into the mechanism and significance of Cand1 function through 1) analyzing Cand1-SCF interactions and effects of substrates at millisecond timescales, 2) investigating effects of Cand1 on Cul1 modifications, 3) evaluating changes in CRL assembly and activity in Cand1-depleted cells. These studies will deepen understanding of the biological role of Cand1 and how the repertoire of CRLs is sustained and regulated.

Wan-Lin Lo

Department of Medicine and Rheumatology, University of California, San Francisco, California

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The role of T Cell receptor-induced sulfenylation in CD4+ T Cell differentiation, with Arthur Weiss

The production of reactive oxygen species (ROS) is required for T cell activation and expansion. Dysregulation of ROS-producing NADPH oxidase or mitochondria causes the alteration of T cell function in several clinical diseases, including cancers. ROS modifies T cell receptor (TCR) signaling cascades, in part, through a post-translational modification known as protein sulfenylation. Deprivation of ROS-mediated sulfenylation impaired T cell proliferation and activation, yet elevated ROS rates in tumor microenvironment also suppressed T cell mediated anti-tumor responses. Though the importance of ROS in TCR signaling and hematopoietic malignancies is apparent, little is known about the roles of ROS-mediated sulfenylation in T cell signaling. We propose to introduce a new chemical probe to detect changes in protein sulfenylation directly in primary T cells. We will elucidate how the sulfenylation of key substrates is controlled by ROS generation and TCR stimulation, and also explore biological impacts of non-sulfenylateable key substrates in T cell function and TCR signaling.

Vicki P. Losick

Department of Embryology, Carnegie Institute of Science, Baltimore, MD

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Drosophila melanogaster spermatheca: a new model for the prostate gland, with Dr. Allan C. Spradling

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’s 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’m an aspiring amateur golfer, jazz enthusiast, and cook.

John Maciejowski Merck Fellow

Laboratory of Cell Biology & Genetics, The Rockefeller University, New York, New York

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Can telomere attrition initiate chromosome shattering?, with Titia de Lange

I am researching the causes of complex, chromosome rearrangements and hypermutation in cancer genomes. Recently uncovered by next generation sequencing, these catastrophic phenomena are understood to play a major part in cancer progression, but the instigating mechanisms are not clear. Telomere crisis occurs during tumorigenesis when depletion of the telomere causes chromosome to chromosome fusions. These fusion events result in the formation of dicentric chromosomes, which are known to be destabilized during cell division. I hypothesize that these fusion events can precipitate chromosome fragmentation and thus fuel more complex chromosome rearrangements and hypermutation. I am using genetic and cell biological techniques, including high resolution time-lapse imaging, to investigate the immediate fate of these fused chromosomes, as well as next generation sequencing to identify the genomic consequences of their ultimate resolution.

Lindsey J. Macpherson

Department of Biochemistry and Molecular Biophysics Columbia University, New York, NY

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Molecular characterization of gustatory labeled lines, with Charles Zuker

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’s 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’s been a year since the move, and while I’m still a San Diegan at heart, New York has given me a fresh perspective on life and science.

Florian T. Merkle

Department of Molecular and Cellular Biology, and Department of Stem Cell and Regenerative Biology Harvard Medical School, Cambridge, MA

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Generation of hypocretin Neurons from narcoleptic patients, with Alexander Schier

The sleep disorder narcolepsy is caused by the degeneration of hypocretin neurons. The goal of my research is to derive hypocretin neurons from narcoleptic patients to study the cause of hypocretin neuron loss.

I was born in Konstanz, Germany and moved to Minnesota at an early age. As a teenager, I decided I wanted to become a neurosurgeon and spent my summers in a neurosurgery laboratory. I discovered I preferred working at the bench and, as an undergraduate at Caltech, I explored different fields of neuroscience. I was most fascinated by the problem of how the brain develops, and studied the lineage and organization of neural stem cells and their progeny in the postnatal brain. My current work combines my interests in cell type specification, the connection of circuitry to behavior, and developing in-vitro models of human diseases. In my free time, I enjoy hiking, cycling, cooking, and bartending.

David G. Mets (HHMI Fellow)

Brainard Department of Physiology, University of California, San Francisco, California

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Identification of genetic constituents of learning in songbirds through a new system for molecular marker development, with Dr. Michael

Prashant Mishra

Division of Biology California Institute of Technology / Pasadena, CA

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I am investigating mechanisms of mitochondrial fusion within cells. The goal is to gain a better understanding of how mitochondrial dynamics are regulated.

My interest in scientific research began when I was young, and was fostered through participation in research programs and science fairs in junior high and high school.  After completing my bachelor’s degree in biochemical sciences at Harvard University, I worked briefly for a biotechnology company developing treatments for patients suffering from rare genetic disorders.  I then entered an MD/PhD program the University of Texas Southwestern Medical Center, allowing me to conduct basic science research while receiving training in patient care.  I currently conduct research as a postdoctoral fellow at the California Institute of Technology, and plan to establish my own basic science laboratory in the future.

Joshua Modell Simons Foundation Fellow

Laboratory of Bacteriology, The Rockefeller University, New York, New York

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Self vs. non-self discrimination during CRISPR-Cas adaptive immunity, with Luciano Marraffini

A hallmark of immune systems is the ability to selectively recognize and destroy invading agents while ignoring the hosts’ own molecular milieu. Remarkably, CRISPR-Cas systems provide single bacterial cells with adaptive immunity by cleaving the nucleotides of previously encountered invaders based on sequence-specific RNA guides. The mechanisms ensuring that these molecular memories are exclusively created from non-self, invading elements are unknown.

I study “adaptation”, the first phase of CRISPR-Cas immunity, whereby short “spacer” sequences of invading DNA are inserted into CRISPR loci. Specifically, I am identifying and characterizing the factors that influence adaptation and allow bacterial hosts to selectively generate spacers from foreign viruses and plasmids. This work will lead to a better understanding of how bacteria have solved a fundamental immunological problem and could provide an additional foundation for the development of CRISPR-Cas-derived technologies.

Sabin Mulepati HHMI Fellow

Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts

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Live cell imaging of chromatin supercoiling dynamics in human cells, with Sunney Xiaoliang Xie

I received my BS in Biochemistry from Susquehanna University and my Ph.D. in molecular biophysics in Professor Scott Bailey’s lab at Johns Hopkins University. Broadly speaking, I am interested in exploring the structure-function relationship of biological macromolecules. For my Ph.D. thesis, I used different structural and biochemical methods to investigate the mechanism by which bacteria use their CRISPR immune system to destroy foreign DNA.

In my postdoc with Professor Sunney Xie at Harvard University, my research focuses on the effects of chromatin structure on eukaryotic gene expression. More specifically, I am interested in understanding the dynamics of DNA supercoiling at a single-cell level. Outside the lab, I enjoy playing soccer and going on hikes.

Alexandre Alves Neves

Fred Hutchinson Cancer Research Center Seattle, WA

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Modeling Myc-induced tumorigenesis in Drosophila, with Robert N. Eisenman

I use Drosophila neural stem cells, and the powerful genetic tools available in this organism, to uncover new genes that regulate how stem cells balance self-renewal with differentiation.

I was born in Brazil and grew up in Brazil, the United Kingdom, and Portugal. I have always been fascinated by how cells acquire different fates during development. I first addressed this question as an undergrad in Portugal, by studying transcriptional regulation of sporulation in the bacterium Bacillus subtilis. Excited about pursuing a scientific career,  I enrolled in the Gulbenkian PhD Programme (Portugal) in Biomedicine. My interest in using a simple genetic system to study central questions in developmental biology led me to work with Jim Priess, an expert in the model system C.elegans. I focused on understanding how the Notch signaling pathway turns on different genes in diverse times and places during development. The Notch pathway, critical for normal development, is also misregulated in many human cancers. In Bob Eisenman’s lab, I’m using the fruit fly Drosophila to look for new genes that regulate stem cell behavior. I enjoy playing/watching soccer, cooking, spending time with my wife Courtney, and being a father to our baby boy!

Eugene Oh

Department of Molecular and Cell Biology, University of California, Berkeley, California

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Investigating the ubiquitin-dependent mechanisms that govern human stem cell maintenance and the course of neurogenesis, with Michael Rape

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.

Brant K. Peterson

Department of OEB, Museum of Comparative Zoology, Harvard University, Cambridge, Massachusetts

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Exploring and exploiting phenotiypic complexity to unearth the genetic architecture of adaptation and disease, with Hopi Hoekstra

Zachary S. Pincus

Department of Molecular, Cellular, and Developmental Biology / Yale University, New Haven, CT

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Quantitative longitudinal analysis of aging C. elegans populations, with Frank Slack

Current research: I am investigating the causes of differences in lifespan between individuals, using the nematode work Caenorhabditis elegans as a model organism.

My overall scientific interest is in the control of noise in biological systems: how do organisms buffer themselves from, or exploit, stochastic events? How do individuals in a population begin to diverge from one another, and what are the consequences?

After growing up in Montana and majoring in biological sciences at Stanford University, I did my PhD training in the lab of Dr. Julie Theriot at Stanford, studying shape variability in populations of bacteria and epithelial cells. This work allowed us to devise qualitative and quantitative models of how the biochemistry of the actin cytoskeleton influences the large-scale geometry of moving cells. I am now with the lab of Dr. Frank Slack at Yale. And to the extent that postdocs permit themselves to venture outside the lab, I like to spend my time hiking and cycling.

Jessica Polka

Department of Systems Biology, Harvard Medical School, Boston, Massachusetts

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Mobility and maintenance of a carbon-fixing micro compartment: bioengineering applications and insights into broad mechanisms of bacterial spatial organization, with Pamela A. Silver and Timothy J. Mitchison

I am interested in the mechanisms that guide proteins to assemble into mesoscale structures, from force-generating cytoskeletal polymers to metabolic microcompartments. While the basic principles underlying these systems underpin much of biological organization, I focus on tractable polymers found in bacteria. For example, as a graduate student in Dyche Mullins’ lab at UCSF, I reconstituted a three-component bacterial plasmid-segregating actin system in vitro and elucidated the multiple regulatory functions of its single accessory protein. As a postdoc, I have investigated the assembly of the carboxysome, a protein organelle in cyanobacteria that we found grows like a crystal until it is rapidly coated by a layer of shell proteins. Currently, I am interested in a long-range protrusive apparatus actuated by chemical changes.

I hope that a thorough understanding of these machines can permit the rational design of self-assembling structures suited for use in nanotechnology, metabolic engineering, and drug delivery.

Jeffrey Rasmussen Merck Fellow

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California

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Interactions between sensory neurons and skin, with Alvaro Sagasti

My work in Alvaro Sagasti’s lab focuses on interactions between the epidermis and the axons of touch-sensing neurons. I am particularly interested in how the epidermis regulates axon repair following injury.

I grew up in Ithaca, NY and received my BS in Computational Biology from Brown University. During my graduate studies at University of Washington in Seattle, WA, I became interested in the remarkable and diverse behaviors of epithelial cells. For my thesis, I studied mechanisms of epithelial tube formation in C. elegans with Jim Priess at the Fred Hutchinson Cancer Research Center. The Priess lab was a great place to learn genetics and cell biology and I am currently applying this training to understand how our largest epithelial organ – the skin – regulates repair of the sensory nervous system. Outside of the lab, my wife and I enjoy exploring Los Angeles with our son.

Elizabeth L. Read (Frederic M. Richards Fellow)

Department of Chemical Engineering Massachusetts Institute of Technology / Cambridge, MA

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Understanding the origin of immunodominance in mouse models and humans with diverse host genetics, with Dr. Arup Chakraborty

T cells recognize diverse molecular signatures of pathogens on the surfaces of infected or antigen-presenting cells, but a significant immune response is mounted against just a few of these signatures during a typical infection. I’m using mathematical models and computer simulations to study the mechanisms of this phenomenon, termed “immunodominance,” and its implications for viral infections, vaccine design, and autoimmunity.

I earned BAs in chemistry and mathematics from the University of Colorado at Boulder in 2003 and a PhD in physical chemistry from the University of California at Berkeley in 2008.  Before I began working in Arup Chakraborty’s group at MIT, I studied light harvesting by photosynthetic plants and bacteria in the laser spectroscopy lab of Graham Fleming at Berkeley. This work inspired my interest in using theoretical and computational modeling to gain mechanistic understanding of complex biological systems. When not pursuing interdisciplinary science, I like to cook, run, swim, and read historical biographies.

Dragana Rogulja

Laboratory of Genetics, Rockefeller University, New York, NY

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A search for the molecular mechanisms and physiological basis of sleep, with Michael Young

I am currently conducting research aimed at understanding sleep: its biological significance and how it is regulated.

I grew up in Belgrade, Serbia, convinced that the only interesting career would be in the arts or literature. Choosing science as my path came as a consequence of the harsh economic reality following the wars of the 1990s. For a while, I felt slightly uncomfortable, seeing myself as an outsider playing the role of a scientist. Now, I am convinced that science is one of the most exciting paths one can follow. I realize that scientists and artists are often cut from the same cloth, using different approaches to understand life. This may be particularly true in neuroscience, which I chose as my focus. Even without a scientific background, one can easily appreciate many of the questions asked in this field  — what does it mean to feel something, what drives us, why do we have to sleep every night? One of my hobbies is taking photographs of great works of art that have sleep as their theme. Chances are that your favorite artist is in my collection.

June L. Round (Merck Fellow)

Division of Biology, California Institute of Technology, Pasadena, California

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The contribution of the intestinal microbiota to development of colon cancer, with Sarkis Mazmanian

I am interested in how commensal bacteria influence the development of the intestinal immune system  and their impact on disease.

Bacterial organisms residing within our bodies outnumber our own cells by an order of magnitude. We are often taught that bacteria cause disease and that our immune systems function to recognize and eradicate them. However, commensal bacteria do not make us sick and our immune systems tolerate their presence. My postdoctoral research is directed at understanding why we allow these bacteria to live with us. We have shown that colonization by one of these commensal organisms  has beneficial consequences for its host as it can protect from  development of inflammatory bowel disease (IBD). As 30 percent of IBD patients develop colonic cancer, colonization by beneficial bacteria might also serve as a potential cancer preventive. Additionally, in studying this bacterium we have uncovered novel mechanisms by which our bodies detect and tolerate bacteria. Understanding what organisms live within our bodies and deciphering how they individually influence the development of immune responses could ultimately lead to the creation of therapies to treat multiple human diseases.

Antoine E. Roux

Department of Biophysics and Biochemistry University of California, San Francisco / San Francisco, CA

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My project focuses on the biology of aging in the nematode C. elegans. I am studying early stochastic determinant of life span that are not linked to hereditary traits.

I grew up in France and moved to Canada to do my PhD work at the University of Montréal, where I studied cellular aging in fission yeast. I developed this yeast species (called S. pombe) as a new model to study aging, describing the first long-lived mutants of this organism. I was passionate about my research and today in Cynthia Kenyon’s lab at UCSF I am tackling new questions in aging using C. elegans as a model.  In the past 20 years, research has demonstrated that aging is not a random process but one that is tightly regulated. We now know about many genes and conditions that extend life span and at the same time delay the onset of age-related diseases. However many mysteries remain: What determines aging at the molecular level? Why are aging rates different between individuals in a given species? Why do some species live longer than others?

Ashley Rowland

Department of Molecular and Cell Biology, University of California, Berkeley

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Ubiquitin regulation of neural development and cell fate

The goal of my postdoctoral research is to discover essential regulatory mechanisms that control neural developmental programs and cell fates in a complex organism. Abnormal neural development is central to many pediatric diseases and the source of many cancers originating in the nervous system. Development requires precise signaling pathways to facilitate cell-cell communication and maintain normal function and prevent disease. Thus, I propose to study neural development in Xenopus tropicalis embryos, an established model system, and identify evolutionarily conserved complexes in human embryonic stem cells undergoing neuronal differentiation. A small modifying protein, ubiquitin is an important part of regulatory pathways that control nearly every aspect of cell physiology and is frequently perturbed in cancer. Recent work has demonstrated that ubiquitin modification is an essential regulator of development and cell fate. I will use combination of genetic, proteomic, biochemical, and cell biology techniques to identify crucial ubiquitin complexes and reveal the molecular mechanism of neural differentiation programs. Together, this work will provide unprecedented insight into the regulation of early embryonic differentiation programs and reveal therapeutic avenues to treat human cancers.

Rahul Roy

Department of Chemistry and Chemical Biology Harvard University, Cambridge, MA

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Role of nuclear organization in gene regulation, with Sunney X. Xie

Current Research: Probing gene expression in live eukaryotic cells at single molecule level

I majored in biotechnology and biochemical engineering at the Indian Institute of Technology in Kharagpur, India and joined the biophysics and computational biology graduate program at the University of Illinois at Urbana-Champaign in 2001.  I received my doctorate in 2007 for my work on understanding the mechanism of various proteins involved in replication and transcription using in vitro single molecule techniques in the Taekjip Ha laboratory. I am currently a post-doctoral fellow in the lab of Sunney Xie.  My current research interests are twofold: 1) development of novel optical imaging techniques to probe the behavior of single biomolecules in live eukaryotic cells; and 2) implementation of single-molecule imaging to understand cellular gene expression and cell-fate determination. My efforts are geared towards extending the usefulness of single molecule techniques to mainstream biology.

Marissa Saunders HHMI Fellow

Department of Biochemistry, University of Utah, Salt Lake City, Utah

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ESCRT-III mediated membrane scission, with Wesley I. Sundquist

Computational modeling will be coupled with experiment to investigate the mechanism by which Endosomal Sorting Complexes Required for Transport (ESCRT)-III complexes remodel and sever membranes. The ESCRT pathway relates to cancer pathogenesis by: mediating downregulation of membrane-bound receptors; catalyzing the abscission stage of cytokinesis; and controlling exosome formation. Of the five essential core ESCRT complexes, the ESCRT-III complex uniquely encodes the membrane severing activity. ESCRT-III subunits form filaments that can bind membranes, selforganize into higher-order assemblies, and use these assemblies to constrict membranes and promote fission. Newly emerging cryo-EM reconstructions of ESCRT-III assemblies make it possible to create the first models of these systems that incorporate discrete subunit structures. Using these models, we will investigate: how these filaments form rings with different diameters; how membrane interactions and curvature affect filament structure; and how lateral interactions between adjacent filaments accommodate changes in curvature. Experimental measurements of the physical properties of wild type and mutant ESCRT-III filaments will be used to validate these models and test their predictive power. This integration of experiment and theory should identify, at a fundamental level, properties driving ESCRT-III-mediated membrane remodeling and fission.

Nicole Schirle HHMI Fellow

Department of Biochemistry and Biophysics & Cellular and Molecular Pharmacology, University of California, San Francisco, California

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Characterization of the endoplasmic reticulum membrane protein complex, with Adam Frost and Jonathan Weissman

Polytopic membrane proteins undergo a complicated folding process, whereby they must be co-translationally targeted to the endoplasmic reticulum (ER) for maturation and export to cellular membranes. While our understanding of the chaperones involved in soluble protein folding has rapidly expanded, there is little known about the chaperones dedicated to folding and quality control of membrane proteins. Recently, a conserved ER membrane protein complex (EMC) was discovered from a genetic screen in yeast aimed at identifying genes that disrupt the ER protein folding environment. Genetic interaction patterns arising from deletion of the EMC and preliminary biochemical data suggest the EMC may function as a chaperone for polytopic membrane proteins. As a postdoctoral fellow in the Frost and Weissman laboratories at UCSF, I plan to use a combination of approaches ranging from cryo-electron microscopy to genetics and cell biology to elucidate how the EMC affects membrane protein topology in yeast and human cells.

Anne-Lore Schlaitz

Department of Molecular & Cell Biology, Division of Cell & Developmental Biology University of California, Berkeley / Berkeley, CA

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The role of organelle-microtubule linker proteins in the spatial organization of the cell, with Rebecca Heald

I am interested in how the internal organization of eukaryotic cells is achieved by the interaction of cytoskeletal elements with organelles.

I was drawn to science early on because of my excellent high school teacher for biology and chemistry. I was particularly fascinated by the fact that relatively simple organic compounds can direct the complex processes we know as “life.”  Consequently, I chose to study biochemistry at the University of Tübingen in Germany to learn more about life’s molecular basis. Again captivated by a wonderful class, this time on cell organelles, I became more interested in how cells work and was able to pursue these questions with both my master’s and PhD theses at the Max-Planck Institute of Molecular Cell Biology in Dresden, Germany. For my postdoc, I was able to combine my chief interests in cell biology, membrane and cytoskeletal cell biology, and given the chance to investigate how linker proteins of microtubules and membranes contribute to the spatial organization of cells.

Edmund C. Schwartz

Department of Neuroscience Columbia University / New York, NY

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Development of optogenetic tools to probe the formation of social memory, with Dr. Richard Axel

I am developing methods to control gene expression and recombination with light.  This will allow greater spatial and temporal control than can be achieved with current genetic and chemical methods.

I majored in chemistry and biology at the University of Virginia, where I worked in the lab of Michael Timko. I discovered that, even though I was studying an algae that most people have never heard of, it was still really cool to be the first in the world to know something.  Also, during my first year, the UVA football team was briefly ranked in the top ten, an accomplishment which I can only assume was thanks to my presence.  In graduate school at Rockefeller University, I did my research in the laboratory of Tom Muir, playing with molecular legos for five and a half years and getting a PhD out of that experience as a bonus.  Currently I’m in Richard Axel’s lab at Columbia, where I feel a little out of place among the real biologists.  All my time outside of work is now taken up chasing around a two-year-old.

Marion Silies

Departments of Neurobiology Stanford University School of Medicine / Stanford, CA

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My current research interest is visual system function in fruit flies. I want to understand how different behaviorally relevant visual cues, such as motion or polarized light information, are processed in the Drosophila brain.

I am from Germany. I studied biology and chemistry at the University of Münster, where I worked in a plant pathology lab as an undergraduate; I also did internships at Washington State University and Edinburgh University.  During that time I became interested in neuroscience and subsequently studied the development of the nervous system for my diploma thesis and PhD at the Department of Neurobiology in Münster. I used the fly embryonic peripheral nervous system to study how neurons and glial cells communicate in order to coordinate axonal outgrowth with glial cell migration. For my postdoc I switched from developmental to functional aspects of neuroscience. Outside the lab, I enjoy exploring the Bay area on my road bike or hiking, and meeting friends.

Elenoe Smith

Department of Hematology and Oncology, Boston Children’s Hospital, Boston, Massachusetts

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DNA elements within BCL11A and its target sequences in globin switching, with Stuart Orkin

This project aims to identify cellular mechanisms contributing to elevation of fetal hemoglobin (HbF, ?2?2) levels, the most promising therapy for patients with sickle cell disease. The characterization of BCL11A, a repressor of HbF production, and potential BCL11A targets within the ?-globin locus, will impact therapy design and treatment of the major hemoglobin disorders whose global health burden is rising. Although BCL11A is dispensable for normal red cell function, studies in mice have determined that it is required for development, presenting a potential obstacle for therapies designed to inhibit BCL11A function by small molecule. Aim1 will determine the dependence of BCL11A erythroid expression on a single nucleotide polymorphism dense region, identified by genome wide association studies. Aim2 will identify a region required for ?-globin gene repression within the A?-? intergenic region of the ?-globin locus. Both aims will utilize DNA targeting of mouse embryonic stem cells and analysis of BCL11A expression and/or globin gene expression in fetal and adult mice. These studies will contribute to a fuller understanding of ?-globin gene regulation, provide in vivo models for molecular characterization of hemoglobin switching, and identify erythroid specific targets for therapeutic intervention.

Swathi Srivasta

Department of Cell Biology, Harvard Medical School

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Understanding gut-to-brain signaling through the vagus nerve

The vagus nerve is a key part of the neuroendocrine axis that controls feeding behavior and metabolism. Within the gastrointestinal tract, vagal sensory neurons detect ingested nutrients and mechanical stretch of the stomach, although underlying sensory transduction mechanisms are not understood. Basic questions remain about how ingested food is sensed, and how inputs are relayed centrally to coordinate systemic responses. Unraveling the functions of different vagal sensory neuron types in feeding behavior and metabolism control would provide a basic understanding of gut-to-brain communication mechanisms, and perhaps provide new therapeutic targets to control appetite and help treat metabolic disorders like diabetes, obesity and anorexia.

I am working towards characterizing a subpopulation of vagal sensory neurons that express cholecystokinin receptor type- A (CCKAR), a receptor for the gut satiety hormone cholecystokinin (CCK). Using transgenic mice, anatomical tract tracing, calcium imaging and optogenetics I want to understand the structure and function of the neural circuits formed by these sensory neurons. These studies will enable long-term efforts to shed light on the sensory biology of the vagus nerve- from understanding signal transduction mechanisms in the periphery to determining the organization of central inputs that orchestrate behavioral and endocrine responses.

 

Mansi Srivastava

Whitehead Institute for Biomedical Research Cambridge, MA

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Many animal species are able to regenerate missing body parts or even entire body plans. I am using molecular and genomic tools to study regeneration and learn whether regeneration mechanisms in various species were inherited from their common ancestor or if they have evolved independently. Discovering conserved mechanisms might reveal previously unknown but potentially critical aspects of regeneration in animals.

During college, I studied development, regeneration, and asexual reproduction in segmented worms. My graduate work focused on the genomes of early animal lineages such as sea anemones and sponges to learn about early animal evolution. Such comparative genomic analyses have allowed us to infer changes in gene content, gene structure, and genomic organization that accompanied the appearance of animals and their subsequent radiation into phyletic lineages. However, we don’t yet understand the functions of the genomic innovations unique to animals.  I am now studying the evolution of a particular biological process, focusing on how the functions of a few genes have evolved. For this research, I have returned to my interest in regeneration which, with the help of modern genetic tools, can be studied at molecular and cell biological levels in many species.

Emerson Stewart

Department of Biology, Stanford University, Stanford, California

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Molecular Mechanisms of presynaptic assembly and maintenance in C. elegans neurons, with Kang Shen

The human brain is a highly ordered structure, consisting of billions of neurons linked through trillions of intercellular connections. Among the most powerful computational machines known to man, the human brain controls everything from our ability to perceive the world around us to higher order functions involved in learning and memory. At the heart of the brain’s processing power lies the synapse.

Synapses are specialized subcellular structures that mediate communication between neurons, thereby dictating information flow within the nervous system. Numerous proteins involved in synapse formation have been identified, yet how active zone and synaptic vesicle proteins coalesce into highly ordered macromolecular complexes remains a fundamental question in neurobiology. I am interested in elucidating the molecular underpinnings that support synapse formation and maintenance.

To this end I will use the Hermaphrodite Specific Neuron in C. elegans to examine how synapses are formed during development and maintained throughout the lifespan of the organism. Through a combinatorial approach employing RNAi and forward genetic screens as well as fluorescent microscopy I will take advantage of the inherent benefits of the C. elegans system to study conserved processes of synapse formation in the context of an intact organism.

Bethany Strunk

Department of Cell and Developmental Biology, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan

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Elucidating mechanistic defects associated with dysregulation of a phosphatidylinositol signaling lipid, with Lois Weisman

Mutations in Fig4 cause the incurable neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and CharcotMarie-Tooth Syndrome (CMT) through dysregulation of phosphatidylinositol (3,5)-bisphosphate (PI3,5P2). A molecular understanding of the mechanisms by which Fig4 regulates both the transient production and rapid turnover of this signaling lipid will be essential for devising therapies. Fig4 is the lipid phosphatase responsible for dephosphorylating PI3,5P2 at the 5 position to produce phosphatidylinositol 3-phosphate (PI3P). Paradoxically, conserved residues in the yeast Fig4 phosphatase active site are required to activate the lipid kinase catalyzing the addition of the very phosphate it hydrolyses. This suggests an internal mechanism for preventing uncontrolled elevation of PI3,5P2 in the absence of the activity required to restore it to basal levels. The research proposed here will use a yeast model to elucidate the conserved mechanisms by which Fig4 controls both the synthesis and turnover of PI3,5P2 and uncover which of these mechanisms are disrupted by disease related mutations.

Calcium signaling is ubiquitous within cells, with numerous implications for cancer biology. I am developing new molecular tools to study spatiotemporal calcium signaling in neurons and other cell types.

My interest in biology originally stemmed from a love for math, engineering, and technology.  High-school experiences on the computer team, and during a summer internship where I worked with circuits and radar, hooked me on engineering, and led to an undergraduate major in electrical engineering.  However, I had a lingering penchant for biology and, during college, when I was exposed to the field of bioengineering, I realized how engineering and biology were truly compatible with one another.  Since then, I’ve had the privilege of full-immersion into both biology and technology. I received my MD/PhD at Johns Hopkins where my incredible mentor, David Yue, helped me realize how beautiful complexity can arise from simple interactions present within cells, and how calcium, in particular, acts as a universal currency of information transfer within cells.  With JCC fellowship support, I plan to develop tools not only to study, but also manipulate calcium signaling in cells — tools that will likely be useful in many branches of biological science.

Frederick J. Tan (HHMI Fellow)

Department of Molecular and Cellular Biology University of California, Berkeley

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A genomic study of homologous recombination between repetitive elements with Douglas Koshland

I am interested in understanding how genome structure affects genome function and evolution.  I am studying how chromosome organization limits homologous recombination between dispersed repetitive DNA elements.

I owe my scientific curiosity to two people: my father, who always took the time to answer my questions when I was young, and my high school biology teacher, Dr. Daniel Walsh, who had an endless supply of knowledge and enthusiasm about science. I’m pursuing an academic research career because I believe that one-on-one mentoring between a principal investigator and a graduate students is an ideal training forum.

Previously, I was a lot more active in sports, mostly cycling and running.  These days, however, when I’m not working, my life centers around my wife and our two dogs.  I am still trying to fit in that occasional run!

Yunhao Tan Merck Fellow

Department of Gastroenterology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts

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Dissecting early host endotoxin sensing mechanisms, with Jonathan Kagan

My first contact with the field of host and pathogen interaction dated back to the time when I was working at Dr. Feng Shao’s Lab at the National Institute of Biological Sciences, Beijing (NIBS), one of the most prestigious research institute in China.   My intern project was to clone and characterize the host substrates of an E3 ubiquitin ligase domain containing effector protein from the vacuolar pathogen Legionella pneumophila. From this experience, I was deeply impressed by the broad array of biochemical mechanisms employed by the bacterial effector proteins to manipulate host functions in order to survive and proliferate inside the host.  Furthermore, this experience built up my passion and determination to launch my research journey in host and pathogen interaction.

A year later after my internship, I went on to pursuit my graduate study in Dr. Zhao-Qing Luo’s Lab at Purdue University.  My research projects have been focused on the manipulation of host membrane trafficking pathways by Legionella effectors.  Specifically, I have discovered that Legionella effector proteins exploited distinct post-translational modification mechanisms, i.e. reversible AMPylation and Phosphorylcholination, to regulate the activities of the host small GTPase Rab1. In summary, these findings highlight the sophisticated nature of host-pathogen interactions and reveals that bacterium has the ability to rewire host signaling events for its own benefit.

Living in the ocean of microorganisms, the innate immune system is the first line of defense to protect host from invading pathogens and to maintain tissue homeostasis.  Thus, for my postdoctoral training, I would like to branch out my research focus from microbial pathogenesis into studying the cell biological and biochemical regulatory mechanisms of the host innate immune response.  Particularly, I will decipher the spatial-temporal relationships among the earliest cell biological events triggered by endotoxin, such as receptor endocytosis, reactive oxygen production, LC3 associated phagocytosis and SMOC formation.  I believe that my proposed research will provide new insights into the previously unexplored area of TLR signaling.

Shiho Tanaka

Department of Chemistry and Chemical Engineering California Institute of Technology / Pasadena, California

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I grew up in Tokyo, Japan, and came to Los Angeles in 2000 to obtain an undergraduate degree in biochemistry. In my junior year at the  University of California, Los Angeles, I joined the protein expression laboratory under Professor Jeanne Perry’s supervision; there, I was fascinated by x-ray crystallography and decided to go to graduate school to learn more about protein structures and functions. During my graduate study at UCLA, I joined Professor Todd Yeates’ laboratory and determined various structures of shell proteins from bacterial microcompartments. I love southern California and am very happy that I get to stay here to do my post-doctoral work at Caltech.

Elçin Ünal (HHMI Fellow)

David H. Koch Institute for Integrative Cancer Research / Massachusetts Institute of Technology, Cambridge, MA

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Deciphering the age effects on meiosis and vice versa, with Angelika Amon

My research focuses on understanding how meiosis affects aging and age-induced cellular damage, as well as understanding how cyclin-CDK regulation impacts meiotic chromosome segregation.

I was born and raised in Turkey. In high school, biology, math and chemistry were my favorite subjects, and a great biology teacher encouraged me to apply to the Molecular Biology and Genetics Department in Bilkent University, Ankara. The department was relatively new, the first of its kind in Turkey, and was accepting few people (15 per year) with full scholarships based on performance in the national university entrance exam. This was a risky decision but ended up being one of the best decisions I made in my life. I graduated from college in 2001 and started my academic journey in the U.S. with very little research experience but with lots of naïve ambition and curiosity.  My doctorate is from the Johns Hopkins University Department of Biology and Carnegie Institute for Science Department of Embryology. Outside of science, I like outdoorsy activities like hiking and running, as well as traveling, cooking yummy Mediterranean food, and making delicious cocktails.

Hannah E. Volkman

Department of Immunology / University of Washington, Seattle, WA

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I am interested in how cells recognize and respond to viral pathogens through detection of viral nucleic acids. My research focuses on understanding innate immune pathways involved in cell intrinsic cytosolic DNA detection and coordination of an inducible antiviral response, and how dysregulation of these pathways leads to autoimmune disease.

I grew up on a California farm, surrounded by the natural world, with parents who continually nurtured my interest in it. This experience, coupled with having mentors who allowed me the freedom to follow my interests in their laboratories, have guided my development as a scientist. Freedom to direct my own research has been a tremendous gift, and I am fortunate to be in a truly collaborative research environment. By moving to Seattle I  became part of an outstanding research institute, and have also been able to pursue nonacademic interests. I have been on nationally-ranked college and club ultimate frisbee teams,  currently help coach the women’s ultimate frisbee team at the University of Washington, and compete as a competitive curler. My experiences have created many awesome friendships and helped me develop discipline, determination and leadership skills, while balancing my life as a research scientist.

Planar cell polarity protein activity and function in developing Drosophila epithelia, with Gary Struhl

Sarah Wacker

Department of Molecular and Cellular Biology, Harvard University and Roberto Kolter, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts

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Dissecting the molecular basis of mutually beneficial interactions between plants and bacteria, with Richard M. Losick

Many bacteria form complex multicellular communities known as biofilms. In these communities, cells are encased in a self-produced matrix that shield bacteria from diverse environmental stresses, antimicrobial agents, and host immune systems. Biofilms impact many arenas, including human health, ecology, and agriculture. Due to the importance and ubiquity of biofilms, there is increased interest in investigating the molecular mechanisms underlying the formation and maintenance of these communities. The soil bacterium Bacillus subtilis forms multicellular communities on the roots of some plants, including tomatoes, resulting in increased plant growth. My research examines how environmental signals are sensed by B. subtilis, initiating the biofilm program.

Zhiping Wang

Division of Biological Sciences, Section of Neuroscience University of California, San Diego. La Jolla, CA

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Characterization of new axon regeneration regulation pathways, with Dr. Yishi Jin

Current research:  I am interested in dissecting the genetic basis of adult axon regeneration in the model organism C. elegans.

My first sixteen years were spent happily in a small town in southeastern China. I didn’t have much experience in biological sciences until I became an biology major at Tsinghua University. In a neuroscience course, a professor introduced to us the fantastic structure of neurons and the intriguing molecular mechanisms underlying how neurons encode external information and learn. From that moment, I was entranced by this field, and chose it as my career path. I came to Michael Ehlers’s lab at Duke University to study the molecular mechanisms of long term plasticity in hippocampal neurons. There, I discovered that an unconventional actin motor is a critical LTP-mediating player. Subsequently, I joined Yishi Jin’s lab as a postdoctoral researcher to explore the genetic mechanisms of adult axon regeneration in C. elegans. Outside the lab, I am a super soccer fan and love fresh-water fishing. My dreams are to watch a Derby game between FC Barcelona and Real Madrid at Camp Nou and to catch a 20-pound large-mouth bass.

Yuxiao Wang HHMI Fellow

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California

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Mechanisms of mitotic spindle positioning by cortical dynein, with Ronald Vale

During mitosis, the position of the spindle determines the size, the relative orientation and the developmental fate of daughter cells. The spindle is positioned by a pulling force generated by cortically localized dynein and exerted on astral microtubules that are connected to the spindle poles. Dynein is anchored to the cell cortex by the protein NuMA and activated to pull on the end of microtubule, the mechanism of which remains unknown. To investigate this, we will first systematically define and characterize the interaction between NuMA and dynein using purified components. Next we will reconstitute the microtubule end capturing and pulling force generation activities of dynein using a microfabricated barrier based system, in which the regulation of dynein by NuMA will be investigated. In addition, we will determine the crystal structure of the complex of NuMA-dynein binding regions to reveal the structural basis for their interactions. Finally, the overall structure of full-length NuMA will be examined using electron microscope and the functional significance of NuMA oligomerization will be determined. Together our proposed study will provide a mechanistic understanding of how dynein is recruited and activated by NuMA to generate cortical pulling force for mitotic spindle positioning.

Siyuan "Steven" Wang

Department of Chemistry and Chemical Biology, Department of Physics, Harvard University, Howard Hughes Medical Institute

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Chromatin imaging with STORM-FRET labels

My current research in Professor Xiaowei Zhuang’s lab at Harvard University focuses on the development and application of super-resolution light microscopy techniques to the study of chromatin organization. In particular, I am interested in the spatial organization of DNA in compact chromatin domains during the interphase.

My graduate research, co-advised by Professor Ned Wingreen and Professor Joshua Shaevitz at Princeton University, presented a series of discoveries regarding the physical properties, dynamics, and organization of the bacterial cytoskeleton and cell wall, including: 1) the mechanical contribution of bacterial cytoskeleton to cellular integrity; 2) the motion of bacterial cytoskeleton driven by cell wall synthesis; 3) the chiral organization and growth dynamics of cell wall in rod-shaped bacteria, derived from the spatial pattern of cytoskeleton; and 4) a possible mechanism for different cytoskeleton components to self-organize into distinct spatial patterns. My dissertation won the 2011 Award for Outstanding Doctoral Thesis Research in Biological Physics from American Physical Society.

Liang Wee Frederic M. Richards Fellow

Department of Molecular and Cell Biology, Physics and Chemistry, University of California, Berkeley, California

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RNA ribosome and RNA polymerase: Three molecules at a time, with Carlos Bustamante

Transcription by RNA Polymerase and translation by the Ribosome are two fundamental and important processes that shape cellular identity. Mutations that disrupt these processes can result in disease such as cancer. We strive to understand the underlying mechanisms of transcription and translation using optical tweezer. This single molecule technique allows us to monitor the actions of individual RNA Polymerase and the ribosome in real time that are often scored as averages in bulk measurements. We currently aim to scrutinize the activities of these molecular motors when coupled in the same reaction. The coupling between RNAP polymerase and the ribosome, which occurs in vivo in E. coli., constitutes an additional layer to control gene expression. A deeper understanding of both transcription and translation either alone or coupled will open up new ideas to curb or to cure diseases that stem from a malfunction in these process.

Christina Woo HHMI Fellow

Department of Chemistry, Stanford University, California

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Development of an isotopic labeling approach for rapid profiling of the O-glycoproteome, with Carolyn Bertozzi

My research involves using isotopic labeling strategies and computational methods to enable a novel chemical glycoproteomics platform termed Isotope Targeted Glycoproteomics (IsoTaG).  Given the strong correlation of altered glycosylation patterns with malignancy, glycosylated proteins may be an information-rich subset of the proteome from which cancer biomarkers can be discovered. We employ metabolic labeling as a means to tag specific classes of glycoproteins for enrichment from human tissue samples and subsequent identification by mass spectrometry. A challenge in this endeavor is defining sites of glycosylation on peptide digests derived from such complex samples. To facilitate this effort, we invented a targeted strategy to enable the detection and identification of glycosylated peptides independent of the mass of the pendant glycan. Collectively, these tools allow us to quantitatively profile changes in protein glycosylation associated with human cancer progression and embryonic stem cell differentiation.

Zeba Wunderlich

Department of Systems Biology, Harvard Medical School, Boston, Massachusetts

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Connecting sequence divergence to quantitative phenotype differences in drosophila, with Dr. Angela Depace

I am currently working on the connection between regulatory region sequence and function by measuring quantitative expression patterns of developmental genes in multiple Drosophila species and creating a biophysical model to interpret these data.

I have always been interested in applying methods from statistics and physics to biological problems.  As an undergraduate at Rutgers University, I majored in molecular biology and statistics and did computational work in a protein NMR lab.  I continued my education in Harvard University’s biophysics program, where I developed mathematical models of a wide variety of biological phenomena, including metabolic networks and protein-DNA interactions.  Following an inspirational summer at the Marine Biological Laboratory’s physiology course, I decided to focus my postdoctoral studies on transcriptional regulation, this time combining my computational work with experiments. Outside of my research, I enjoy spending time outside — rowing, running and cross-country skiing.

Mingshan Xue

Division of Biological Sciences University of California, San Diego / La Jolla, CA

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My current research is focused on understanding the neural circuit mechanism underlying the specific activation of neuronal ensembles by sensory stimuli in the mammalian cortex.

I grew up in a small town in Hunan Province, China. Both my parents are physicians.  In high school, I chanced upon the book, What Mad Pursue by Francis Crick; I was attracted to Dr. Crick’s passion for the “study of life,” and intrigued by the complexity and sophistication of biological systems. I went on to major in biology at Fudan University.

During my senior year, I became interested in neuroscience, and decided to pursuit my graduate study in the US. My graduate research at Baylor College of Medicine focused on the molecular mechanism of synaptic transmission, the process by which neurons communicate with each other.

Now I am extending my scientific interest into the synaptic mechanisms of neural circuit operation in health and disease. In my free time, I like to watch sports, play with our cats and, occasionally, help my wife in her garden.

Teppei Yamaguchi

Departments of Molecular & Cell Biology University of California, Berkeley / Berkeley, CA

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Current research: I am studying changes in the core transcriptional machinery during cellular reprogramming

My interest in studying biology was sparked by my growing up in the countryside of Japan, where I always loved to play in nature. After doing undergraduate work at Kyoto University , I received a master’s degree from Kyoto University in Japan, and a PhD from University of Basel, Switzerland. There, I studied the transcriptional regulation of immune cell differentiation, using mouse genetics with Patrick Matthias at the Friedrich Miescher Institute for Biomedical Research. While completing my PhD study, I developed a strong interest in exploring more mechanistic aspects of the transcriptional regulation dictating cellular identity. To pursue this interest, I joined the lab of Robert Tjian at UC Berkeley. Here, I’m enjoying not only the great scientific environment, but also outdoor activities and the unique Bay Area culture.

Oh Kyu Yoon (HHMI Fellow)

Department of Molecular and Cell Biology, University of California, Berkeley / Berkeley, CA

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Genome-wide indentification of regulatory non-coding RNAs in S. cerevisiae, with Dr. Rachel B. Brem

The goal of my project is to perform a genome-wide identification of regulatory non-canonical transcripts in budding yeast, using natural genetic variation between outbred individuals. I received my BS and MS in chemistry from Seoul National University, Korea, and an MS in electrical engineering and PhD in chemistry from Stanford University.

My graduate research was on developing a novel mass spectrometer, called Hadamard Transform Time-of-Flight, which has higher spectral scan rate with applications in real-time solution kinetics.

For postdoctoral research, I have made a big switch to genetics and genomics, where I use next-generation sequencing to profile the 3’ UTRs of RNA. In the future, I hope to combine my interdisciplinary expertise to study the regulation of mRNA and protein post-processing, and the effects of their misregulation on human disease.  Outside of the lab, I like to play tennis and drink coffee.

Barry Zee

Department of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

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Analysis of dosage compensation in Drosophila, with Mitzi Kuroda

I am interested in how binding of protein modifications contributes to the functions of chromatin complexes. Currently I am developing biochemical and proteomic methods to identify the histone modifications associated with malignant brain tumor (MBT) domain-containing proteins in human tissue culture cells and in fruit flies. The human and fly MBT-containing homologues participate in various aspects of Polycomb group silencing and tumor suppression. Since the MBT domain acts as a methyl lysine-binding module, it is likely that specific modification interactions together with protein interactions enable the localization of otherwise broadly pervasive MBT complexes to specific genomic regions. My graduate training in mass spectrometry complements my postdoctoral training in affinity pulldown of labile interactions with regard to uncovering these potential modification targets.

Assaf Zemach

Plant & Microbiology Department / University of California, Berkeley / Berkeley, California

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Comparative genomic analysis of DNA methylation in animals, with Daniel Zilberman

I am studying the role of DNA methylation in gene transcription and chromatin structure in eukaryotes.

I graduated from The Weizmann Institute of Science in Rehovot, Israel. Under the guidance of Professor Gideon Grafi, I gained my molecular, biochemical and imaging skills and, just as important, my passion for science.  Now in the lab of Professor Daniel Zilberman at UC Berkeley, I am expanding my knowledge of genomics — a situation which, to me as a biologist, feels like a dream come true.  Using deep-sequencing technology we are studying the function of DNA methylation various plants, animals and fungi, of which many are not classical eukaryotic model organisms. Besides being thrilled to be doing my science work, I find that living in California is a wonderful experience for both me and my family. The weather, the natural world around us, the culture, the food, and San Francisco close by — who could ask for more?!

Quicen Zhang

Department of Physics, University of Illinois at Urbana-Champaign, Illinois

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Determining the transition of genomic softness in the cancer progression, with Taekjip Ha

The explosion of high-throughput sequencing methodologies has created a vast repository of genomic knowledge of cancer. However, compared to the sequence, the physical structure of cancer genome is far less understood. Since structure determines functions, it is urgent to develop new tools to probe physical properties of cancer genome, and establish a quantitative framework correlating the intrinsic structure of genome to its biochemical roles and further to the cancer progression. Therefore, we propose to measure one fundamental physical property of genome – the genomic softness. We plan to determine how DNA sequences are locally different in softness across the whole genome and search for its connection with the macroscopic pathological states. The new tool we are developing is named “Loopseq”, which combines single molecular screening of soft DNA segments fragmented from the genome with next generation sequencing to attain a genome mapping of the local softness in a high-throughput fashion. The result of the project will provide high-resolution information of the structure of the cancer genome. Combined with present biochemical knowledge, it will provide unprecedented insights into the causes and origins of cancer – the mission of the Jane Coffin Childs Memorial Fund.

Jin Zhang

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York

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Functional segregation of taste-responsive neurons, with Charles Zuker and Tom Maniatis

I am studying the function of the mammalian taste system, in particular the molecular identity and diversity of taste-responsive neurons.  The five basic taste qualities -sweet, sour, salty, bitter and umami, are detected on the tongue and palate epithelium by distinct classes of taste receptor cells (TRCs).  The geniculate ganglion is the first neural station between the tongue and the brain; our lab recently showed that ganglion neurons are also tuned to specific taste qualities.  My studies are aimed at understanding how TRC maintain the highly specific transfer of taste information between taste cells and the central nervous system, particularly given that TRCs turn over every few days.  I have optimized a number of approaches to perform single-cell RNA sequencing both in TRCs and ganglion neurons, and am characterizing and classifying taste neurons into distinct classes.  We hope to define molecular markers that will allow us to manipulate the connectivity, function and behavior of TRCs, and the taste system.

Xu Zhou

Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut

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Counter-inflammatory mechanisms in tissue inflammation, with Ruslan Medzhitov

Many human diseases are associated with aberrant inflammation. While the inflammatory response functions to protect an organism against harmful pathogens or to restore tissue homeostasis, excessive inflammation is known to alter tissue functions and damage host tissues. This phenomenon is termed immunopathology and is a major contributor to human morbidity. Therefore, limiting immunopathology is critical in many pathological scenarios. There are two potential means to control immunopathology: to act on immune cells to directly suppress the generation of inflammatory response (“anti-inflammatory” mechanisms), or to act on target tissues to reduce or reverse the deleterious effects caused by inflammation (“counter-inflammatory” mechanisms). A body of previous works has contributed to our knowledge of the anti-inflammatory mechanisms, but the counter-inflammatory mechanisms remain largely elusive. Currently, I am using cellular responses to inflammatory cytokines as the experimental system to identify the counter-inflammatory signals. Meanwhile, I am characterizing their potential mechanisms by taking advantage of the computational and systematic approaches.

Christina Zimanyi

Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts

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Noxious chemical sensing by the TRPA1 ion channel, with Rachelle Gaudet

I am using structural techniques to study pain transduction by transient receptor potential (TRP) ion channels. TRPs comprise a large family of pain sensors activated by diverse stimuli from noxious temperatures to small molecules. My work focuses on understanding the regulation of ion channel opening by such stimuli at the atomic level.

My interest in biochemistry was piqued after taking organic chemistry as an undergraduate at UC Berkeley. I followed my interest in molecular detail to graduate school where I discovered my love for protein structure. During my PhD work at MIT, my studies of the enzyme ribonucleotide reductase led to a thesis focused entirely on allosteric regulation. Since then, I have been intrigued by how proteins use allostery to perform remarkable structural transformations that affect function. TRP channels are master integrators of allosteric signals. They are an ideal system for studying complex allostery and an atomic level understanding of TRP channel activation will provide a foundation for understanding pain.

Roberto Zoncu

Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology Cambridge, MA

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Not just a recycle bin: the role of lysosomes in nutrient sensing by the mammalian target of rapamycin, with Dr. David Sabatini

I am studying the molecular mechanisms by which nutrients activate the mTOR kinase, a central regulator of the growth of cells and organisms.

I am a native of Italy, where I earned a BSc in biological sciences from the University of Pisa. I entered the PhD program at Yale to study how membranes are trafficked to and from the surface of the cell, and how these mechanisms contribute to the function of synapses and to neuronal transmission. To this end, I applied advanced live microscopy techniques such as total internal reflection (TIR).  During my PhD work, I became interested in the role of cellular membranes in propagating signals that originate at the cell surface, and how these processes become aberrant in cancer.  To pursue this direction I joined the laboratory of David Sabatini at the Whitehead Institute in 2008. Here, I am combining biochemical techniques with advanced microscopy to investigate how the lysosome, an organelle involved in the degradation and recycling of cellular components, participates in the activation of mTOR complex 1 (mTORC1). In my free time I enjoy running, martial arts, sailing on the Charles River and playing bass in a rock band.

Ling-Nian Zou

Center for Systems Biology, Harvard University, Cambridge, MA

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I am using mouse embryonic stems cells to understand the sources of cell-to-cell variation during early development, and examining what these variations can tell us about mechanisms regulating early development.

I was first attracted to science by learning that the amazing diversity of life arose from the operation of a simple abstract principle — natural selection. At university, I turned towards physics, studying how diverse macroscopic physical phenomena (e.g. elasticity and electrodynamics), arising from distinct microscopic laws, can be described on the basis of similar abstract physical concepts. That idea, and the fact that we can extract basic properties of a physical system from apparently random fluctuations, guided my doctoral research.

My current research asks whether these ideas from physics can be useful to the study of biological processes. Consider the variable responses of cells in a culture dish when exposed to the same stimulus. Can we extract information about how cells make decisions by a careful analysis of this variability? Although the simplest cells are far more complex than any physical material, such questions are worth asking. Even if we cannot answer them, the inquiring may point towards some essential characteristics of biological processes.

Beth Zucconi

Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland

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Acetylomics of the leukemia protein MOZ, with Philip Cole

Once thought to be limited to histones, protein acetylation has now expanded to include a plethora of other protein substrates.  I am utilizing human protein microarrays to identify novel targets of the lysine acetyltransferases p300 and CBP, two commonly mutated proteins in hematological and other malignancies.  Additionally we plan to identify the acetylation sites on these novel substrates by mass spectrometry, the cellular consequences of their acetylation, and the specific mechanisms of these effects using semi-synthetic protein constructs.  Of high interest are substrates of which the acetylation is modulated by a small molecule bromodomain ligand.  I am also characterizing the effect of this ligand on nucleosome acetylation.  The importance of the bromodomain in regulating p300/CBP activity will be clarified by p300 bromodomain mutants.