biology RESEARCH PROGRAMS INprinciples and practices of structural biology, particularly in respect...

biology

graduate school of arts and science

RESEARCH PROGRAMS IN

3focus on research

5the academic program

7the coursework

9the faculty

28boston college campusthe boston environment

30graduate admissions

focus on research

❖ The role of methylation in cellular aging and in maintaining protein stability

❖ Nuclear import and export of viral and cellular macromolecules

❖ Glucose detection and cAMP signaling in fission yeast

❖ The genes that cause epilepsy in mice, and the neurochemistry of seizure susceptibility

❖ Cell cycle control in B lymphocytes, by B cell antigen receptor (BCR)-mediated signal transduction and growth arrest byinhibitory BCR co-receptors

❖ The molecular genetic analysis of soluble-compound chemotaxis in C. elegans

❖ Developmental regulation of expression and molecular evolution in Drosophila eggshell genes

❖ The molecular organization of amyloids in Alzheimer's and other neurodegenerative diseases

❖ DNA replication and nucleosome assembly in mammalian cells

❖ Synaptic ribbons and the use of mutant mice to study retinal structure and visual function

❖ Regulation by and detoxification of metal ions in yeast

❖ Control of cytoplasmic polyadenylation in developing systems

❖ Regulation of cytokinesis in animal cells

❖ Membrane adhesion proteins in demyelinating diseases

❖ Chromosome and microtubule dynamics in fission yeast, Schizosaccharomyces pombe

❖ Host-parasite interactions between malaria parasites and their mosquito hosts

❖ Genetic and cell biological analysis of Notch-mediated signal transduction in Drosophila

❖ Computational biology/bioinformatics

Research FacilitiesOur department, in Higgins Hall, is well-

equipped for modern molecular, genomic, and pro-

teomic research, biochemistry, imaging, and

bioinformatics.

Departmental genomics and proteomics infra-

structure includes capacities for Beckman and LiCor

DNA sequencing and DNA fragment polymorphism

analysis, Affymetrix microarray spotting and scan-

ning, Beckman robotics, and Alpha-Innotech two-

dimensional gel proteomic analysis. We possess

state-of-the-art cell culture and protein purification

systems, including the BioCad SPRINT perfusion

chromatography system, HPLC, FPLC, and prepara-

tive isoelectric focusing.

Our imaging facilities include a Leica confocal

microscope, a Phillips transmission electron micro-

scope, departmental and individual laboratory Zeiss

and Nikon fluorescence and Nomarski compound

microscopes, Molecular Dynamics phosphoimager

and densitometer workstations, and x-ray diffraction

capability. Our digital graphics and image processing

facility includes numerous MacIntosh (G4) worksta-

tions with multiprocessor CPU configurations, cou-

pled with high-resolution scanners. A large-format

poster printer and dye sublimation printers support

preparation of high-quality posters and print com-

munications.

We have initiated development of a bioinformat-

ics server platform, to which undergraduates, gradu-

ate students, and faculty have access, expanding

departmental computing capabilities beyond our

MacIntosh, IBM, Sun, and Silicon Graphics worksta-

tions. Our bioinformatics server, clavius.bc.edu, is

currently comprised of a 20 CPU rack-mount compu-

tational cluster, with 1.2 terabytes of fiber-attached

network storage. The server is heterogeneous, com-

prised of dual processor Intel Pentium III/Linux and

dual processor Apple/Mac OS X nodes. Research

computing time, available free of charge, affords

substantial research and educational opportunities

for students and faculty.

Research lies at the heart of the biology experience at BostonCollege. The department offers a wide array of opportunities for sci-entific investigation within the areas of molecular cell biology andgenetics, cell cycle, neurobiology, developmental biology, structuraland cellular biochemistry, vector biology, infectious disease, andbioinformatics. Specific areas of research in the department includethe following:

Assistant Professor Stephen Wicks and Ph.D. Student Brian D’ell

Orfano review a genetic mapping experiment designed to identify a

gene required for normal detection of water soluble compounds

(chemotaxis). Dr Wicks’ laboratory is interested in the neurobiology of

the chemosensory system. They are using molecular genetic, cell bio-

logical, and behavioral techniques to examine the chemosensory sys-

tem of the small nematode roundworm, Caenorhabditis elegans. They

are hoping to better understand the interactions of the various cell

types that occur during the formation of an intact sensory organ, as

well as the function of the intact organ in adult animals.

the academic program

The Biology Department at Boston College offers programs ofstudy leading to the M.S. and Ph.D. degrees in Biology with concentrations in several fields of study, including the following:

❖ Bioinformatics

❖ Cell Cycle

❖ Developmental Biology

❖ Immunology

❖ Molecular Cell Biology & Genetics

❖ Neurobiology

❖ Structural & Cellular Biochemistry

❖ Vector Biology

Total Enrollment

M.S.

Ph.D.

80% range of GRE

Math

Verbal

Average GPA

Average Age

Programs at a Glance

30

10

20

1200-1300

680-700

520-600

3.3

25

During the first year, students arerequired to complete the graduatecore curriculum, BI 611, BI 612, BI614, and BI 615 (Advanced Genetics,Graduate Biochemistry, GraduateMolecular Biology, and Advanced CellBiology). M.S. students participate intwo nine-week laboratory rotationsduring the first year and select theirthesis research laboratory during thesecond semester. Typically, three addi-tional graduate courses, at least oneof which is a graduate seminarcourse, are required, as well as fourcourses directed toward completionof a thesis. M.S. candidates must sub-mit and orally defend a written thesisbased on their research.

M.S. Program

The basis of the Ph.D. program is the development of a body oforiginal research that is publicly presented and defended in a pub-lishable Ph.D. dissertation.

During the first year, students are required to complete thegraduate core curriculum, BI 611, BI 612, BI 614, and BI 615(Advanced Genetics, Graduate Biochemistry, Graduate MolecularBiology, and Advanced Cell Biology). Ph.D. students also take fiveadditional graduate courses, at least three of which are graduateseminars.

The graduate seminars stress critical and creative thinkingthrough the discussion of research literature in specialized fields.Students are also encouraged to explore the many different areasof research represented by the faculty and therefore are required tocomplete three nine-week laboratory rotations during the first year.Students then select their thesis research laboratory at the end oftheir third rotation.

To advance to candidacy for the Ph.D., students must success-fully present and defend a research proposal before a faculty com-mittee. The dissertation committee formed for each student meetsannually to evaluate the student's progress and to offer scientificadvice. Ph.D. candidates are required to write a dissertation anddefend it in a publicly presented seminar.

Ph.D. Program

BI 506 Recombinant DNA TechnologyThis course will describe the theory and practice of recombinant DNAtechnology, and its application within molecular biology research. Topicswill include the cloning of genes from various organisms, plasmid con-struction, transcriptional and translational gene fusions, nucleic acidprobes, site-directed mutagenesis, polymerase chain reaction, and trans-genic animals. The goal of the course is to make the research-orientedstudent aware of the wealth of experimental approaches available throughthis technology.

BI 507 Computational BiologyIntroduction to computational molecular biology, with focus on the devel-opment and implementation of efficient algorithms for problems generallyrelated to genomics. Sample topics include sequence homology and align-ment, phylogenetic tree construction ("All about Eve"), hidden Markovmodels and their applications (e.g., multiple sequence alignment, recogni-tion of genes), RNA secondary structure prediction, protein folding on lat-tice models, and determination of DNA strand separation sites induplication and replication. Algorithmic content of course: genetic algo-rithms, simulated annealing, clustering, dynamic programming, recursion.

BI 509 Vertebrate Cell Biology This is an advanced cell biology course focusing on the integration ofgene activity, subcellular structure, extracellular signals, and specializedfunction in vertebrate cells. The course will involve an in-depth study ofdifferentiated cell types, including erythrocytes, nerve and muscle cells,epithelia, and cells of the immune system. The molecular and geneticbases for diseases affecting these cell types will be discussed. The coursewill also include recent developments in the area of cell cycle control andthe transformation of normal cells into cancerous cells.

BI 510 General EndocrinologyMany tissues (e.g., the brain, heart, kidney) as well as the classicalendocrine organs (e.g., adrenal, thyroid) secrete hormones. This course isconcerned with normal and clinical aspects of hormone action. The effectsof hormones (and neurohormones) on intermediary metabolism, somaticand skeletal growth, neural development and behavior, development ofthe gonads and sexual identity, mineral regulation and water balance, andmechanisms of hormone action will be considered.

BI 515 Biophysical ChemistryThis course includes lectures on a number of the most important physico-chemical methods for determining the structures of macromolecules.Topics include electrophoresis, sedimentation, viscosity, light scattering,UV and visible spectroscopy, CD spectroscopy, x-ray crystallography, andNMR spectroscopy.

BI 533 Cellular Transport and DiseaseThe biology of intracellular traffic is in an exciting period of development.New techniques of molecular and cell biology are leading to discoveries ofthe transport signals and the major carriers. Topics covered in this courseinclude: (1) transport of proteins and different classes of RNAs into andout of the nucleus, (2) transport of proteins into mitochondria and intoER, and (3) vesicular transport. Specific transport deficiencies causing dis-eases will be discussed. In addition, the course will describe how differentviruses (HIV, papillomaviruses, adenoviruses, influenza virus) exploit theintracellular transport pathways of host cells during their life cycle.

BI 535 Structural Biochemistry of Neurological DiseaseStructural biology relates molecular form to biological function, character-izing biological processes in terms of various molecular structures and theinteractions of their constituents. This course introduces students to theprinciples and practices of structural biology, particularly in respect to itsapplications to understanding neurological diseases. Lectures that intro-duce and discuss various methodologies will be followed by demonstra-tions of the actual techniques, focusing primarily on membrane and x-rayfiber diffraction, and electron microscopy.

BI 538 The Cell CycleThe cell cycle ensures successful cell division and multicellular develop-ment. Its importance is evident by the recent Nobel Prizes awarded inmedicine. Mutations in cell cycle and checkpoint genes are found in manycancers, and basic research is expected to provide novel therapies. Whilethe concept of "cell cycle genes" emerged from genetic approaches inyeast, it is applicable to all eukaryotes. Topics covered include: cell divi-sion cycle (cdc) genes, cyclin dependent kinases as universal regulators,phosphorylation and irreversible degradation as means to control cellcycle progression, checkpoint pathways, and the role of nuclear importand export in checkpoint control.

BI 541 ImmunobiologyThis course will focus on the regulation of the immune response at themolecular level. Topics will include the regulation of B and T cell develop-ment; function of B and T lymphocytes in the immune response; themolecular basis underlying the generation of antibody and T cell receptordiversity; and antigen processing via MHC I and MHC II pathways. Thecourse will place a heavy emphasis on experimental approaches to study-ing immune regulation and will make extensive use of the research litera-ture in order to cover recent advances in areas such as lymphocyteactivation, tolerance, and clonal deletion.

the coursework

BI 554 Physiology This is a study of the fundamental principles and physicochemical mecha-nisms underlying cellular and organismal function. Mammalian organ-sys-tems will be studied, with an emphasis on neurophysiology, cardiovascularfunction, respiratory function, renal function, and gastro-intestinal func-tion.

BI 555 Laboratory in Physiology This laboratory course investigates both the four major organ systems(respiratory, cardiovascular, renal, and gastro-intestinal) and neurophysiol-ogy. The majority of the course consists of computer simulations and tuto-rials. A few wet labs will be used to illustrate specific principles.

BI 556 Developmental Biology Developmental biology is in the midst of a far-reaching revolution thatprofoundly effects many related disciplines, including evolutionary biology,morphology, and genetics. The new tools and strategies of molecular biol-ogy have begun to link genetics and embryology and to reveal an incredi-ble picture of how cells, tissues, and organisms differentiate and develop.This course describes both organismal and molecular approaches whichlead to a detailed understanding of (1) how it is that cells containing thesame genetic complement can reproducibly develop into drastically differ-ent tissues and organs; and (2) the basis and role of pattern informationin this process.

BI 557 Neurochemical GeneticsThis course covers classical, biochemical, and molecular genetics relatedto inherited disorders of the nervous system. Attention is devoted to suchcurrent topics as trinucleotide repeats, genomic imprinting, genetic het-erogeneity, and gene-environmental interactions. These topics are present-ed in relationship to a number of neurological diseases includingHuntington's disease, Tay-Sachs disease, phenylketonuria, Alzheimer'sdisease, multiple sclerosis, autism, and complex multifactorial diseasessuch as mood disorders and epilepsy. Also presented are strategies forgene and dietary based therapies for neurological diseases. Referencematerials include handouts of current research articles.

BI 570 Biology of the Nucleus This course provides an in-depth treatment of the molecular biology ofDNA and RNA, with particular emphasis on the control and organizationof the genetic material of eukaryotic organisms. Topics covered includechromatin structure and function, DNA replication, nucleosome assembly,introns, RNA processing, and gene regulation.

BI 580 Molecular Biology LaboratoryAn advanced project laboratory for hands-on training in the experimentaltechniques of molecular biology under close faculty supervision. In addi-tion to formal lab training and discussion sections, students will haveaccess to the lab outside class hours to work on projects intended to pro-duce publication quality data. Methods taught will include macromolecu-lar purification, electrophoretic analysis, recombinant DNA and cloningtechniques, DNA sequencing, polymerase chain reaction, and the use ofcomputers and national databases for the analysis of DNA and proteinsequences. Ideal for students who desire a solid introduction to the meth-ods of molecular biology through practical training.

BI 581 NeuroscienceThis course presents selected topics in the broad field of neuroscience,focusing primarily on the mammalian nervous system. The course text(Neuroscience: Exploring the Brain by Bear, et al.) is designed for future neu-roscience researchers and premedical students. Topics include historicalfoundations of neuroscience, synaptic and neurotransmitter systems, neu-rocellular anatomy, fundamentals of the nervous system organization,neural development, sensory and motor systems, motivation, and learningand memory. Readings from the text are supplemented with handoutsrelated to current research articles.

BI 611 Advanced GeneticsThis course is designed for graduate students who have successfully com-pleted an undergraduate genetics course. Topics include the principles ofDNA replication and repair, transmission genetics, microbial genetics,transposition, epistasis and complementation, and gene mapping.

BI 612 Graduate Biochemistry This course is designed for graduate students who have successfully com-pleted an undergraduate biochemistry course. The course concentrates onthe biochemistry of biologically significant macromolecules and macro-molecular assemblies. Topics include the elements of protein structureand folding, principles of protein purification and analysis, enzymology,nucleic acid biochemistry, and the structure and function of biologicalmembranes.

BI 614 Graduate Molecular Biology This course concentrates on the biochemistry of biologically significantmacromolecules and macromolecular assemblies. Topics include the ele-ments of protein structure and folding, principles of protein purificationand analysis, enzymology, nucleic acid biochemistry, and the structure andfunction of biological membranes.

BI 615 Advanced Cell Biology Topics include the principles of cellular organization and function, regula-tion of the cell cycle, and interactions between cells and cellular signalingpathways.

Examples of 800 level graduate seminars offered over the past few years:

BI 819 Advanced Topics in Biochemistry

BI 834 Seminar in Translational Regulation

BI 835 Seminar in Structural Neurochemistry

BI 848 Seminar in Cellular Biology: Nuclear Import and Export Pathways

BI 864 Seminar in Developmental Biology

BI 865 Seminar: Cell Motility

BI 867 Current Topics in Chromosome-Microtubule Dynamics

BI 880 Responsible Conduct of Research and Professional Development

The nuclear DNA of eukaryotes is organized bystructural and regulatory proteins to form the nucleo-protein complex termed chromatin. The primary func-tional unit of chromatin is the nucleosome, a particlecontaining histone proteins and approximately 200 basepairs of DNA. Research in my laboratory is directedtoward understanding the processes involved in nucleo-some assembly during DNA replication. Just as theDNA in dividing cells must be replicated once each cellcycle, so too must sufficient histones (and other chro-matin proteins) be synthesized to assemble nucleo-somes on the newly replicated DNA. The properassembly of chromatin during cell division is of vitalimportance, because the presence or absence of nucleo-somes (and the precise positioning of nucleosomes withrespect to DNA sequences) can determine which genesare transcribed, and when. To make our results as rele-vant as possible to human cell biology, our experimentsare performed using HeLa cells, a transformed humancell line.

The faithful transmission and assembly of chro-matin requires that many independent cellular process-es be coordinated. As DNA is being replicated, histonesare synthesized, then modified by enzymatic acetylation,transported to the nucleus, and assembled into nucleo-somes. Moreover, supercoiled chromatin higher-orderstructures must first "unwind" to allow access to theDNA, and then condense again after replication is com-pleted. In my laboratory the specific questions currentlybeing investigated include: the modification status ofparental histones that are segregated to progeny chro-mosomes, and the mechanisms of histone depositiononto newly replicated DNA; the involvement of histoneacetylation in nucleosome assembly, and the propertiesof the enzymes (histone acetyltransferases) involved; therole of histone phosphorylation and methylation in reg-ulating chromatin folding; and the isolation and charac-terization of somatic nucleosome "assembly factors," todefine the in vivo assembly pathway.

In order to address these questions we use a num-ber of approaches, including DNA replication systems(in vivo and in vitro), histone acetylation assays, in vitroassembly reactions using purified components, andyeast molecular genetics. We also take advantage of anti-bodies directed against specific histones, histone modifi-cations, and non-histone chromatin proteins, to purifyand analyze newly replicated nucleosomes and theirassembly intermediates. Our aims are to identify majorcellular components needed to generate nucleosomes invivo, and to characterize the stages of chromatin biosyn-thesis. Ultimately, these studies should provide a betterunderstanding of the regulation of chromatin organiza-tion during DNA replication, and of the processesinvolved in the faithful assembly of transcriptionallyactive and inactive chromatin structures.

Ph.D., University of Massachusetts atAmherst, 1979

Postdoctoral Fellow, Scripps Clinic andResearch Foundation, La Jolla, CA, 1984

Representative Publications

Annunziato, A.T. 2005. Split decision: What happens to nucle-osomes during DNA replication? Journal of BiologicalChemistry 280: 12065–12068.

Benson, L.J., and Annunziato, A.T. 2004. In vitro analysis ofhistone acetyltransferase activity. Methods 33: 45–52.

Makowski, A.M., Dutnall, R.N., and Annunziato, A.T. 2001.Effects of Acetylation of Histone H4 at Lysines 8 and 16 onActivity of the Hat1 Histone Acetyltransferase. Journal ofBiological Chemistry 276: 43499–43502.

Anthony T. Annuziato Professor of Biology

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Fields of InterestMolecular biology; DNA replication andchromatin assembly in mammalian cells

Research in the laboratory is in a sub-area of cellbiology. Specifically, we are interested in how cellschange shape or form and how that is precisely regulat-ed using the cytoskeleton. Molecular motors usingcytoskeletal tracks are required for such intracellularmovements as cytokinesis, endocytosis, exocytosis, axon-al transport and organellar movement in general.Although motors are required, many relatively basicquestions are unanswered. Work in the laboratory focus-es on one of these problems. A critically important cellshape change under investigation is cytokinesis, thedivision of the cytoplasm during mitosis that is mediat-ed by an actin-myosin based contractile ring in the cleav-age furrow. One of the outstanding questions in thestudy of cell division is how timing and placement of thecontractile ring is coupled to mitotic controls. Usingmicromanipulation, reverse genetics, as well as bio-chemical approaches in dividing echinoderm eggs, we

have sought to determine how the timing of cytokinesisis coupled to the mitotic cycle. These experiments sug-gest that the timing of cytokinesis is a function of thedelivery of a positive cleavage stimulus to the corticalcytoskeleton. We have found that cytokinesis in embry-onic cells requires inactivation of the mitotic spindlecheckpoint but not mitotic exit. We also find that newmembrane addition occurs in a final stage of cytokinesisand requires mitotic exit. Studies are underway to deter-mine the nature of the cleavage stimulus and theresponse system orchestrating the assembly and dynam-ics of the contractile ring.ing to identify the protein thatthe antibody recognizes. This work involves the tech-niques of molecular biology, cell biology, and biochem-istry. This protein will very likely serve as a uniquemarker for these neurons and perhaps allow us toextend our understanding of synaptic vesicle exocyto-sis/endocytosis in neurons.


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Shuster, C.B., and Burgess, D.R. 2002. Targeted new mem-brane addition in the cleavage furrow is a late, separate eventin cytokinesis. Proceedings of the National Academy of SciencesUSA 99: 3633–3638.

Shuster, C.B., and Burgess, D.R. 2002. Transitions regulatingthe timing of cytokinesis in embryonic cells. Current Biology 12(10): 854–858.

Shuster, C.B., and Burgess, D.R. 1999. Parameters that specifythe timing of cytokinesis. Journal of Cell Biology 146: 981–992.

Ph.D. University of California, Davis, 1974

Postdoctoral Fellow, University ofWashington, Friday Harbor Laboratory,

1976

David BurgessProfessor of Biology

Fields of InterestCytokinesis, polarization of the

cytoskeleton

My laboratory at Boston College is interested inunderstanding the molecular signaling pathways thatregulate antigen-dependent humoral immune responses.An effective humoral response requires a given B lym-phocyte population to express a repertoire of receptorscapable of recognizing a distinct array of antigens (Ags),while at the same time maintaining tolerance. Ag-specif-ic B cells can undergo activation/ proliferation, or pro-grammed cell death. These “fate” decisions aredependent on the developmental stage of the lympho-cyte, Th cell help, and signal input from co-receptors,which serve to modulate B-cell antigen receptor (BCR)signaling threshold. Our research contributions can begrouped into four areas: 1) regulation of CREB phospho-rylation; 2) regulation of cyclin D2 gene transcription; 3)the role of cdc37/hsp90 molecular chaperones in nega-tive signaling following BCR and FcγR co-cross-linking;and 4) identification of molecular components involvedin CD5+/B-1 cells proliferation.

Our approach to identify protein kinases necessaryfor linking the BCR to CREB S133 phosphorylation hasbeen comprehensive in nature, utilizing highly selectivecell permeable activators/inhibitors of kinases and micenull for individual protein kinases linked to the B-cellsignalosome. We are currently evaluating the require-ment for novel PKC isoform(s) in BCR-induced CREBS133 phosphorylation.

Emphasis is to define signalosome components anddownstream signaling pathways that contribute to denovo cyclin D2 gene expression in mature B cells. Arequirement for functional hsp90 and MEK1/2 in BCR-induced cyclin D2 transcription has been uncovered. Weare also currently using mice deficient in the p85α geneproduct of PI-3K to evaluate the role of PI-3K in cyclinD2 gene expression.

We are also investigating whether negative signalstriggered by BCR-FcγR co-cross-linking promote growtharrest by targeting components of the cyclin D2-cdk4-pRb pathway. In B cells undergoing negative signaling,cyclin D2-cdk4 complexes are disrupted and unable tophosphorylate pRb. During this time, cdc37 is induciblyphosphorylated and along, with hsp90, does not stablybind cdk4. Thus, inhibition of cdc37 function by phos-phorylation may likely contribute to the observed growtharrest.

Studies continue to investigate the unique hyperre-sponsiveness of peritoneal B-1/CD5+ cells with respect toproliferation. B-1 cells proliferate in response to activa-tion of PKC alone, whereas B-2 cells require PKC activa-tion and calcium mobilization. We have also found thatcyclin D3 protein accumulates, coincident with S phaseentry, suggesting that cyclin D3 holoenzymes contributto endogenous pRb phosphorylation during G1/S transi-tion.


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Thomas ChilesChairperson,Professor of Biology

Piatelli, M.J., Tanguay, D., Rothstein, T.L., and Chiles, T.C.2003. Cell cycle control mechanisms in B-1 and B-2 lympho-cyte subsets. Immunologic Research 27: 31–52.

Piatelli, M.J., Doughty, C., and Chiles, T.C. 2002. Role of ahsp90-dependent, Mek-1/ERK signaling module that regu-lates B cell antigen receptor-induced cyclin D2 transcription.Journal of Biological Chemistry 277: 12144–12150.

Tanguay, D.A., Colarusso, T.P., Pavlovic, S., Doughty, C.,Rothstein, T.L., and Chiles, T.C. 2001. Differential signalingrequirements for activation of assembled cyclin D3-cdk4 com-plexes in B-1 and B-2 lymphocyte subsets. Cutting Edge:Journal of Immunology 166: 4273–4277.

Fields of InterestMolecular immunobiology ofB lymphocytes

Ph.D., University of FloridaCollege of Medicine, 1988

Postdoctoral Fellow. Boston UniversitySchool of Medicine, 1990

Instructor, Department of Medicine, BostonUniversity School of Medicine, 1991

Large scale DNA sequencing has ushered in a newera in biology. There are now hundreds of organisms inwhich nearly all the genomic sequence is known, makingit possible to thoroughly analyze and compare species attheir most atomistic genetic level. At the same time, mas-sive phenotypic datasets, such as whole-genome expres-sion arrays, have become increasingly available. My lab isinterested in computational and mathematical approach-es to analyzing such large data sources, to understandhow genomes function and evolve.

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Comparative sequence data can be used to infer thefunctional sequences within genomes. Just as morpho-logical features conserved among species (e.g. all verte-brates have a spine) are likely to be important to thosespecies, conserved DNA sequences are likely to be func-tional. One of the lab’s goals is to identify DNAsequences that regulate the transcription or translation ofnearby genes. For example, we have used comparativetechniques to identify functional sites in the promotersof the Saccharomyces genus of yeasts. Such sequencecomparisons can yield predictions of not only individualDNA/protein binding sites, but also broader features,such as the types of genes likely to be under the mostcomplex regulation. The lab also collaborates with severalexperimental groups to validate functional sequence pre-dictions, in species including malaria and zebrafish.

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Evaluating the functional significance of conservedsequences is still a major challenge, partly because themutation patterns of non-functional, or neutral, DNA arenot well understood. Another direction of the lab istherefore to characterize neutral mutation rates. Onepuzzle is why neutral rates are uniform in some species,

such as the sensu stricto yeasts, while rates vary by loca-tion in species such as mouse and human. Some currentquestions include what sequence features can affectmutation rates, and also whether mutational heterogene-ity can have a selective benefit.

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Currently, only a small fraction of the binding sitesfor transcription factors are known. As more transcrip-tion factor binding sites are discovered and mapped totheir counterparts in other species, it will be possible tolearn how transcription regulation has evolved. We areinterested in computational methods to study transcrip-tion evolution, using both sequence and experimentaldata. Some questions in which we are interested are:How quickly do binding sites and transcription factorschange between different species? How much of thischange is neutral? And, how much is due to selection?


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Jeffrey ChuangAssistant Professor of Biology

Ph.D., Massachusetts Institute ofTechnology, 2001

Postdoctoral Fellow, University of California,San Francisco, 2005

Chin, C.S., Chuang, J.H., and Li, H. 2005. Genome-wide regu-latory complexity in yeast promoters: separation of functionaland neutral sequence. Genome Research 15: 205–213.

Chuang, J., and Li, H. 2004. Functional bias and spatialorganization of genes in mutational hot and cold regions inthe human genome. PLoS Biology 2: 0253–0263.

Ito, K., Chuang, J., Alvarez-Lorenzo, C., Watanabe, T., Ando,N., and Grosberg, Yu. A. 2003. Multiple point adsorption in aheteropolymer gel and the Tanaka approach to imprinting:Experiment and Theory. Progress in Polymer Science 28: 1489–1515.

Fields of InterestComputational biology and bioinfor-

matics. Comparative genomics, generegulation, molecular evolution

My research focuses on computationalbiology/bioinformatics. Topics of interest include RNAand protein structure determination, application ofmachine learning methods to biological classificationproblems, time warping applications to functionalgenomics, and extensions of sequence alignment algo-rithms. As previous Genzten Chair of TheoreticalComputer Science at the University of Munich, I playeda key role in developing a Bioinformatics Programthere, and published Computational Molecular Biology:An Introduction, John Wiley & Sons, Ltd. (2000). For thepast three years, I have co-organized the MITBioinformatics Seminar.

Before pursuing computational biology in theBiology Department, my research focused on theoreticalcomputer science (an area at the intersection of mathe-

matics and computer science), and I worked on topicssuch as complexity of propositional proof systems,bounded arithmetic, complexity of higher type function-als, and Boolean functions and circuits.


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Ph.D., Duke University, 1979

Doctorat d'Etat Mathematics, Université Paris VII, 1985

Clote, P. Performance comparison of generalizedPSSM in signal peptide cleavage site and disulfidebond recognition. 2003. In Third IEEE Symposium onBioinformatics and Bioengineering (BIBE ‘03), ed. N.Bourbakis.

Clote, P., and Kranakis, E. 2002. Boolean Functions andComputation Models. Springer-Verlag. ISBN3-540-59436-1

Clote, P., and Backofen, R. 2000. ComputationalBiology: An Introduction. Wiley & Sons. ISBN 0-471-87251-2 (hardback) and ISBN 0-471-87251-0 (paper-back).

Peter CloteProfessor of Biology

Courtesy appointment, Computer Science

Fields of InterestComputational biology/bioinformatics

The bioinformatics server, clavius.bc.edu, is comprised of a 20 CPU

rack-mount computational cluster, with 1.2 terabytes of fiber-attached

network storage. The server is heterogeneous, comprised of dual processor

Intel Pentium III/Linux and dual processor Apple/Mac OS X nodes.

Research computing time, available free of charge, affords substantial

research and educational opportunities for students and faculty.

My laboratory research has focused on the symbiot-ic association of nitrogen-fixing Rhizobium meliloti withits host plant alfalfa. The specific interaction of the bac-teria with alfalfa root hairs results in the development ofroot nodules, differentiated plant structures containingintracellular bacteria. These bacteria reduce atmosphericnitrogen to ammonia, thus providing a major source ofavailable nitrogen for human consumption. The develop-ment of root nodules and the subsequent ability to fixnitrogen requires new gene expression from both symbi-otic partners. My lab has investigated the induction ofnodule-specific plant genes using a variety of bacterialmutants, each blocked at varying stages of intracellulardevelopment. Our results from numerous studies haveshown that induction of certain nodule-specific genesrequires entry of the bacterium into the plant cell but isindependent of further bacteriod development. Thismay reflect a developmental program that is initiated bythe infecting bacterium, but subsequently facilitated byplant processes. Following this reasoning, we hypothe-sized that plant developmental mechanisms may be con-served, and used PCR to identify several MADS boxgenes whose expression is found in the infected cells.Since plant MADS box genes have been implicated inflower development, it is intriguing to speculate thatsimilar mechanisms may be involved during noduledevelopment. Currently, we believe that three alfalfaMADS box genes are involved in a signal transductionpathway that is initiated by the infecting bacterium andresults in differentiation of the infected cell. The infect-ed differentiated cell has the appropriate environment tosupport the nitrogen-fixing bacteria. Further work isneeded to identify the ultimate target genes and to deter-mine the extent to which various programs for organdevelopment overlap.

After a fellowship and sabbatical leave at theRadcliff Public Policy Center, I developed a new researchinterest revolving around science policy and careerdevelopment. Currently, I am working with colleaguesin the Carroll School of Management to examine successstrategies for mid-career scientists working in academia.Our goal is to identify institutional, cultural and person-al factors that influence research productivity throughone’s mid-life, a period of documented transition.Special attention is being directed to the research suc-cess of women, and the unique problems that they faceas an academic scientist.


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Zucchero, J., Caspi, M., and Dunn, K. 2001. ngl9: A thirdMADS box gene expressed in alfalfa root nodules. MolecularPlant-Microbe Interactions 14: 1463–1467.

Ganter, G., Duquette, M., and Dunn, K. 2000. Separation ofroot nodule cells and identification of tissue-specific genes.Plant Cell Reports 19: 921–925.

Heard, J., and Dunn, K. 1995. Symbiotic induction of a MADS-box gene during development of alfalfa root nodules.Proceedings of the National Academy of Sciences, USA 92:5273–5277.

Ph.D., University of North Carolina at Chapel Hill, 1982

Postdoctoral Fellow, Harvard Medical School, 1985

Kathleen DunnAssociate Professor of Biology

Fields of InterestRegulation of gene expression; microbi-

ology and infectious disease; sciencepolicy and women's career development

The protozoan parasiteToxoplasma gondii is amember of the phylum Apicomplexa and can causesevere disease in humans. This parasite is easily grownand manipulated in vitro and has in recent years devel-oped as a safe and versatile model for other apicomplex-an parasites (e.g. malaria). We are using and developingforward, reverse and functional genetic tools using enzy-matic as well as fluorescent protein reporter assays incombination with cell sorting and fluorescencemicroscopy to learn more about the parasite’s cell biolo-gy.

Parasite replication is conserved, yet are variationson a theme in different apicomplexan parasites.Toxoplasma divides by an internal budding processcalled endodyogeny where two daughters are beingassembled inside the mother, which is significantly dif-ferent from mammalian cell division. The parasite’scytoskeleton, consisting of microtubules as well as amembrane skeleton in combination with intermediate

protein filaments (the inner membrane complex orIMC) serves as a scaffold for daughter assembly.Recently we identified several components that act inthe cytoskeleton assembly as well as daughter formationwhich are currently being characterized in detail.

Host cell invasion is an essential step in the lifecycle of Apicomplexa and identifying essential stepsand/or molecules in the process would provide attractivepotential therapeutic targets. To identify key moleculesin invasion, a set of conditional parasite invasionmutants has been generated through random as well asinsertional (conditional) mutagenesis. Mutants arebeing analyzed through a set of cell biological assayswhile at the same time the mutated genes are beingidentified using DNA library complementations as wellas plasmid rescues.

A third field of interest is the interaction of the par-asite with its host cell. Although there is plenty evidencethe parasite modifies its host cell to ensure its own sur-vival, exactly how the parasite achieves this in unclear. Itis also unclear if there are any essential host cell compo-nents the parasite requires from the host cell, whichwould be good interference targets as well. Severalgenetic screens using flow cytometric cell sorting aswell fluorescent protein based growth screens are eitherplanned or underway.


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Ph.D., Utrecht University, the Netherlands,2000

Postdoctoral Fellow, University of Georgia,USA, 2005

Gubbels, M.-J., Striepen, B., Shastri, N., Turkoz, M., andRobey, E. 2005. Class I MHC presentation of antigens thatescape from the parasitophorous vacuole of Toxoplasmagondii. Infection and Immunity 73: 703–711.

Howe, D.K., Gaji, R.Y., Mroz-Barrett, M., Gubbels, M.-J.,Striepen, B. and Stamper, S. 2005. Sarcocystis neurona mero-zoites express a family of immunogenic surface antigens thatare orthologues of the SAG/SRS surface antigens inToxoplasma gondii. Infection and Immunity 73: 1023–1033.

Gubbels, M.-J., and Striepen, B. 2004. Fluorescent proteinsas tools to study the cell biology of protozoan parasites.(Review). Microscopy and Microanalysis 10: 1–12.

Marc-Jan GubbelsAssistant Professor of Biology

Fields of InterestGenetic approaches towards the cellbiology of Toxoplasma gondii

Gene expression can be regulated at several differ-ent levels. While the primary control of gene expressionis at the level of transcription (synthesis of specificmRNAs from a DNA template) in recent years it hasbecome apparent that regulation at the level of transla-tion (the synthesis of proteins from messenger RNA) isalso very important.

Translational regulation linked to changes inmRNA poly(A) tail length is necessary for progressionthrough meiosis, early development and localized trans-lation at the neuronal synapse. This mechanism is called“polyadenylation induced translation”. Essentially,mRNAs containing a long poly A tail (50-300 nt) aretranslated, whereas those with a short poly A tail (<50nt) are not. Molecular events that alter the length of thepoly A tail therefore directly influence the translation ofthe mRNA.

Our research is currently focused on dissecting themolecular machinery of polyadenylation-induced transla-tion and the signal transduction cascade that regulatesthis process during Xenopus oocyte meiosis.

We use Xenopus oocytes and eggs because we canobtain large amounts of material for examining themolecular machinery of polyadenylation-induced transla-tion and we can induce the meiotic signal transductioncascade by adding progesterone to explanted oocytes.Microinjection allows us to explore the influence of vari-ous mRNAs and proteins on meiosis and the metabo-lism of components of meiosis and polyadenylation-induced translation.

Current projects include analysis of the regulationand metabolism of CPEB, identification and characteri-zation of XGef and CPEB interacting proteins, andexploration of the role of XGef and small GTPases inprogesterone stimulated meiosis.


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Martinez, S., Yuan, L., Lacza, C., Ransom, H., Mahon, G. M.,Whitehead, I. P. and Hake, L.E. 2005. XGef mediates earlyphosphorylation of CPEB during Xenopus oocyte meiotic mat-uration. Molecular Biology of the Cell 16: 1152–64.

Reverte, C.G., Yuan, L., Keady, B.T., Lacza, C., Attfield, K.R.,Mahon, G.M., Freeman, B., Whitehead, I.P., and Hake, L.E.2003. XGef is a CPEB-interacting protein involved in Xenopusoocyte maturation. Developmental Biology 255: 383–398.

Reverte, C.G., Ahearn, M.D., and Hake, L. E. 2001. Stockpilingand degradation of CPEB during Xenopus oogenesis andoocyte maturation. Developmental Biology 231: 447–458.

Ph.D., Tufts University, 1992

Postdoctoral Fellow, Worcester Foundationfor Biomedical Research, 1997

Laura E. HakeAssociate Professor of Biology

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C-mos mRNA in the prophase I oocyte is translationally repressed byinteraction between CPEB, a repression complex and the cap bindingprotein eIF4E. During progesterone stimulated meiotic resumption,XGef, a Rho-family guanine nucleotide exchange factor, influences thephosphorylation of CPEB by Aurora A kinase. This activates CPEB,which then recruits Cleavage and Polyadenylation Specificity Factorand Poly A Polymerase to the mRNA, and the poly A tail is elongated.Poly A Binding Protein then associates with the poly A tail and recruitseIF4G. This displaces the repressing complex, the 43 S ribosome isrecruited and translation begins.

Fields of InterestTranslational regulation and signal

transduction during meiosis and in earlyanimal development

How do eukaryotic cells sense their environmentand regulate biological processes in response to environ-mental signals? To address this question, my lab studieshow glucose triggers repression of transcription of thefbp1 gene in the fission yeast Schizosaccharomyces pombe.Depending upon the carbon source in the medium, S.pombe cells regulate fbp1 transcription over a 200-foldrange.

Combining classical yeast genetics with molecularbiology, we have identified a number of genes requiredfor both repression and derepression of fbp1 transcrip-tion. Glucose repression requires the function of ninegit genes leading to the activation of protein kinase A(PKA; cAMP-dependent protein kinase). These genesinclude seven genes required for activation of adenylatecyclase, one gene encoding adenylate cyclase (git2/cyr1),

and one gene encoding the catalytic subunit of PKA(pka1/git6). Four of the genes required for adenylatecyclase activation encode alpha, beta, and gamma sub-units of a heterotrimeric G protein, the same type ofprotein that regulates mammalian adenylate cyclaseactivity, and a seven transmembrane protein that mayfunction as a glucose receptor. We are presently study-ing the interactions between these proteins and adeny-late cyclase. We have also found that both adenylatecyclase and phosphodiesterase activities are regulated tocontrol cAMP signaling. The remaining three git genes,appear to work independently from the G protein. Thegit1 protein is unique to S. pombe, while git7 and git10have orthologs in other organisms that have been shownto physically interact and to work in a variety of process-es. We are currently studying the roles of these proteinsin cAMP signaling, as well as the mechanisms by whichthey carry out these roles.


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Ph.D., Tufts University, Sackler School, 1986

Postdoctoral Fellow, Harvard Medical School, 1990

Ivey F.D., and Hoffman C.S. 2005. Direct activation of fissionyeast adenylate cyclase by the Gpa2 Gα of the glucose signal-ing pathway. Proceedings of the National Academy ofSciences USA 102: 6108–6113.

Hoffman C.S. 2005. Except in every detail: comparing andcontrasting G-protein signaling in Saccharomyces cerevisiaeand Schizosaccharomyces pombe. Eukaryotic Cell 4: 495–503.

Hoffman C.S. 2005. Glucose sensing via the protein kinase Apathway in Schizosaccharomyces pombe. Biochemical SocietyTransactions 33: 257–260.

Charles Hoffman

Professor of Biology

Fields of InterestGlucose sensing, signal transduction,and transcriptional regulation in the fis-sion yeast Schizosaccharomyces pombe

Signaling pathway

Functional sequence variations cause phenotypicdifferences, and can lead to hereditary diseases.Functional or not, polymorphisms are landmarks allow-ing us to track how segments of DNA have been passeddown through past generations. My laboratory is inter-ested in various aspects of sequence variation research.

PPoollyymmoorrpphhiissmm ddiissccoovveerryy ttoooollss. Building onPolyBayes, a SNP discovery tool we have developed atWashington University, we continue working on effi-cient, accurate, mathematically rigorous polymorphismdiscovery algorithms that can detect genetic variationsin DNA sequences from varied sources and quality stan-dards.

PPooppuullaattiioonn GGeenneettiicc mmooddeelliinngg. Large data miningefforts found millions of polymorphic sites in thehuman genome. These large data sets make it possibleto study the molecular and demographic processes that

have shaped the genome landscape of human variations.Our primary interest is in interpreting the effects oflong-term demographic history on genome-wide humanvariation data using coalescent modeling approaches,and determining the model structures and modelparameters that best account for the observed patterns.This will allow us to better understand human pre-histo-

ry and to obtain quantitative computer models ofhuman polymorphism structure.

HHuummaann hhaapplloottyyppee ssttrruuccttuurree. An ambitious initia-tive, the International HapMap project is underway tomap out human haplotype structure at the kilobase scalein hundreds of reference samples from a handful ofpopulations. Its utility for medical research will bedetermined by the degree to which allelic associationpatterns observed within the HapMap reference samplesactually pertain to patients. An important research focusof my lab is to understand the demographic differencesin the haplotype structure among human populationsand to develop tools with which to extrapolate thestrength of allelic association from reference samples toclinical samples.


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D.Sc., Washington University, 1994

Postdoctoral Research Associate, Washington University, 2000

Staff Scientist,National Institutes of Health, 2003

Marth, G.T., et al. 2004. The allele frequency spectrum ingenome-wide human variation data reveals signals of differen-tial demographic history in three large world populations.Genetics 166: 351–372.

Marth, G.T., et al. 2003. Sequence variations in the publichuman genome data reflect a bottlenecked population history.Proceedings of the National Academy of Sciences USA 100:376–381.

Marth, G.T., et al. 1999. A general approach to single-nucleotide polymorphism discovery. Nature Genetics 23:452–456.

Gabor MarthAssistant Professor of Biology

Fields of InterestDNA sequence variation, genome datamining and informatics, populationgenetics, medical genetics

The basic paradigm for nuclear import is that aprotein containing a nuclear localization signal (NLS)interacts directly, or via an adapter, with an importreceptor belonging to the karyopherin beta/importinbeta (Kap beta/Imp beta) superfamily; is translocatedthrough the nuclear pore complex and released in thenucleus. We had previously identified and characterizedseveral nuclear import pathways for proteins containinga classical nuclear localization signal: hnRNP A1 andInfluenza virus RNA.

My current research program focuses on the identi-fication and characterization of the nuclear import path-ways for the proteins and DNA of human papillomaviruses (HPVs). More than 100 HPV genotypes havebeen isolated and characterized, with roughly half infect-ing the skin and the other half the oral/anogenitalmucosal epithelial tissues. Mucosal HPVs have demon-strated varying degrees of oncogenic potential. High riskHPVs, such as types 16, 18, and 45, are frequentlydetected in invasive cervical carcinomas. Low risk HPVs,such as types 6 and 11, are more often associated withbenign exophytic condylomas. HPVs are small, nonen-veloped, icosahedral DNA viruses that infect squamousepithelial cells. The virion particles (52-55 nm in diame-ter) consist of a single molecule of 8 kb double-strandedcircular DNA contained within a spherical capsid com-posed of 72 homopentameric L1 capsomeres and L2molecules of L2 minor capsid protein. During the latephase of viral infection, HPV L1 major capsid proteinsenter the nuclei of terminally differentiated epithelialcells and, together with the L2 minor capsid proteins,assemble the viral DNA into virions.

Nuclear import and export of HPV proteins andnucleic acids are crucial for the viral life cycle and patho-

genesis. Projects in my lab include: identification andcharacterization of the nuclear import pathways for L1and L2 capsid proteins and for E6 and E7 oncoproteinsof both high and low risk HPVs; the molecular mecha-nisms for nuclear import of HPV genomic DNA; andnuclear export pathways for E6 oncoproteins and viraltranscripts. Our studies defining the transport pathwaysfor HPV proteins and nucleic acids will make a signifi-cant contribution to the understanding of the HPV lifecycle and pathogenesis.


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Fay, A., Yutzy, W. H. IV, Roden, R. B. S., and Moroianu, J. 2004.The positively charged termini of L2 minor capsid proteinrequired for bovine papillomavirus infection function separatelyin nuclear import and DNA binding. Journal of Virology 78:13447–13454.

Darshan, M. S., Lucchi, J., Harding E., and Moroianu, J. 2004.The L2 minor capsid protein of human papillomavirus type 16interacts with a network of nuclear import receptors. Journal ofVirology 78: 12179–12188.

Nelson, L.M., Rose, R.C., and Moroianu, J. 2002. Nuclearimport strategies of high risk HPV16 L1 major capsid protein.Journal of Biological Chemistry 277: 23958–23964.

Ph.D. in Cell Biology, Rockefeller University, 1996

Postdoctoral Associate, Rockefeller University, 1997

Junona Moroianu Associate Professor of Biology

Fields of InterestNuclear import and export of viral and

cellular macromolecules

Research in my lab is being conducted in threeareas: signal transduction during development in thefruit fly, Drosophila melanogaster; host-parasite interac-tions in the malarial mosquito, Anopheles gambiae; andendosymbiosis, pathogenesis, and bleaching in marineinvertebrates

Mechanisms that underlie the adoption of cell fatesin Drosophila also operate in other multicellular organ-isms, including humans. We are focusing on under-standing in flies the Notch signal transduction pathway,which also operates in humans and is central to the cor-rect specification of cell fates and hence to pattern for-mation within embryonic, larval, and adult tissues. Weare studying the Delta-Notch pathway—implicated inlymphoma and genetic syndromes in humans—usingmorphological, genetic, molecular, and cell biologicalapproaches. These studies focus on understanding theregulation of signalling by Delta, a cell surface protein;

the relationship between the structure of the Delta pro-tein and its function as a signal during development; andthe mechanisms by which Delta stimulates activation viaproteolysis of the cell surface receptor Notch. This aspectof our research is of particular interest because Deltastimulates proteolysis of Notch by a Drosophila homo-logue of Presenilin, an intramembrane protease that hasbeen implicated in Alzheimer's disease in humans.

The continuing transmission of human malariadepends, in part, on reproduction of the malarial para-site, Plasmodium spp., within mosquitos. We are investi-gating the midgut, one of the mosquito tissues central tothe reproduction of malarial parasites, using morphologi-cal, molecular, and cell biological techniques. We are alsoinvestigating cellular and molecular aspects of interac-tions between malarial parasites and the midgut duringthe course of parasite reproduction and growth in themalarial vector mosquito Anopheles gambiae, usingmolecular genetics and DNA microarray-based geneexpression profiling. By better understanding this impor-tant host-parasite interaction, we hope to developapproaches to disrupt it, thereby reducing the transmis-sion of malaria within human populations.

Corals and other marine invertebrates often harborunicellular endosymbionts. Such endosymbionts providephotosynthetic resources to the host, and the host pro-vides endosymbionts with nitrogenous resources andphysical protection. We are studying one such endosym-biont, the dinoflagellate Symbiodinium microadriaticum,in an attempt to better understand the establishment andmaintenance of these endosymbiotic relationships incorals (Acropora spp.) and anemones (Aiptasia spp.).These studies will extend our understanding of themechanisms of endosymbiosis between dinoflagellatesand invertebrates, an interaction vital to the health anddiversity of tropical coastal marine ecosystems.


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Ph.D., Stanford University, 1981

Postdoctoral Fellow, Harvard University, 1984

Klueg, K.M., Alvarado, D., Muskavitch, M.A.T., and Duffy, J.B.2002. Creation of a GAL4/UAS-coupled inducible geneexpression system for use in Drosophila cultured cell lines.Genesis 34: 119–122.

Pavlopoulos, E., Pitsouli, C., Klueg, K., Muskavitch, M.A.T.,Moschonas, N., and Delidakis, C. 2001. Neuralised encodes aperipheral membrane protein involved in Delta signalling andendocytosis. Developmental Cell 1: 807–816.

Parks, A.L., Klueg, K.M., Stout, J.R., and Muskavitch, M.A.T.2000. Ligand endocytosis drives receptor dissociation andactivation in the Notch pathway. Development 127: 1373–1385.

Marc MuskavitchDeLuca Professor of Biology

Fields of InterestMolecular cell biology of Notch signal-ing during development. Molecular cellbiology of host-pathogen interactions invector insects

The goal of our research is to understand the physi-ological significance of a protein carboxyl methyltrans-ferase (PCMT) that esterifies unusual isoaspartylresidues in proteins. Isoaspartyl residues are not incor-porated into proteins during translation, but arise spon-taneously during aging. The introduction of anisoaspartyl residue into a protein produces a "kink" inthe protein backbone, which can inactivate the protein.In purified systems, PCMT initiates the structural repairof the damaged substrate, and it has been proposed thatPCMT helps to prevent the accumulation of damagedproteins in cells. Judging from the nearly ubiquitous dis-tribution of PCMT activity in living organisms, PCMTfunction may be a fundamental component of cellularprotein metabolism. We are currently using both bio-chemical and genetic experiments to study the signifi-cance of PCMT activity.

To define the biochemical pathway initiated by car-boxyl methylation, we have been following the fate ofisoaspartyl-containing proteins following their microin-jection into Xenopus laevis oocytes. These experimentshave shown that cells recognize isoaspartyl-containingsubstrates as abnormal and target them for degradationunless they are modified by PCMT, consistent with therole of PCMT in protein repair. We have further charac-terized the degradation pathway and found that proteinsare degraded by the 26S proteasome in a novel pathwaythat does not involve ubiquitination.

We are also using the fruitfly Drosophilamelanogaster to understand the effects of PCMT duringaging. Drosophila makes a particularly suitable model forthese studies because of the reproducible phenotypesassociated with the aging process, which occurs over aperiod of about six weeks. In addition, many of the fun-damental mechanisms underlying development andneural function are conserved from Drosophila to mam-

mals. We have recently shown that overexpression ofPCMT in adult flies causes a dramatic extension in theadult lifespan at 29 degrees centrigrade, but not at 25

degrees centrigrade. The results suggest that proteinrepair is important in the control of lifespan. PCMTfunction may be particularly important at slightly elevat-ed temperatures, where proteins are more flexible andprone to isoaspartate formation. We are now construct-ing other Drosophila mutants to determine if there is aquantitative relationship between the level of PCMTexpression and longevity.


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❖ Chavous, D.A., Jackson, F.R., and O'Connor, C.M. 2001.Extension of the Drosophila lifespan by overexpression of aprotein repair methyltransferase. Proceedings of the NationalAcademy of Sciences 98: 14814–14818.

Tarcsa, E., Szymanska, G., Lecker, S., O'Connor, C.M., andGoldberg, A.L. 2000. Ca2+-free calmodulin and calmodulindamaged by in vitro aging are degraded by 26S proteasomeswithout ubiquitination. Journal of Biological Chemistry 275:20295–20301.

Szymanska, G., Leszyk, J.D., and O'Connor, C.M. 1998.Carboxyl methylation of deamidated calmodulin increases itsstability in Xenopus oocyte cytoplasm: Implications for pro-tein repair. Journal of Biological Chemistry 273: 28516–28523.

Ph.D., Purdue University, 1977

Postdoctoral Fellow, Division of Biology,California Institute of Technology, 1980

Postdoctoral Fellow, Molecular BiologyInstitute and Department of Chemistry

and Biochemistry, University of Californiaat Los Angeles, 1984

Clare O’ConnorAssociate Professor of Biology

Fields of InterestProtein methylation and the repair of

age-damaged proteins

The interests of my laboratory center around themolecular and developmental biology of the fruit flyDrosophila melanogaster. We utilize the follicular epithe-lial cells of the ovary to investigate the mechanismswhich allow genes to be turned on and off in a sex-, tis-sue-, and developmental stage-specific manner. Thesecells produce proteins which form the protectiveeggshell surrounding the mature oocyte. Our laboratoryand others have characterized many of the genes andproteins involved in making the two layers of theeggshell: the vitelline membrane (VM) and the chorion.

In the case of the genes encoding the proteins forthe vitelline membrane, we have found that they areexpressed only in the adult female, only in the follicularepithelium, and only during stages 8, 9, and 10 of eggchamber development. Our long-term goal is to eluci-date the details of how such a specific pattern of controlof gene expression is regulated. To this end we havecloned the genes for two vitelline membrane proteins,VM26A1 and VM34C, and fused their modifiedupstream regulatory regions to b-galactosidase and chlo-ramphenicol acetyl transferase reporter genes. Theseconstructs have then been reintroduced into flies via P-element-mediated germline transformation. Using thisapproach, we have been able to define roughly 100 basepair long regions adjacent to both genes which containthe key, independently acting sex-, tissue-, and stage-spe-cific control functions. In addition, we have found anumber of dependent control elements which require afunctional independent element and which affect thespatial pattern of expression within the follicular epithe-lium and the quantitative levels of expression. We arenow utilizing these defined cis-acting elements and gelretardation assays to search for the transacting mole-cules involved in switching on the VM genes. We haveidentified one factor which binds specifically to the key

independent control region of the VM26AI gene.Current work involves characterizing this factor andrecovering a clone for its gene from an ovarian cDNAexpression library.

A second area of research in the lab involves thefield of molecular evolution. While sequencing thegenes for VM proteins, we discovered that hidden withinthe coding sequence of each gene was a highly con-served 38-40 amino acid peptide we call the VMdomain. We immediately wondered if the conservationof this VM domain extended beyond the melanogasterspecies, and hence might serve as a new model for theevolution of insect eggshells in general via the formationof a multi-gene family. We are currently using PCR andother techniques to search for VM domain-relatedsequence in other classes of insects.


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❖ Rounds, E., and Petri, W.H. 2003. A Drosophila ovarian-specif-ic splice variant of dTAFII25O associates with a developmen-tal control region of the VM26AI genes. In preparation.

Scherer, L.F., Harris, D.H., White, M.K., Steel, L.F., Jin, J., andPetri, W.H. 1993. Comparative analysis of the sequence andstructure of two Drosophila melanogaster genes encodingvitelline membrane proteins. Gene 136: 121–127.

Jin, J., and Petri, W.H. 1993. Developmental control elementsin the promoter of a Drosophila vitelline membrane gene.Developmental Biology 156: 557–565.

Ph.D., University of California atBerkeley, 1972

Research Fellow, Harvard University,1976

William PetriAssociate Professor of Biology

Fields of InterestDevelopmental regulation of gene

expression and molecular evolution ofDrosophila eggshell genes

My research interests have included the biologicalroles of metal ions such as zinc and iron as well as themechanisms for protection against the toxic effects ofmetals such as cadmium and copper, using the fissionyeast Schizosaccharomyces pombe as a model system foreukaryotic cells. Recent studies have examined mecha-nisms for protection against copper and cadmium. Theproperties of metal-binding peptides known as Class IIImetallothioneins, as well as the conditions for their syn-thesis, have been the object of several studies.

Work on copper resistance has involved the isola-tion of a copper-resistant strain of S. pombe, which,unlike S. cerevisiae, does not contain a gene for a ClassII metallothionein that accounts for copper resistance inthe latter organism. Rather, the resistance trait in S.pombe results from a single recessive chromosomalmutation that appears to affect the properties of the

cytoplasmic membrane with the consequence that entryof copper into the cell is inhibited.

Studies involving resistance to cadmium ions havefocused on the synthesis of Class III metallothioneins(sometimes called phytochelatins) that have the overallstructure [γGlu-Cys)nGly]. These peptides, present inhigher plants, occur in S. pombe as well, and their syn-thesis is stimulated in response to a variety of metalions, cadmium being the most effective. Peptide synthe-sis is catalyzed by the constitutive enzyme γGlu-Cysdipeptidyl transpeptidase (phytochelatin synthase), thatuses glutathione (γGlu-Cys-Gly) as an initial substrate.Complexes are formed with metal ions and several pep-tide molecules, often of heterogeneous lengths, fre-quently containing inorganic "labile" sulfide as well.Our work has focused on delineation of the stoichiome-tries and structures of the complexes formed with cad-mium and zinc, as well as the conditions required fortheir formation and their possible biological functionsin addition to a likely detoxifying role.Representative Publications

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Ph.D., Massachusetts Institute ofTechnology, 1961

Plocke, D.J., and Lauro, M.M. 1999. Synthesis and propertiesof Class III metallothioneins of S. pombe in response to cad-mium and zinc, in metallothionein IV (C. Klaassen, ed.) Basel:Birkhåuser Verlag 195–199.

Plocke, D.J., and Kagi, J.H.R. 1992. Spectral characteristics ofcadmium-containing phytochelatin complexes isolated fromSchizosaccharomyces pombe. European Journal of Biochemistry207: 201–205.

Whiteside, S.G., and Plocke, D.J. 1992. Selection and charac-terization of a copper-resistant subpopulation ofSchizosaccharomyces pombe. Journal of General Microbiology138: 2417–2423.

Donald J. Plocke, SJAssociate Professor of Biology

Fields of InterestMolecular biology; structure and func-tion of Class III metallothioneins; metalions as regulators in microbial systems;metal ion detoxification mechanisms

Our research program focuses on dietary therapiesfor epilepsy, brain cancer, and neurodegenerative lipidstorage diseases. These therapies include caloric modifi-cation, fasting, and the ketogenic diet. Our goal is tomanage complex diseases through principles of metabol-ic control theory. This theory is based on the idea thatcompensatory metabolic pathways are capable of modify-ing the pathogenesis of complex neurological diseasesdespite the continued presence of the genetic or environ-mental defects responsible for the disease. By shiftingthe brain metabolic environment, diet therapies canpotentially mask or neutralize molecular pathology. Theneurochemical and genetic mechanisms of these phe-nomena are under investigation in genetic animal mod-els and include the processes of inflammation,programmed cell death, angiogenesis, and bioenergetics.


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❖ Greene, A., Todorova, M.T., and Seyfried, T.N. 2003.Perspectives on the metabolic management of epilepsythrough dietary reduction of glucose and elevation of ketonebodies. Journal of Neurochemistry. In press.

Mukherjee, P., El-Abbadi, M.M., Kasperzyk, J., and Seyfried,T.N. 2002. Dietary restriction reduces angiogenesis andgrowth in an orthotopic mouse brain tumour model. BritishJournal of Cancer 86: 1615–1621.

Greene, A., Todorova, M.T, McGowan, R., and Seyfried, T.N.2001. Caloric restriction inhibits seizure susceptibility inepileptic EL mice by reducing blood glucose levels. Epilepsia42: 1371–1378.

Ph.D., University of Illinois, Urbana-Champaign, 1976

Thomas SeyfriedProfessor of Biology

Fields of InterestGene-environmental interactions in

epilepsy and brain cancer

I advocate a multidisciplinary approach for address-ing questions regarding the insect transmission ofpathogens. Using tools from the diverse scientific disci-plines of molecular biology, biochemistry, cell biology,immunocytochemistry, genomics, and proteomics, mylaboratory investigates how the malaria parasite is trans-mitted from one human to another by using the mos-quito as vector. The projects of my laboratory can beclassified into four major areas: (1) the development ofthe mosquito stage of malaria parasites; (2) the biologyof the mosquito as it relates to malaria transmission; (3)molecular interaction between the malaria parasite andmosquito; and (4) mosquito responses to malaria para-site invasion.

Our goal is to identify crucial parasite and mosqui-to molecules that can be targeted to develop malariatransmission-blocking strategies.

Soon after the ingestion by mosquitoes with blood,the parasites emerge from the gametocyte as male andfemale gametes, which fertilize to form zygotes. Thezygote transforms into a motile ookinete and exits from

the blood bolus. The ookinete crosses the midgutepithelium and lies between the midgut cells and thebasement membrane, where it develops as an oocyst.Inside the oocyst, the parasite multiplies to form thou-sands of sporozoites. In about two weeks, sporozoitesare released from the oocyst into the insect blood,invade the salivary gland and remain there until injectedinto a human during a subsequent blood meal.

My lab has shown that chitinase secreted by themalaria parasite is required for its escape from theblood bolus. Blocking chitinase activity in the mosquitomidgut blocks Plasmodium development in the mosqui-to. This makes chitinase a candidate for development ofa malaria transmission-blocking vaccine. In a series ofsubsequent studies, we described the cellular composi-tions of Aedes aegypti mosquito midgut. We have discov-ered that a carbohydrate-mediated ligand helps the avianmalaria parasite, Plasmodium gallinaceum, which we useas a model, adhere to the midgut epithelium. We alsofind that the parasite appears to preferentially invade aspecific cell type in the mosquito midgut. Recently, wediscovered a novel differential partitioning of maternallipids in the mosquito, where phospholipids are accu-mulated in the larval intestine.

Transmission of the malaria parasite by mosquitossuggests that the parasite sporozoite stage is able toevade the potent insect antimicrobial immune response,which efficiently clears bacteria and fungi from theinsect blood. To understand how the sporozoites sur-vive in the mosquito, we have been using transgenicinsect and gene microarray technologies. We have foundthat the malaria sporozoite modulates expression of anumber of Drosophila genes involved in immunity, sig-nal transduction, and metabolic pathways. Research toidentify the Anopheles homologues of these Drosophilasporozoite-responsive genes and to determine theeffects of malaria parasite infection on these genes iscurrently underway.

Ph.D., 1990, University of Edinburgh, Scotland

Postdoctoral Visiting Fellow, National Institutes ofHealth, Bethesda, MD, 1993

Visiting Associate, National Institutes of Health,Bethesda, MD, 1996

Investigator, National Institutes of Health, Bethesda,MD, 2003

Mohammed ShahabuddinAssistant Professor of Biology

Fields of InterestBiology of disease transmission by insects


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❖ Atella, G., and Shahabuddin, M. 2002. Differential partition-ing of maternal fatty acid and phospholipid in neonate mos-quito larvae. Journal of Experimental Biology 205: 3623–3630.

Neto, M.S., Atella, G., and Shahabuddin, M. 2002. Inhibitionof Ca2+-Calmodulin-dependent protein kinase blocks mor-phological differentiation of Plasmodium gallinaceum zygoteto ookinete. Journal of Biological Chemistry 277(16):14085–14091.

Schneider, D. and Shahabuddin, M. 2000. Malaria parasitedevelopment in a Drosophila model. Science 288: 2376–2379.

My laboratory is interested in how cells keep theirchromosomes intact. The ends of linear chromosomespose a particular problem, because they must be differ-entiated from broken DNA ends that result from DNAdamage. Most eukaryotes solve this problem by cappingtheir chromosomes with specialized protein: DNA struc-tures, or telomeres. Telomeres shield the chromosomeends from the checkpoint proteins that survey thegenome looking for DNA damage, and from theenzymes that degrade and repair broken DNA ends.

Telomeres are not completely impenetrable – theymust transiently open to allow telomerase to gain accessto the chromosome end. Telomerase is the enzyme thatadds new telomeric DNA onto the ends of chromo-somes, and thus compensates for the inability of con-ventional DNA polymerases to fully replicate linearDNA molecules. In humans, telomerase is turned off inmost terminally differentiated cells, but telomerase isreactivated in most types of tumors, and this reactiva-tion correlates with the ability of tumor cells to prolifer-ate indefinitely. Therefore, understanding howtelomerase is regulated is of great interest to cancerbiologists.

We are studying telomeres and telomerase in amodel organism that proliferates continuously, the bud-ding yeast Saccharomyces cerevisiae. We use geneticsand biochemistry to investigate how the telomere isremodeled and how telomerase activity is regulated overthe course of the cell cycle. Telomerase contains bothprotein and RNA components, and interactions betweenthese components and specific telomere binding pro-teins are emerging. We are currently investigating howthese interactions contribute to the recruitment, activa-tion and release of telomerase at telomeres.

We have also uncovered a mechanism by whichtelomerase can be recruited to broken DNA ends, where

it can instigate a crude form of DNA repair: telomerasecan add telomeric DNA to the site of the break, whichenables the broken chromosome to be capped with atelomere. This telomere healing mechanism is costly togenome integrity, since all DNA sequence distal to thebreak is lost, however it enables the checkpoint to bereleased and the cell to resume growth. We are workingto understand the regulatory circuits that control telom-erase activity at broken DNA ends. We are also investi-gating whether some types of chromosomal damage aredependent on this mechanism for DNA repair, andwhether potential sites for telomere healing are nonran-domly distributed across the genome.


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Ph.D., University of California, SanFrancisco, 1997

Postdoctoral Fellow, Fred HutchinsonCancer Research Center, 2004

Stellwagen, A. E., Haimberger, Z.W., Veatch J. R., andGottschling, D. E. 2003. Ku interacts with telomerase RNA topromote telomere addition at native and broken chromo-some ends. Genes & Development 17: 2384–2395.

Peterson, S. E. , Stellwagen, A.E., Diede, S. J., Singer, M. S.,Haimberger, Z. W., Johnson, C. O., Tzoneva, M., andGottschling, D. E. 2001. The function of a stem-loop intelomerase RNA is linked to the DNA repair protein Ku.Nature Genetics 27: 64–67.

DuBois, M. L., Diede, S. J., Stellwagen, A. E., and Gottschling,D. E. 2001. All things must end: telomere dynamics in yeast.Cold Spring Harbor Symposium on Quantitative Biology 65:281–296.

Anne Stellwagen Assistant Professor of Biology

Fields of InterestTelomeres, telomerase and chromosome

stability

My laboratory is interested in the neurobiology ofthe chemosensory system. We use molecular genetic,cell biological, and behavioral techniques to examine thechemosensory system of the small nematode round-worm, Caenorhabditis elegans. We are interested in twodistinct aspects of this problem.

First, we wish to understand the development ofthe various cell types that must interact during the for-mation of an intact sensory organ. How is the regula-tion of this process organized? How is the develop-mental program executed? Many human sensory disor-ders arise as a consequence of errors in the develop-ment and maintenance of the sensory organ.Understanding the genetic control of this process in C.elegans may help us diagnose and treat these human dis-eases. To study this process in C. elegans we take advan-

tage of an assay of structural integrity of the adultorgan. When animals are soaked in a lipophilic dye, thedye is occluded from entering the animal at all pointsexcept the exposed tips of the chemosensory neurons.The sensory neuronal membrane thus fluoresces withthe intercalated dye in a wild type animal. Mutationsthat perturb the development of the sensory organ (the"amphid" in the worm) or the sensory neurons them-selves, lead to a dye-filling defective (Dyf) phenotype.We then clone these mutations using modern moleculargenetic and genomic technologies.

Second, we also wish to understand the function-ing of the intact chemosensory system. That is, once thechemosensory organ is in place, how does the animalcome to select one taste over another? This is a complexquestion that we try to address in two ways. First weexecute genetic screens—based on direct assays ofbehavior—for animals that can taste, but that have analtered preference for one taste relative to another.Second, we turn to nematodes in the natural world andtry to understand the impact of strain variation on tastepreference. Not all isolates of C. elegans share the sametaste preferences, just as not all people share the sametaste preferences. Since all strains are raised under iden-tical conditions in the lab, much of this strain variationmust be under a genetic locus of control. Each of theseapproaches presents a unique set of challenges to thegeneticist, and consequently we have developed, andcontinue to refine, new methodologies and resources forforward genetics in C. elegans.

Ph.D., University of British Columbia, 1996

NSERC Postdoctoral Fellow, The Netherlands Cancer Institute, 1999

Postdoctoral Fellow, Royal Dutch Academy ofScience, 2002


Wicks, S.R., Yeh, R.T., Gish, W.R., Waterston, R.H., andPlasterk, R.H.A. P. 2001. Rapid gene mapping inCaenorhabditis elegans using a high density polymorphismmap. Nature Genetics 28: 160–164.

Wicks, S.R., de Vries, C.J., van Luenen, H.G.A.M., and Plasterk,R.H.A. 2000. CHE-3, a cytosolic dynien heavy chain isoform isrequired for sensory neuron structure and function in C. ele-gans. Developmental Biology 221: 295–307.

Rankin, C.H., and Wicks, S.R. 2000. Mutations of theCaenorhabditis elegans brain-specific inorganic phosphatetransporter eat-4 affect habituation of the tap-withdrawalresponse without affecting the response itself. Journal ofNeuroscience 20: 4337–4344.

Stephen WicksAssistant Professor of Biology

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Fields of InterestNeurobiology of the chemosensory system

Boston College is a coeducational university with an enroll-ment of 8,900 undergraduate and 4,600 graduate students repre-senting every state and more than 95 countries. Founded in 1863,it is one of the oldest Jesuit, Catholic universities in the UnitedStates. US News & World Report ranks Boston College 38thamong national universities.

Boston College confers more than 3,800 degrees annually inmore than 50 fields of study through 11 schools and colleges. Its641 faculty members are committed to both teaching andresearch, and have set new marks for research grant awards ineach of the last 10 years.

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Boston and Bostonians have been at the heart of movementsand events that have shaped the United States, from the AmericanRevolution to the computer revolution. This translates into a com-munity that is at once rich in intellectual, cultural, political, andhistorical traditions, and alive with innovation and invention.

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Applicants for graduate training should have a bachelor'sdegree and undergraduate coursework in calculus, physics, bio-chemistry, biology, and chemistry, including organic chemistry.Strong consideration is given to letters of recommendation, par-ticularly from faculty closely familiar with the applicant'sresearch experience. The application deadline for fall admissionis February 1st, but applications received after this date will beevaluated on a continual basis until April 15th. Applications sub-mitted after February 1st may be at a disadvantage for financialaid consideration. All applicants, including those from foreigncountries, must complete the Graduate Record Examination(GRE). Applicants whose native language is not English mustachieve a score of 550 or better (written test) or 213 or better(computer-based test) on the Test of English as a ForeignLanguage (TOEFL).

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Request application materials from Graduate School of Arts & Sciences website at www.bc.edu/schools/gsas/Click on the Admissions and Financial Aid link for more information.

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Graduate Admission DirectorDepartment of BiologyBoston College140 Commonwealth AvenueChestnut Hill, MA 02467Phone: 617.552.3540Email: [email protected]

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Associate Professor Laura Hake and Postdoctoral

Associate Susana Martinez review an autoradi-

ogram of an in vivo phosphorylation assay. Dr.

Hake's laboratory is interested in the molecular

mechanisms of RNA regulation during gametogen-

esis and early development. Their current focus is

on the mechanisms of cytoplasmic polyadenylation

during early development of Xenopus laevis.

boston college chestnut hill, massachusetts 02467

DEPARTMENT OF BIOLOGY

HIGGINS HALL 355

140 COMMONWEALTH AVENUE

CHESTNUT HILL, MA 02467-3809

617.552.3540 [email protected]

WWW.BC.EDU/BIOLOGY

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