Research

The Costes laboratory specializes on various aspect of computational biology. Areas of expertise:

  1. Radiation biology
  2. Modeling and radiation system biology
  3. Live cell imaging
  4. High-content image analysis
  5. Analysis of gene expression and sequencing
  6. DNA damage response
Three-dimensional human mammary epithelial cell cultures known to mimic human breast in vitro are the primary biological systems used in the lab. These systems have been used to quantify the effect of ionizing radiation at the DNA and extra-cellular level. The lab is currently involved with four multi-investigators interdisciplinary projects:

NASA Specialized Center of Research (NSCOR)

  1. Analysis of gene expression in mouse mammary glands exposed to cosmic radiation. In collaboration with Dr. Mao, Jian-Hua, staff scientist at the Berkeley lab, microarray analysis correlating tumor incidence, tumor type and radiation quality are underway. Analysis is based on a large set of mammary gland expression data from mice exposed to various doses and types of ionizing radiation.
  2. Modeling DNA damage patterns in human cells exposed to cosmic radiation. The spatial distribution of DNA damage measured by markers such as phosphorylated histone H2AX or p53 binding protein 1 (53BP1) were compared to theoretical predictions from a mathematical model developed in our lab. These comparisons led to the conclusion that damages are not detected at their original site of damage, but instead at specific location in the nucleus. Our lab is currently investigating if this is the result of nuclear reorganization following ionizing radiation or the clustering of DNA damage into repair centers. Reorganization of damages into specific regions in the nucleus has important consequences for evaluating risk of cosmic rays on human, a topic of interest for our lab as well.
  3. Modeling disruption of organized cell population following ionizing radiation. We are currently establishing an agent-based model that mimics cell behavior when grown as monolayer or in three-dimension. These in silico cell cultures are currently being used to test the impact of radiation on cell death, cell proliferation and how this translates at the phenotype level.

DOE low-dose radiation Program.

This project evaluates chromatin modifications following exposure to low dose of low-LET radiation. We are working under the current hypothesis that DNA damage elicits chromatin modification necessary for DNA repair which can lead in some cases to permanent changes in the epigenetic status of a cell. Dr. Costes group focuses on characterizing by image analysis permanent changes in chromatin organization in primary and immortalized human mammary epithelial cells (HMEC) and fibroblasts at different time points after low and high dose irradiation. The Costes lab also provides assistance in analyzing ChIPseq data acquired in human breast cells exposed to low dose of ionizing radiation, in an attempt to better characterize epigenetic changes taking place after exposure to radiation. This type of studies offers an alternative mechanism for explaining persistent phenotype acquired following exposure to ionizing radiation such as Epithelial-Mesenchymal Transition (EMT) or Genomic Instability (GI).

Bay Area Physical Sciences - Oncology Center (PSOC)

As part of this multi-investigator program, we have developped computer algorithms that can mimic breast cell behavior in three-dimensional context. The overarching goal of this work is to develop a fundamental understanding of the key functions necessary to lose homeostasis in the breast epithelium, a hallmark of cancer. To that extent, we have integrated agent-based models (ABM) with high-content image analysis of cultured mammary epithelial cells to describe how cell interactions lead to the emergent property of 3-dimensional organization. The ABM identified acceptable ranges for proliferation, apoptosis, and polarization necessary to maintain morphological homeostasis and provides novel insight into oncogenic events that disrupt morphogenesis.

Caritas St. Elizabeth's Medical Center for Cancer Systems Biology Program (ICBP)

This center is one of the NCI's Integrative Cancer Biology Programs (ICBP). In collaboration with Professor of Mathematics and Physics at UC Berkeley, Dr. Rainer Sachs, our group has been developing visual tools and integrating physical laws such as friction, diffusion and elasticity in the ABM model developed in parallel with the PSOC project.

News

Oct 2015: Costes speaks at the 70 year anniversary of the A-bomb organized by UC Berkeley.

October 2015

On September 30 and October 1st, the Center for Japanese Studies at UC Berkeley, the Japan Society for the Promotion of Science and Nuclear Engineering Department of UC Berkeley held an international symposium entitled: “Perspective on 70 years of the nuclear age from Berkeley, a birthplace of the atomic bomb”. This symposium brought together scientists, historians, and other experts to share their views on past, present and future in an open, cross-disciplinary exchange. Costes gave an overview of the low dose program at the DOE and how new data generated by this program can be used to develop better regulation of radiation levels. A key point: individual sensitivity and biomarkers must be used to move into 21st century personalized risk assessment. More information and presentations can be found here.

Sept 2013: Our work for NASA published in Stem Cells and in the news

September 2013

Our recent work was published in Stem Cells, a premier journal for stem cell research. Our work sheds light into why children exposed to ionizing radiation have a substantially greater breast cancer risk later in life than adults. The work was also featured in the news:

  • LBL News Center
  • The Daily Californian

    		•

    Jan 2013: Our paper published in Integrative Biology on modeling acini formation was the 5th most downloaded manuscript in the journal for 2011

    Certificate

    See the certificate sent to us from Harpal Minhas, the managing editor of Integrative Biology.

    June 2012: Jon Tang receives Best Postdoc Presentation Award at the NASA Space Radiation Investigators' Meeting

    nasa

    Jon Tang from the Costes Lab attended the 23rd Annual NASA Space Radiation Investigators' Workshop at Duke University in Durham, NC.. He received the best postdoc presentation award for his oral summary and scientific poster presentations on his work for the NASA Specialized Center of Research.

    December 2011: Our work published in PNAS and in the news

    Our recent work on low-dose radiation was published in the Proceedings of the National Academy of Sciences. We believe this study is the first to report on DNA double-strand breaks clustering and the formation of DNA repair centers in human cells. The work was also featured in the news:

  • LBL News Center
  • World Nuclear News

    • September 2011: John Tang recieves Honorable Mention at the NASA Space Investigators' Meeting

    nasa logo

    Jon Tang from the Costes Lab attended the 22nd Annual NASA Space Radiation Investigators' Workshop in League City, Tx. He received an honorable mention award for his oral summary and scientific poster presentations on his multi-scale in silico model of the mammary gland to study the contribution of non-targeted effects on HZE cancer risk.

    July 2011: Sylvain Costes elected as the Physics Councilor for the Radiation Research Society

    Sylvain Costes has been elected Physics Councilor of the Radiation Research Society for the next three years. Dr. Costes has been an active member of the Society and a member of the Radiation Research Podcast Team since 2006. The Society's objectives are to encourage in the broadest manner the advancement of radiation research in all areas of the natural sciences; to facilitate cooperative research between the disciplines of physics, chemistry, biology and medicine in the study of the properties and effects of radiation; and to promote dissemination of knowledge in these and related fields through publications, meetings and educational symposium.

    March 2011: Our work on the cover of Integrative Biology and in the news

    Our work was published in a special themed issue of Integrative Biology honoring cancer biologist, Mina Bissell. Our work also made the cover for the issue. For more information, check out this article in Chemistry World featuring the work, or read the original manuscript
    Group Photo

    Team Members

    Position

    Bio

    Publications

    Title

    Authors

    Journal

    Year

    Characterizing the DNA Damage Response by
    Cell Tracking ALgorithms and Cell Features
    Classification using High-Content Time-Lapse Analysis.

    		Georgescu W, et al. PLoS One

    2015
    Genetic background modulates
    lncRNA-coordinated tissue response
    to low dose ionizing radiation.     		Tang J, Huang Y, et al. Int J Genomics 2015
    Understanding Cancer Development Processes after
    HZE-Particle Exposure: Roles of ROS, DNA
    Damage Repair and Inflammation.     		Sridharan DM, et al. Radiat Res 2015
    Densely ionizing radiation acts via the
    microenvironment to promote aggressive Trp53-null mammary carcinomas.     		Illa-Bochaca I, Ouyang H, Tang J, et al. Cancer Res 2014
    Combinatorial DNA damage pairing model based on
    X-ray-induced foci predicts the dose and LET
    dependence of cell death in human breast cells.     		Vadhavkar N, et al. Radiat Res 2014
    Irradiation of juvenile, but not adult, mammary gland
    increases stem cell self-renewal and estrogen receptor negative tumors.     		Tang J, Fernandez-Garcia I, Vijayakumar S, et al. Stem Cells 2014
    Nuclear dynamics of radiation-induced foci in euchromatin and heterochromatin Chiolo I, Tang J, Georgescu W, Costes SV Mutat Res 2013
    Beta1-integrin via NF-kappaB signaling is essential
    for acquisition of invasiveness in a model of
    radiation treated in situ breast cancer     		Nam JM, Ahmed KM, Costes SV, et al. Breast Cancer Res 2013
    Rapid and Automated Fluorescence Microscopy Profiling of 3D Human Breast Cultures Park CC, Georgescu W, Polyzos A, Pham C, Ahmed KM, Zhang H, Costes SV Integr Biol 2013
    The Cell Cycle Timing of Centromeric Chromatin Assembly
    in Drosophila Meiosis Is Distinct from
    Mitosis Yet Requires CAL1 and CENP-C     		Dunleavy EM, Beier NL, Gorgescu W, Tang, J, Costes SV, Karpen GH PLoS Biology 2012
    Evidence for formation of DNA repair centers
    and dose-response nonlinearity in human cells     		Neumaier T, Swenson J, Pham C,
    Polyzos A, Lo AT, Yang P, Dyball J,
    Asaithamby A, Chen DJ, Bissell MJ,
    Thalhammer S, Costes SV.     		PNAS 2011
    Interplay between BRCA1 and RHAMM Regulates
    Epithelial Apicobasal Polarization
    and May Influence Risk of Breast Cancer     		Chistopher A. Maxwell, et al. PLoS Biology 2011
    Phenotypic transition maps of 3D breast acini
    obtained by image-guided agent-based modeling
    (Featured on the cover for the issue and is the 5th most downloaded article in Integrative Biology of 2011.)     		Tang J, Enderling H,
    Becker-Weimann S, Pham C,
    Polyzos A, Chen CY, Costes SV     		Integr Biol 2011
    Double strand breaks in heterochromatin move
    outside of a dynamic HP1a domain to complete
    recombinational repair.     		Chiolo I, Minoda A, Colmenares SU,
    Polyzos A, Costes SV, Karpen GH     		Cell 2011
    Lack of radiation dose or quality dependence of
    epithelial-to-mesenchymal transition (EMT)
    mediated by transforming growth factor β     		Andarawewa KL, Costes SV, Fernandez-Garcia I,
    Chou WS, Ravani SA, Park H, Barcellos-Hoff MH     		Int J Radiat
    Oncol Biol
    Phys     		2011
    Persistence of γ-H2AX and 53BP1 foci in proliferating
    and non-proliferating human mammary epithelial cells
    after exposure to γ-rays or iron ions     		Groesser T, Chang H, Fontenay G,
    Chen J, Costes SV, Helen Barcellos-Hoff M,
    Parvin B, Rydberg B     		Int J Radiat
    Biol     		2011
    Depletion of nuclear actin is a key
    mediator of quiescence in epithelial cells     		Spencer VA, Costes SV, Inman JL,
    Xu R, Chen J, Hendzel MJ, Bissell MJ     		J Cell Sci 2011
    Mesenchymal cells stimulate capillary
    morphogenesis via distinct proteolytic mechanisms     		Ghajar CM, Kachgal S, Kniazeva E,
    Mori H, Costes SV, George SC, Putnam AJ     		Exp Cell Res 2010
    Spatiotemporal characterization of ionizing radiation
    induced DNA damage foci and their relation to chromatin
    organization     		Costes SV, Chiolo I, Pluth JM,
    Barcellos-Hoff MH, Jakob B     		Mutat Res 2010
    Promotion of variant human mammary epithelial cell
    outgrowth by ionizing radiation: an agent-based model
    supported by in vitro studies     		Mukhopadhya R., Costes SV, Bazarov A.,
    Hines WC, Barcellos-Hoff MH, Yaswen P     		Breast Cancer Res 2010
    Stochastic properties of radiation-induced DSB: DSB
    distributions in large scale chromatin loops, the HPRT
    gene and within the visible volumes of DNA repair foci     		Ponomarev AL, Costes SV, Cucinotta FA Int J Radiat
    Biol     		2008
    Targeted and non-targeted effects of
    ionizing radiation that impact genomic instability     		Maxwell CA, Fleisch MC, Costes SV, Erickson AC,
    Boissiere A, Gupta R, Ravani SA, Parvin B,
    Barcellos-Hoff MH     		Cancer Res 2008
    Inhibition of metastatic outgrowth from single
    dormant tumor cells by targeting the cytoskeleton     		Barkan D, Kleinman H, Simmons JL, Asmussen H,
    Kamaraju AK, Hoenorhoff MJ, Liu ZY, Costes SV,
    Cho EH, Lockett S, Khanna C, Chambers AF, Green JE     		Cancer Res 2008
    Ionizing Radiation Predisposes Nonmalignant Human
    Mammary Epithelial Cells to Undergo Transforming
    Growth Factor Induced Epithelial to Mesenchymal Transition     		Andarawewa KL, Erickson AC, Chou WS, Costes SV,
    Gascard P, Mott JD, Bissell MJ, Barcellos-Hoff MH     		Cancer Res 2007
    Image-based model reveals dynamic redistribution
    of DNA damage into nuclear sub-domains
    (Featured on the cover of the issue.)     		Costes SV, Ponomarev A, Chen JL,,
    Nguyen D, Cucinotta FA, Barcellos-Hoff MH     		PLoS Comput
    Biol     		2007
    Intensity-based signal separation algorithm for
    accurate quantification of clustered centrosomes
    in tissue sections     		Fleisch MC, Maxwell CA, Kuper CK,
    Brown ET, Barcellos-Hoff MH, Costes SV     		Microsc Res
    Tech     		2006
    Imaging features that discriminate between high
    and low LET radiation-induced foci in human fibroblasts     		Costes SV, Boissière A, Ravani S,
    Romano R, Parvin B, Barcellos-Hoff MH     		Radiat Res 2006
    A systems biology approach to multicellular and
    multi-generational radiation responses     		Barcellos-Hoff MH
    and Costes SV     		Mutat Res 2006
    Kinetic and molecular analysis of nuclear export
    factor CRM1 association with its cargo in vivo     		Daelemans D, Costes SV,
    Lockett S, Pavlakis GN     		Mol Cell Biol 2005
    Role of murine leukemia virus nucleocapsid protein in virus assembly Muriaux D, Costes SV, Nagashima K,
    Mirro J, Cho E, Lockett S, Rein A     		J Virol 2004
    In vivo HIV-1 Rev multimerization in the nucleolus
    and cytoplasm by fluorescence resonance energy transfer     		Daelemans D, Costes SV, Cho EH,
    Erwin-Cohen RA, Lockett S, Pavlakis GN     		J Biol Chem 2004
    Automatic and quantitative measurement of
    protein-protein colocalization in live cells     		Costes SV, Daelemans D, Cho EH,
    Dobbin Z, Pavlakis GN, Lockett S     		Biophys J 2004
    Human CD8+ T cells store RANTES in a unique secretory
    compartment and release it rapidly after TcR stimulation     		Catalfamo M, Karpova T, McNally J, Costes SV,
    Lockett SJ, Bos E, Peters PJ, Henkart PA     		Immunity 2004
    The transformation suppressor Pdcd4 is a novel
    eukaryotic translation initiation factor 4A
    binding protein that inhibits translation     		Yang HS, Jansen AP, Komar AA, Zheng XJ,
    Merrick WC, Costes S, Lockett SJ,
    Sonenberg N, Colburn NH     		Mol Cell Biol 2003
    FRAP model to determine the bi-directional transport
    rate of proteins across the nuclear membrane and the
    mobile fraction in the cytoplasm and nucleus.     		Costes S, Slobodskaya O, Cho E,
    Tsopanomihalu-Nglotsu M, Pavlakis GN, Lockett SJ     		Proc. SPIE 2002
    Radiation quality and tissue-specific
    microenvironments following exposure to 1 GeV/amu Fe     		Costes S and Barcellos-Hoff MH Adv Space Res 2002
    Large-mutation spectra induced at hemizygous
    loci by low-LET radiation: evidence for
    intrachromosomal proximity effects     		Costes S, Sachs R, Hlatky L,
    Vannais D, Waldren C, Fouladi B     		Radiat Res 2001
    Quantitative image analysis of laminin immunoreactivity
    in skin basement membrane irradiated with 1
    GeV/nucleon iron particles     		Costes S, Streuli CH,
    Barcellos-Hoff MH     		Radiat Res 2000
    Applications of quantitative digital image
    analysis to breast cancer research     		Ortiz De Solorzano C, Costes S,
    Callahan DE, Parvin B,
    Barcellos-Hoff MH     		Microsc Res
    Tech     		2002
    MIRD pamphlet No. 17: the dosimetry of nonuniform activity
    distributions--radionuclide S values at the voxel level     		Bolch WE, Bouchet LG, Robertson JS, Wessels BW,
    Siegel JA, Howell RW, Erdi AK, Aydogan B,
    Costes S, Watson EE     		J Nucl Med 1999
    An overview of Boron Neutron Capture Therapy
    and desired characteristics of neutron beams     		Vujic J and Costes S VINCA Institute of Nuclear Sciences Bulletin (VINBULL) 1997 
    Downloads
    

    Install Instructions:
    

1. Install DipImage MATLAB library:

      Download DipImage       Reference: DipImage
      
For Windows, first download the installer and install the library, then the environmental path needs to be set: 
1. open Control Panel -> System and Maintenance -> System -> Advance system settings 
2. under the Advanced tab, clicked "Environmental Variables..." 
3. under System variables, find a variable name "Path", Edit it. 
4. insert a ";" and then the path to dipImage lib at the end, default should be ";C:\Program Files\DIPimage 2.3\win64\lib"
5. ok to apply.

For Linux, download the .tbz compressed file. Uncompress it, and then put the "dip" folder under /opt. 

2. Install Matlab Compiler Runtime (MCR):

You can find the links of MCR Installer for different platforms. 
Please use the default MCR Install path to install MCR, as we will need this path information in 3. 

3. Install Bio-Formats image reading library:

      Download loci.jar       Reference: LOCI | Laboratory for Optical and Computational Instrumentation
Download loci.jar and put it under the path: 
For Windows, please put it under: 
      C:/Program Files/MATLAB/MATLAB Compiler Runtime/ 
For Linux, please put it under: 
      /opt/MATLAB/MATLAB_Compiler_Runtime/ 

4. Download and use the package tools:

For Windows, simply find the .exe file and execute it. 
For Linux, open a command line and type: 
      $~ [path_to_your_downloaded_package]/run_[package_name].sh /opt/MATLAB/MATLAB_Comipler_Runtime/v715/ 

 
MATLAB Compiler Runtime (MCR) Installer v715

Linux x64   Windows x64 

foci analysis BETA v1.1

Linux x64   Windows x64 

Pearson Screening BETA v1.0

Linux x64   Windows x64

    Openings

    TBD