Research

COMPUTATIONAL MOLECULAR BIOLOGY & BIOCHEMISTRY

Counterion Condensation on DNA: Experiment and Simulation
Homopolymer Tract Characterization
Open Source Code Bioinformatics
DNA Melting Simulation-MELTSIM as a Bioinformatics Tool
Vis/Datamining of Large Genomic Databases(joint with IVPR)

SMART SYSTEMS

QCM Studies of Cells-Cellular Biosensor Development
Polymeric Thin Films
Stem Cell Isolation Technology
Parasitology/Molecular Biology

COMPUTATIONAL MOLECULAR BIOLOGY & BIOCHEMISTRY

Counterion Condensation on DNA: Experiment and Simulation

A longstanding research area of the CIB and its Director has been the study of condensed DNA structures. Originally model systems for the structure of DNA in bacteriophage and virus heads, these tertiary structure states are now of interest because of their relevance to potential gene therapy mechanisms via DNA structures condensed with cationic lipids and other agents. Many of our previous publications in this subject area have dealt with the final structure and mechanism of DNA condensation. These have been studied with both biochemical and biophysical approaches such as TEM. Recently, we have worked on simulating the condensation of mixtures of different valence counterions onto the DNA prior to its forming a condensed tertiary structure state. In particular, Manning Theory has been extended and shown to be useful in simulating counterion condensation of mixed valence cation systems. These studies have been able to explain the DNA charge fraction neutralized and are in agreement with the reduced mobility exhibited by DNAs in gel electrophoresis experiments in specific ion environments.

Prof. Kenneth A. Marx, Department of Chemistry, CIB
Dr. Anzhi Li, Visiting Research Scholar, Genome Therapeutics, Inc.
Dr. George C. Ruben, Department of Biological Sciences, Dartmouth College

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Homopolymer Tract Characterization

These simplest of repetitive sequence elements in all eukaryotic genomes are found with quite varying but higher than expected frequencies that suggest functional roles in cells. We have characterized poly [d(A).d(T)] and poly [d(G).d(C)] tracts in an AT -rich organism D. discoideum, the slime mold. This has been done both experimentally and by accessing and characterizing these sequences in the GENBANK database. This study is being extended to a range of other organisms of varying phylogeny as well as AT base composition, whose DNA sequences are available in GENBANK.

Prof. Kenneth A. Marx, Department of Chemistry, CIB
Adj. Prof. R.D. Blake, Department of Chemistry, CIB
Dr. Iman Assil, Ph.D. awarded (advisor: Marx), Department of Chemistry, CIB
Mr. Jeff Bizzaro, Ph.D. student, CIB
Ms. Yue Zhou, Ph.D. student, CIB
Mr. Dang Duc Long, Ph.D. student, CIB

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Open Source Code Bioinformatics-www.bioinformatics.org

The Loci Project is an international collaboratory and a part of The Open Lab. It's aim is the development of open source code software in bioinformatics and cheminformatics. Loci is a UNIX based network-distributed system of clients and servers ('loci') for data processing. Clients include control structure and graphical user interface loci.  All loci are represented as nodes in a 'Workflow Diagram' and are joined by lines depicting network connections. This network forms the basis for a graphical scripting language. The network distributed nature of loci deals with large datasets in a unique way with GUI loci residing on a local workstation while compute intensive processing loci execute remotely on high performance computers. The joining of loci across the internet can be used to form worldwide collaborations. Numerous development tools include: Python, GTK+ , the Gnome environment, CORBA, DOM, XML, etc.

Department of Chemistry, CIB:
Mr. Jeff Bizzaro, Coordinator, The Open Lab, Ph.D. candidate Dept. Chemistry, UML
Prof. Kenneth A. Marx, Prof. Chemistry UML, Director CIB

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DNA Melting Simulation-MELTSIM as a Bioinformatics Tool

Bioinformatics tools are needed to analyze the massive sequence databases resulting from the Human Genome Project. Raw DNA sequence can be studied in terms of its equilibrium thermodynamic melting behavior. We have developed the use of MELTSIM to simulate DNA equilibrium melting properties. MELTSIM is a suite of programs built around a statistical mechanical algorithm that simulates the equilibrium melting states of any DNA sequence. We have shown that MELTSIM accurately simulates the experimental melting behavior of an entire eukaryotic genome (yeast-S. cereviseae:  12,067,277 bp). MELTSIM can also calculate and display the melting behavior or regions along any given sequence. For example, we have demonstrated the utility of the positional melting feature of MELTSIM to identify exons in multi-exon genes in the AT-rich organisms D. discoideum  and S. mansoni, as well as to display the melting along entire yeast chromosomes. We are extending MELTSIM to address other interesting bioinformatics problems.

Prof. Kenneth A. Marx, Department of Chemistry, CIB
Adj. Prof. R.D. Blake, Department of Chemistry, CIB
Mr. Jeffrey Bizzaro, Ph.D. student, Department of Chemistry, CIB
Mr. Dang Duc Long, Ph.D. student, Department of Chemistry, CIB

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Vis/Datamining of Large Genomic Databases (joint with IVPR)

We are carrying out visualization and data mining analyses of genomic DNA and protein sequence data from the Human Genome Project, as well as other large biotechnological and pharmaceutical company functional genomics datasets. Funding from Pfizer, Millenium Pharmaceuticals and Genetics Institute has supported the work in collaboration with the IVPR at UML. In addition, a novel approach is being investigated using the mutual information function based classification of protein structures and coding DNA sequence regions from different organisms. We are also now actively involved in setting up a joint Bioinformatics Option Program at the B.S., M.S. and Ph.D. level in the Computer Science, Biology and Chemistry Departments at UML. Another aim is to support, through research collaboration, a commercial professional services software company, AnVil Informatics, Inc., spun-off from UML technology. A portion of the technology base of AnVil Informatics, Inc. was developed in the longstanding joint IVPR/CIB technology activity that began in 1992.  The company focus initially is on targeting pharmaceutical, biotechnological and clinical therapeutics companies.

Prof. Kenneth A. Marx, Department of Chemistry, CIB
Prof. Georges Grinstein, IVPR at UML
Prof. Haim Levkovitz, IVPR at UML
Prof. Gene Stanley, Boston University
Ivo Grosse: Ph.D. Physics Boston University
Dr. A. Li. Department of Chemistry, CIB; Genome Therapeutics, Inc.
Marjan Trutschl: D.Sc. candidate(Grinstein)
Alex Gee: D.Sc. candidate(Grinstein)
Urska Cvek: D.Sc. candidate(Grinstein)
Dang Duc Long: Ph.D. candidate(Marx)
Yue Zhou: Ph.D. candidate(Marx)

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SMART SYSTEMS
 
QCM Studies of Cells-Cellular Biosensor Development

In this collaboration with the research group of Prof. Susan Braunhut in the Dept. of Biological Sciences at UML, we are examining the attachment and viscoelastic properties of normal and transformed endothelial cells binding to the gold electrode surface of the Quartz Crystal Microbalance. It may be possible to develop a useful sensor for whole cell properties using this approach. This approach could be used as a complex and sensitive cell based biosensor of interest to the biotechnology and pharmaceutical industry for the detection of molecules having distinct effects on attached cells. We have also received NIH Grant funding to investigate the growth stimulation effects and uncover the mechanism of underlying negative potentials on adhering endothelial cells as a model for wound healing.

Prof. Kenneth A. Marx, Department of Chemistry, CIB
Prof. Susan Braunhut, Department of Biological Sciences, CIB
Dr. Tiean Zhou, Postdoctoral Fellow, CIB
Mrs. Anne Montrone, Biology Dept.

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Polymeric Thin Films

We are collaborating with the group of Prof. A. Angelopoulos, UML, on the creation of  polymeric thin film modified surfaces using self-assembly and enzymatic polymerization  as well as electrochemical polymerization techniques. These films may have applications in semiconductor microfabrication and in biotechnology.

Prof. Kenneth A. Marx, Department of Chemistry, CIB
Prof. A. Angelopoulos, Department of Chemistry, CIB
Dr. Tiean Zhou, Postdoctoral Fellow, CIB
Mr. Samuel Oh, Ph.D. candidate (Angelopoulos)

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Stem Cell Isolation Technology

A collaboration to develop a stem cell isolation procedure from fractionted blood is being conducted in conjunction with Morphogenesis, Inc. The approach utilizes immobilized antibodies to isolate pluripotent stem cells. A mechanism for binding, sensing and subsequent release is being developed.

Prof. Kenneth A. Marx, Department of Chemistry, CIB
Dr. Michael Lawman, Morphogenesis, Inc.
Dr. Patricia Lawman, Morphogenesis, Inc.

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Parasitology/Molecular Biology

In a collaboration with the Center for Tropical Diseases, the CIB has carried out research on the cloning of a Ca-ATPase gene from S. mansoni as part of a study of the mechanism of praziquantel drug resistance in Schistosomiasis . This project has been active for the past few years and we have also studied the experimental DNA melting of the three major Schistosoma human pathogen species worldwide: S. mansoni, S. japonicum and S. haematobium and compared these data to their simulation using MELTSIM.

Prof. Kenneth A. Marx, Department of Chemistry, CIB
Prof. Patrick Skelley, Harvard School of Public Health
Dr. Liang Feng Tao, U. Mass. Lowell, CTD, Millennium Pharmaceuticals, Inc.
Dr. Meng Hsien Tsai, Ph.D. degree awarded Chemistry Dept, UML in Nov. 1998 (Marx)

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