Brown University Center for Computational Molecular Biology

Events

CCMB Distinguished Inaugural Lectures 2005-2006

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CCMB Distinguished Lecture Series

Richard J. Roberts, Ph.D.
New England BioLabs

Restriction Enzyme and Genomes

Abstract:

With more than 300 bacterial and archaeal genomes completely sequenced and the total sequence content of GenBank still growing exponentially, we can now gain some impression of the distribution of RM systems in the real world. Surprisingly, these RM systems, or the relics of them, are much more abundant than might have been guessed from the classical biochemical screening of strains in the laboratory. In particular, Type I systems are widely distributed in Nature and many instances of solitary specificity subunits are found. More than 100 potential Type III and Type IV systems are found and on average about 4 DNA methyltransferase genes are found per genome. Solitary M genes, in which the R gene is either missing or non-functional, are much more common than expected. However, our ability to identify M genes accurately is made difficult by the presence of conserved motifs in genes that methylate molecules other than DNA. Analyses of the many environmental samples in GenBank suggests that the rate of evolution of both M and R genes is quite high and confirms previous findings that the direct cloning of intact RM systems into E. coli is difficult with current technology. Importantly, there is little reason to think that our current collection of 256 Type II specificities is more than a small sample of the specificities present in the environment.

Biography:
Dr. Richard J. Roberts is the Chief Scientific Officer at New England Biolabs, Ipswich , Massachusetts. He was educated in England , attending the University of Sheffield where he obtained a B.Sc. in Chemistry in 1965 and a Ph.D. in Organic Chemistry in 1968. His postdoctoral research was carried out in Professor J. L. Strominger's laboratory at Harvard, where he studied the tRNAs that are involved in the biosynthesis of bacterial cell walls. From 1972 to 1992, he worked at Cold Spring Harbor Laboratory, reaching the position of Assistant Director for Research under Dr. J. D. Watson. He began work on the newly discovered Type II restriction enzymes in 1972 and in the next few years more than 100 such enzymes were discovered and characterized in Dr. Roberts' laboratory. Dr. Roberts has also been involved in studies of Adenovirus-2 and discovered split genes and mRNA splicing in 1977 for which he received the Nobel Prize in Physiology or Medicine in1993. His laboratory sequenced the 35,937 nucleotide Adenovirus-2 genome, and wrote some of the first programs for sequence assembly and analysis. DNA methyltransferases are an area of active research interest and, in collaboration with Dr. X. Cheng, DNA base flipping was discovered in 1993. Current interests focus on the identification of restriction enzyme and methylase genes within the GenBank database and the development of rapid methods to assay their function.

Wednesday, May 10, 2006
4:00 - 5:00 p.m.
CIT Bldg, Room 368
115 Waterman Street

Host: Professor Sorin Istrail

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Michael Waterman, Ph.D.
University of Southern California

Whole Genome Optical Mapping

Abstract:

An innovative new technology, optical mapping, is used to infer the genome map of the location of short sequence patterns called restriction sites. The technology, developed by David Schwartz, allows the visualization of the maps of randomly located single molecules around a million base pairs in length. The genome map is constructed from overlapping these shorter maps. The mathematical and computational challenges come from modeling the measurement errors and from the process of map assembly.

Research Interests:

I have been using computational approaches to study molecular sequence data. With the era of genome sequencing and large-scale datasets such as from microarrays, the importance of computational methods and bioinformatics to molecular biology is certainly growing proportionally.

My work concentrates on the creation and application of mathematics, statistics and computer science to molecular biology, particularly to DNA, RNA, and protein sequence data. I am the co-developer of the Smith-Waterman algorithm for sequence comparison and of the Lander-Waterman formulas for physical mapping and sequencing. I am a founding editor of Journal of Computational Biology , am on the editorial board of seven journals, and am author of the first text in this area: Introduction to Computational Biology: Maps, Sequences and Genomes .

Dr. Waterman is a Professor of Biological, Mathematical and Computer Sciences at the University of Southern California . He is a Member of the National Academy of Sciences and a Member of the French Academy of Sciences.

Friday, April 21, 2006
3:00 - 4:00 p.m.
CIT Bldg, Room 368
115 Waterman Street

Host: Professor Sorin Istrail

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Ken A Dill, Ph.D.
Department Pharmaceutical Chemistry
University of California, San Francisco

Folding Proteins by Computer: A Global Optimization Problem

Abstract:
If we could predict the structures of protein molecules using computers, it would have great value for the discovery of new drugs. The problem is that protein molecules have large numbers of degrees of freedom, and we need to find the single global optimum structure in a space that grows exponentially with the length, N, of the chain. We have explored various strategies, including methods from computational linguistics and including new fast search methods that mimic the physics of protein folding.

Research Interests:
Properties of Proteins. We are interested in the physical properties of proteins. In particular, we are exploring: (1) the molecular forces that drive proteins to fold into their biological native structures, (2) how amino acid sequences encode those structures, (3) the thermodynamic factors that stabilize proteins against unfolding and aggregation, and (4) the rates and mechanisms by which proteins fold. We believe that knowledge of these physical properties can contribute to computer-based methods for predicting protein structures, dynamics, conformational changes, and their biological mechanisms.

Properties of Water. We are interested in the structure and physical Properties of water. In particular, we have been developing simplified models that can be explored analytically and through Monte Carlo computer simulations, for the properties of pure water, for understanding hydrophobic interactions, and for ion solvation. We believe that better understanding of water as a solvent will have value in improving models in computational biology for the folding of proteins and RNA molecules and for ligand docking and drug design.

CV & contact info: http://www.dillgroup.ucsf.edu/~dill/kad.html

Wednesday, March 22, 2006
4:00 - 5:00 p.m.
CIT Building
Room 368 (3rd floor)

Host: Professor Sorin Istrail

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Albert-Laszlo Barabasi
Dana Farber Cancer Institute at Harvard University, Emil T. Hofman Professor of Physics at University of Notre Dame

Network Biology: Understanding the Cell's Functional Organization

Abstract:
Post-genomic biology requires us to move beyond the single gene description, and understand the intricate genetic networks that mediate most cellular processes. In the last few years we learned that cellular networks are not random, but their structure carries the signature of self-organizing processes governed by simple but generic laws. The analysis of the metabolic network and the protein interaction network of several organisms indicates that, despite significant variances in their individual components, these networks display identical topologic and scaling properties. The hubs, highly connected nodes common in such networks, have important implications for the cell's robustness and functionality. I will show that cellular networks have a hierarchical architecture, allowing us to identify the organization of the functional modules embedded in the cellular topology.

For more information see http://www.nd.edu/~alb

BIO: Albert-László Barabási, currently at the Dana Farber Cancer Institute at Harvard University, is the Emil T. Hofman Professor of Physics at University of Notre Dame. Educated in Bucharest and Budapest, he received a Ph.D. in physics in 1994 from Boston University. After spending a year at IBM T.J. Watson Research Center he joined Notre Dame in 1995. His research has lead to the discovery and understanding of scale-free networks, capturing the structure of many complex networks in technology and nature, from the World Wide Web to the cell. His current research focuses on applying the concepts developed by his group for characterizing the topology of the www and the Internet to uncovering the structural and topological properties of complex metabolic and genetic networks. He is a Fellow of the American Physical Society and an external member of the Hungarian Academy of Sciences. His recent general audience book entitled Linked: The New Science of Networks (Perseus, 2002) is available on ten languages. For more information see http://www.nd.edu/~alb.

Wednesday, January 25, 2006
4:00 - 5:00 p.m.
Lubrano Conference Room (CIT 4th Floor)

Host: Professor Sorin Istrail

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Jun Liu, Ph.D.
Department of Biostatistics
Harvard University
Cambridge MA

From Sequence Information to Gene Expression

Abstract:

Understanding how genes are regulated in various circumstances (e.g., heatshock, starvation, etc.) is a central problem in molecular biology. The adoption of large-scale biological data generation techniques such as the mRNA microarrays has enabled researchers to tackle the gene regulation problem in a global way. Using the baker's yeast as a model system, we explore the combined use of gene upstream sequence signals to explain the observed mRNA variations and to model the clustering effect based on multiple microarray experiments. We will briefly discuss our methods for finding sequence signals, and our use of variable selection techniques to screen out uninteresting ones.

Wednesday, November 30th, 2005
4:00 - 5:00 p.m.
Brown University Biomedical Center
Eddy Auditorium ~ Room 291
171 Meeting Street

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Samuel Broder, M.D.
Celera Genomics
Rockville, MD

The Human Genome: Implications for Understanding Human Biology and Medicine

Abstract:

We now live in a world in which the 3 billion letter sequence (nucleotide base pairs) of the human genome is available as a resource for scientific discovery and medical practice. Some of the findings from the completion of the human genome were expected, confirming knowledge presaged by many decades of research in both human and comparative genetics. Other findings are unexpected in their scientific and philosophical implications. In either case, the availability of the human genome is likely to have significant implications, not only on science per se, but on how we view the human condition.

One fundamental issue is the extent to which knowledge of genomic DNA sequence defines the evolution of our species and the essence of who we are, including the determination of risk for illness and behavior in various settings. Should we embrace or reject the genome in a deterministic way, believing that the human condition will ultimately be seen entirely as a manifestation of sequence information and computation? This talk provides reflections on what the new genomic knowledge might mean for the future of medicine and society.

Wednesday, September 21, 2005
4:00 - 5:00 p.m.
Brown University Biomedical Center
Eddy Auditorium ~ Room 291
171 Meeting Street

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