March 2010

Systems Biology for Biochemists Merging the Experimental and Theoretical

 

Meetings---De-Crecy-Lagard
Valérie de Crécy-Lagard

In October 2009, approximately 60 scientists met for the first “Systems Biology for Biochemists” American Society for Biochemistry and Molecular Biology Special Symposium at Granlibakken resort in Lake Tahoe, Calif. As biology is now fully in the post-genomic era, the question of how the availability of more than a thousand genome sequences changes the way biochemists design and conduct their experiments is a pressing one.

Arcady Mushegian of Stowers Institute for Medical Research organized the meeting to allow experimental and theoretical scientists to come together and see how biochemistry is now integrated at several levels with many other fields. This integration was apparent during the first evening, when Gregory A. Petsko of Brandeis University presented his work that combined yeast genetics and three-dimensional structures to rapidly identify drug targets and drug candidates in Parkinson’s disease. Another “big picture” presentation was given by Eugene V. Koonin of the National Center for Biotechnology Information, who showed that evolutionary principles can be extracted from whole genome sequences as evolutionary biology goes from “stamp collecting to physics.”

Meetings---Morozov
Alexandre V. Morozov

The emphasis of the next day’s session was on reconstructing ancestral and minimal biochemical pathways. In the morning, Vadim Gladyshev of Harvard Medical School and Valérie de Crécy-Lagard of the University of Florida emphasized the power of using comparative genomic approaches to discover new pathways and physiological trends. Gladyshev presented an impressive analysis of players in metal trace-element metabolism in 700 genomes (1). De Crécy-Lagard showed that in silico data-mining approaches can be used to identify many missing tRNA modification genes. The field of synthetic biology was represented by Mikkel Algire of the J. Craig Venter Institute. He described a general method that eliminates ligation steps in gene, operon or plasmid assembly that was used to assemble a whole Mycoplasma mycoides genome in yeast and transplant it into Mycoplasma capricolum (2). Eric Gaucher of the Georgia Institute of Technology combined phylogeny reconstruction with gene synthesis to express “ancestor proteins.” Using EF-Tu as a molecular thermometer, he analyzed the melting temperature of specific reconstituted ancestor proteins, which pointed to a possible thermophilic origin of life.

For more information

• The meeting program and slides from several of the lectures can be found here.

•To learn more about systems biology, check out the Journal of Biological Chemistry thematic minireview series, “Computational Biochemistry: Systems Biology."

The afternoon continued with an “origin of life” theme as Armen Mulkidjanian of Universitat of Osnabruck presented evidence for his “zinc world hypothesis,” in which photosynthesizing ZnS precipitating around primeval hot springs in high-pressure environments could have driven the synthesis of organic molecules (3). Other afternoon talks covered a range of topics: Frederic F. Pio of Simon Fraser University talked about automated long range homology algorithms, network analysis and experimental methods used to identify the “inflammasome,” and Georgy P. Karev of the National Institutes of Health presented a modification of the Eigen “error catastrophy” model that would allow biological systems to evolve. Literature mining was at the core of the Medscan platform Ilya Mazo of Ariadne Inc. designed to infer relationships between genes and/or compounds using scattered and non-homogeneous literature sources. The afternoon ended with Peter D. Karp of SRI International presenting the Pathway Tools platform.

The focus of the next day’s morning session was the progress of the structural genomics initiative. SG is a large-scale structure determination program with an emphasis on previously uncharacterized protein families. Nick Grishin of the University of Texas Southwestern, John-Marc Chandonia of Lawrence Berkeley National Laboratory, Aled Edwards of the University of Toronto and Alexey G. Murzin of the MRC Laboratory of Molecular Biology described the role of SG in improving protein classification schemes and providing new functional insights. In particular, Chandonia used bioinformatic analysis based on the SCOP structural classification database (4) to argue that new SG structures have greatly enhanced our knowledge of protein families while at the same time decreasing the average cost of solving a protein structure. Edwards discussed SG contributions to characterizing structural and chemical biology of human proteins, with a focus on epigenetic targets such as histone methyl transferases which have been implicated in various human diseases. Murzin described how structure-guided analysis can be used for protein function prediction.

The afternoon session started with a talk by Alexandre V. Morozov of Rutgers University on the theoretical principles of protein folding and evolution. Morozov argued that many evolutionary phenomena (such as increased evolvability of more stable proteins) can be understood using a simple model in which organismal fitness is proportional to the probability of a protein to be folded and therefore functional. The next speaker, Warren DeLano* of DeLano Scientific LLC, provided a brief introduction to the main features of a popular open-source molecular visualization software PyMOL. Other speakers in the session discussed how structural and functional genomics can be used to benchmark large-scale predictions of protein function (Ambrish Roy of the University of Kansas), catalog structurally uncharacterized protein families (Mensur Dlakic of Montana State University), employ mass spectrometry in proteomics (Vlad Petyuk of the Pacific Northwest National Laboratory) and study diversity of polyamine biosynthesis pathways with comparative genomics methods (Anthony J. Michael of the Institute of Food Research).

On the final day of the meeting, the focus shifted from large-scale protein structure determination to studies of genetic and protein networks. Frederick Roth of Harvard University spoke about a systems biology approach to deciphering genetic interactions in Saccharomyces cerevisiae— a useful technique for identifying protein complexes, ordering genes in pathways and finding synergistic drug combinations. Andrey Rzhetsky of the University of Chicago described information overload in modern molecular biology caused by an avalanche of new data and ideas and showed how text-mining techniques could be used to extract both active and forgotten knowledge from vast scientific literature. Arcady Mushegian described the state of the art in creating similarity metrics for biological networks starting from vectors of experimental data assigned to each gene or protein. Mushegian also introduced a novel iterative algorithm, PSI-SQUARE, designed to search for similarities between network nodes. Finally, David Sprinzak of the California Institute of Technology presented a time-lapse microscopy study of the Notch-Delta signaling pathway — the canonical pathway for communication between neighboring cells during development. He found an ultrasensitive protein-level switch between mutually exclusive sending and receiving signaling states and argued that the biochemical mechanism of the Notch-Delta switch could serve as a new design principle in many other intercellular networks.

This meeting, hopefully, was the first in a long series of workshops, as it clearly fills an urgent need of integrating biochemistry with systems biology.

* It is with a great sadness that the meeting participants and the scientific community learned that on Nov. 3, 2009, Warren Delano, 37, passed away unexpectedly. In honor of his work in bioinformatics, ASBMB has created the Delano Award for Computational Biosciences.

References

1. Zhang, Y., and Gladyshev, V. N. (2010) General Trends in Trace Element Utilization Revealed by Comparative Genomic Analyses of Co, Cu, Mo, Ni, and Se. J. Biol. Chem. 285, 3393–3405.

2. Lartigue, C., Vashee, S., Algire, M. A., Chuang, R-Y., Benders, G. A., Ma, L., Noskov, V. N., Denisova, E. A., Gibson, D. G., Assad-Garcia, N., Alperovich, N., Thomas, D. W., Merryman, C., Hutchison, C. A., Smith, H. O., Venter, J. C., and Glass, J. I. (2009) Creating Bacterial Strains from Genomes That Have Been Cloned and Engineered in Yeast. Science 325, 1693–1696.

3. Mulkidjanian, A. Y., and Galperin, M. Y. (2009) On the Origin of Life in the Zinc World. 2. Validation of the Hypothesis on the Photosynthesizing Zinc Sulfide eEdifices as Cradles of Life on Earth. Biology Direct 4, 27.

4. Murzin, A.G., Brenner, S.E., Hubbard, T., and Chothia, C. (1995) SCOP: A Structural Classification of Proteins Database for the Investigation of Sequences and Structures. J. Mol. Biol. 247, 536−540.

Valérie de Crécy-Lagard (vcrecy@ufl.edu) is an associate professor in the department of microbiology and cell science at the University of Florida. Alexandre V. Morozov (morozov@physics.rutgers.edu) is an assistant professor in the department of physics and astronomy and the BioMaPS Institute for Quantitative Biology at Rutgers University.



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