The BER Program was instrumental in creating the Genomic Revolution Some BER contributions

1. DOE Resources & Facilities for Biological Discovery : Realizing the PotentialPresentation to the BERAC25 April 2002

2. “The advent of the genomic revolution has changed science profoundly. We can never look at a problem of biological understanding in just the same way again.”

3. The BER Program was instrumental in creating the Genomic RevolutionSome BER contributions • GenBank created (1983) • Human Genome Project started (1987) • Critical genomic technology development: • Capillary electrophoresis technology used to sequence the genome • Large insert cloning technology (BAC’s) • First cDNA library sequencing effort • Microbial genome project started (1993) • JGI made major production contributions to genome sequencing (1999-2002)

4. The Science has changedA new era is beginning • The first phase is ending - genomic information is readily available • The next, transforming phase is beginning – the understanding of full, complex biological systems • The potential for the nation’s science base and for critical DOE missions is immense • GTL is the nucleus for the next phase within DOE, but more is needed

5. The Science has changed • High data densities are needed to interrogate complex systems • High-throughput technologies are essential to current biological research • New research instrumentation and methods are rapidly emerging, e.g. • Protein and nucleic acid arrays • Proteomic methods • High resolution and high information imaging

6. The Science has changedNew technical facilities & resources needed • The scientific goals of the GTL program are key to the next phase, but more is needed to realize the opportunities • New science dictates the need for new technical resources and facilities (GTL goals) • Molecular machines of life • Gene regulatory networks • Microbial interactions • Computational capabilities for biological systems • Science examples can illustrate some of these changes and opportunities

7. EXAMPLE 1Precise structures are encoded in genomes of microbial cells • Calcium carbonate and silicate structures are formed by functions encoded and controlled by genomic information • Genomic variations induce structural variations • These are examples of where genomic / proteomic analyses can elucidate new mechanisms • Mechanisms can enable engineering – precise, automatic control at the sub-micron level.

32. Genomic Variation  Structural Variation How does the genetic program control the nanostructures? How can we engineer it?

34. Silicatein: • Structure-directing catalyst • Polymerizes Silica, Methyl- and Phenyl-silsesquioxanes !

37. TiO growth on Silicatein Courtesy of Dan Morse, UCSB

38. EXAMPLE 2A System at the experimental-theoretical interface(E. H. Davidson et. al., Science 2002, 295, 1669) • Early development of the sea urchin embryo • Genetic networks for cell determination, interaction and function • Regulatory network consists of transcription factor genes (40 genes) and their regulatory sequences • Program moves forward only – no homeostasis • An example of building a complex predictive model by experimentation

39. A regulatory gene network model for endomesoderm specification Skeletogenic

40. Needed Capabilites • Compilation of a comprehensive list with prioritization is needed • Matching of facilties and resources to goals of GTL and other needs is essential • Suggested list in our document • Existing resources to be incorporated • Non-inclusive list of proposed capabilties

41. Resources to be incorporated • Sequencing: draft and finishing – JGI (LANL, Stanford, ORNL…) • Microbial Database Center at TIGR • NMR facilities and isotope labeling capabilites • Mass Spectroscopy • Mouse Facility • RDP at Michigan State • National Center for High Performance Computing • Electron microscopes & other imaging facilites • X-ray stations at synchrotrons • Neutron diffraction stations (HFIR, LANSCE and SNS in future) • Several technology centers of technology development

42. New Resourcesfacilities with a functional focus • Analysis of multiprotein complexes • Mapping and Modeling Gene Regulatory Networks • Microbial Growth & Interaction • Combinatorial chemistry for “chemi-genomics” functional probes • Molecular imaging: Cryo-EM, small angle X-ray … • Production Proteomics • Integration of computing resources in biology • Large-scale protein production • Mouse facility: new technologies, production transgenics, ENU mutagenesis …

43. New Resourcescont’d: pilot facilities • Protein production: new method development, focus on systematic production for the community • High-throughput proteomics facility • New approaches to intermediate-scale imaging facilties (multi-protein scale: e.g. ribosome) • Analysis of nano-scale biological structures – genomics, chemistry and bio-control of 3-D structures and materials • Large-scale DNA sequencing of targeted regions

44. Implementation and Managementsuggested principles • BERAC, ASAC and broad scientific community planning, involvement • Open, peer-reviewed competitive process • Strong integration of sites, laboratories and users • across disciplines and • National Laboratory-University-Industry boundaries • Pro-active evaluative process, pilot projects etc.. – try new approaches

45. Summary & Conclusions • The science has changed • New capabilites and resources are needed • Its history and current thrusts position BER to make major contributions • GTL provides the rationale and nucleus of a broader program • BERAC and ASCAC should move to recommend specific action on a bold new program incorporating new facilities and resources