DOE Resources & Facilities for Biological Discovery : Realizing the Potential

Presentation to the BERAC25 April 2002

“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.”

The BER Program was instrumental in creating the Genomic Revolution

Some 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)

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

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

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

EXAMPLE 1

Precise 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.

Genomic Variation Structural VariationHow does the genetic program control the nanostructures?

How can we engineer it?

Silicatein:

• Structure-directing catalyst

• Polymerizes Silica, Methyl- and Phenyl-silsesquioxanes !

TiO growth on Silicatein

Courtesy of Dan Morse, UCSB

EXAMPLE 2

A 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

A regulatory gene network model for endomesoderm specification

Skeletogenic

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

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

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 …

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

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

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