[Federal Register Volume 67, Number 221 (Friday, November 15, 2002)]
[Notices]
[Pages 69208-69214]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-29022]


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DEPARTMENT OF ENERGY


Office of Science Financial Assistance Program Notice 03-05: 
Genomes to Life

AGENCY: Department of Energy.

ACTION: Notice inviting grant applications.

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SUMMARY: The Office of Biological and Environmental Research (OBER) and 
the Office of Advanced Scientific Computing Research (ASCR) of the 
Office of Science (SC), U.S. Department of Energy (DOE), hereby 
announce their interest in receiving applications for research in the 
following areas that support the Genomes to Life research program 
(http://www.doegenomestolife.org/):
    (1) Technologies and strategies to image individual proteins and 
multi-protein complexes in microbes and to image complex microbial 
communities;
    (2) Technologies for the high-throughput synthesis of proteins and 
their biological characterization;
    (3) Molecular tags to identify individual proteins and to 
characterize multi-protein complexes in microbial cells;
    (4) High resolution, quantitative microbial biochemistry;
    (5) New genomic strategies and technologies for studying complex 
microbial communities;
    (6) Pathway inference in prokaryotes;
    (7) Implications for society, the law, education, and technology 
transfer; and
    (8) Other novel and innovative technologies and research strategies 
to address the core goals of the Genomes to Life research program.

DATES: Statements of intent to apply, including information on 
collaborators, areas of proposed research and technology development, 
and a short (one page) summary of the proposed research should be 
submitted by Tuesday, January 7, 2003.
    Formal research applications are due by 4:30 PM E.D.T., Tuesday, 
April 22, 2003.

ADDRESSES: Statements of intent to apply should be sent to Ms. Joanne 
Corcoran by e-mail at: [email protected] with copies to 
Dr. David Thomassen at: [email protected] and Dr. Gary 
Johnson at: [email protected].
    Formal applications in response to this solicitation are to be 
electronically submitted by an authorized institutional business 
official through DOE's Industry Interactive Procurement System (IIPS) 
at: http://e-center.doe.gov/. IIPS provides for the posting of 
solicitations and receipt of applications in a paperless environment 
via the Internet. In order to submit applications through IIPS your 
business official will need to register at the IIPS website. The Office 
of Science will include attachments as part of this notice that provide 
the appropriate forms in PDF fillable format that are to be submitted 
through IIPS. Color images should be submitted in IIPS as a separate 
file in PDF format and identified as such. These images should be kept 
to a minimum due to the limitations of reproducing them. They should be 
numbered and referred to in the body of the technical scientific 
application as Color image 1, Color image 2, etc. Questions regarding 
the operation of IIPS may be e-mailed to the IIPS Help Desk at: 
center.doe.gov">HelpDesk@e-center.doe.gov or you may call the help desk at: (800) 683-
0751. Further information on the use of IIPS by the Office of Science 
is available at: http://www.science.doe.gov/production/grants/grants.html.
    If you are unable to submit an application through IIPS please 
contact

[[Page 69209]]

the Grants and Contracts Division, Office of Science at: (301) 903-5212 
in order to gain assistance for submission through IIPS or to receive 
special approval and instructions on how to submit printed 
applications.

FOR FURTHER INFORMATION CONTACT: Dr. David Thomassen, telephone: (301) 
903-9817, e-mail: [email protected], Office of Biological 
and Environmental Research, SC-72/Germantown Building; U.S. Department 
of Energy; 1000 Independence Avenue, SW.; Washington, DC 20585-1290.
    A complementary request for proposals from DOE national 
laboratories has been issued, Program Solicitation LAB 03-05.

SUPPLEMENTARY INFORMATION: Biology has entered a new era--the era of 
systems biology--in which we will understand entire living organisms 
and their interactions with the environment. While scientists have long 
tried to understand the workings of individual genes or small groups of 
genes this new era in biology will focus research on entire networks of 
genes and even entire biological systems--small, single celled 
organisms at first and later more complex creatures ultimately 
including humans.
    This dramatic advance is possible, in large part, because of the 
scientific and technical successes of the Human Genome Project. The 
information and technology now available to all scientists on the human 
genome and on a rapidly growing list of the genomes of other organisms 
from microbes to plants to worms to mice not only gives us new 
perspectives on the inner workings of biological systems but provides 
new opportunities to use this knowledge to solve problems in energy.
    The Genomes to Life program is a systems biology research program 
that offers the possibility of biotechnology solutions that can give us 
abundant sources of clean energy yet control greenhouse gases like 
carbon dioxide, a key factor in global climate change, and that can 
help us clean up past contamination of the environment.
    The overall goals of the Genomes to Life program include 
understanding:
    1. Natural, multi-protein molecular machines of complex living 
systems.
    2. Complex networks that control the assembly and operation of 
these machines.
    3. The organization and biochemical capabilities of complex 
microbial communities.
    These three goals will only be achieved if we develop:
    4. A computational infrastructure for systems biology that enables 
the development of computational models for complex biological systems 
that can predict the behavior of these complex systems and their 
responses to the environment.
    The Genomes to Life program supports a combination of large, well 
integrated, multidisciplinary research teams and smaller, focused 
research projects. This solicitation will support smaller, focused 
research projects to develop new technologies, research strategies, or 
research resources needed by the Genomes to Life program. Future 
solicitations will likely request applications for both large, well 
integrated, multidisciplinary research teams and smaller, focused 
research projects.
    Information on the research projects currently funded by the 
Genomes to Life program and a description of project goals and overall 
program organization can be found at: http://www.doegenomestolife.org/.
    Other useful Web sites include:
    Microbial Genome Program Home Page--http://www.sc.doe.gov/ober/microbial.html.
    DOE Joint Genome Institute Microbial Web Page--http://www.jgi.doe.gov/JGI_microbial/html/.
    Microbes of Interest to DOE. The initial focus of Genomes to Life 
is on microbes (including fungi) directly relevant to DOE mission needs 
in energy (cleaner energy, biomass conversion, carbon sequestration) or 
the environment (cleanup of metals and radionuclides at DOE sites). 
Research in Goals 1 and 2 takes advantage of and focuses on microbes 
whose complete DNA sequence is already known. Research in Goal 3 
focuses on microbes or microbial communities of interest to, directly 
relevant to, or that will contribute substantially to an ability to 
address DOE mission needs. Selected, well-justified research using 
yeast is appropriate as a means of quickly generating data that 
addresses the needs of the Genomes to Life Program. However, the use of 
yeast as a long-term research focus will not be encouraged.
    Data and Other Results. Any data and results generated through the 
investigations into Goals 1 through 4 that are appropriate to share 
with the broader community should be provided in timely, open, and 
machine-readable format where possible or appropriate. Microbial DNA 
sequence data will be publicly released according to the ``Data Release 
Requirements: Microbial Genome Sequencing Projects'' (http://www.sc.doe.gov/production/ober/EPR/data.html).
    Software Development and Distribution. Software developed by 
research teams that is appropriate for distribution beyond the research 
team shall be made available to the biological and computational 
community. It is our intent that this software be accessible, useful, 
affordable, and interoperable with other software and with data. 
Applications should include plans for assuring availability, stating 
whether: the software will be available as binary or source code, a fee 
will be charged for the use of the software, some users (e.g., 
commercial) will be charged while others not, in what way derivative 
products will be treated, etc. Statements such as that by the 
International Society for Computational Biology on Bioinformatics 
Software Availability, http://www.iscb.org/pr.shtml, may be used for 
reference.

Research Focus

(1) Technologies and Strategies to Image Individual Proteins and Multi 
Protein Complexes in Microbes and to Image Complex Microbial 
Communities

    This solicitation will promote the development of imaging 
technology (probes, instrumentation and computational methodology) 
needed to accomplish the Genomes to Life program goals. Applications or 
development of imaging technology should be directed to or easily 
adapted to the study of microbes. Development of probes and 
instrumentation should be complementary to and facilitate completion of 
Genomes to Life program goals, including currently funded projects (see 
currently funded projects at: http://www.doegenomestolife.org/).
    Additional information on the projected imaging needs of the 
Genomes to Life program can be found at: http://www.doegenomestolife.org/technology/imaging/GTLimaging2002.pdf.
    Specific research needs include:
    [sbull] Development of novel probes (fluorescent, electron dense, 
vibrational tags, etc.) with optimum physico-chemical properties that 
enable:

--Visualization, tracking, assembly and disassembly of multi-protein 
molecular machines and their individual components. Multifunctional 
probes that measure structure, including post-translational 
modification and function in real time, are needed.
--Rapid visualization and quantitation of intracellular processes with 
high spatial resolution.
--Visualization and quantitation of microbial populations and 
communities with respect to their structure, functions, stability and 
response to environmental stress.

[[Page 69210]]

Probes should be developed to determine the spatial and temporal 
concentration of nutrients, metabolites, signaling molecules, elements, 
extra cellular matrices and other biomolecules critical to maintaining 
microbial community structure and function. This should also include 
dynamic measuring of oxidative states and energy transfer kinetics.

    Probes should be selective, non-perturbative, and resistant to 
degradation and should have unique spectroscopic signatures. 
Unambiguous experimental systems to validate probe performance should 
be presented.
    [sbull] Development of new high-throughput tagging methods for 
chromophores, electron dense and other probes. Methods should be 
capable of being transported to the broader scientific community.
    [sbull] Development of innovative optical and non-optical 
instrumentation that will visualize and quantitate dynamic aspects of 
molecular machines over a wide range of dimensions and time scales; 
enable simultaneous co-localization of different intra-cellular 
processes with high spatial resolution; and/or permit visualization of 
bacterial community composition and functions in the field as well as 
in the laboratory.
    [sbull] Development of computational methods for rapid processing, 
storing, reconstructing, and three dimensional modeling of large image 
data sets, e.g., from cryoelectron microscopy. Computational methods 
are needed that can predict capabilities and limitations of various 
probes and instruments over a wide range of size and time scales. Novel 
computational tools are needed to integrate cellular image data sets 
derived from different instruments and technologies. Models of 
bacterial community structure, growth, functions and adaptive responses 
should be constructed based on experimental data and should facilitate 
development of alternative experimental approaches.

(2) Technologies for the High-Throughput Synthesis of Proteins and 
Their Biophysical Characterization

    This solicitation seeks to promote the development of techniques 
and protocols for high-throughput, low-cost synthesis of full-length 
proteins directly from coding sequence and for their subsequent 
biophysical characterization. Availability of proteins will enable the 
production and confirmation of selective, non-perterbutive probes and 
molecular tags needed to address the broad goals of the Genomes to Life 
program.
    An essential early requirement for turning genome information into 
biological understanding is having access to purified samples of at 
least the majority of the proteins encoded in the genomes of interest. 
Even within the microbial-focus of Genomes to Life, this requirement is 
daunting. It must encompass, within the next decade, hundreds of 
different microbes and therefore many tens of thousands of proteins. 
Both the production and characterization goals are significantly 
broader than those of structural genomics programs. In those programs 
the goals are limited to the structural characterization of a 
relatively small fraction of proteins, and often protein fragments, 
that represent structurally novel motifs.
    It is recognized that no satisfactory general approach currently 
exists and that not all proteins will likely yield to the same 
techniques. It is expected that a variety of both cell-free and cell-
based systems will be required, as well as multiple characterization 
methods. Production and characterization technologies should be 
scalable, economic, and sufficiently robust to meet the production goal 
of milligram quantities of approximately 10,000 proteins per year.
    An essential early need is the development of improved techniques 
for predicting from sequence what production and purification 
approaches are most likely to succeed with each protein. Thus, 
informatics is an integral component. Algorithms based on data from 
successful and failed protein expressions are expected to substantially 
inform and improve future protein production efficiency.
    Informatics coupled with biophysical characterizations are expected 
to provide functional insights that may also explain why such a large 
number of biologically important, full-length proteins either can not 
be expressed in soluble form, or have whose structures that cannot be 
determined once expressed. These proteins may include substantial 
disordered regions that adopt structures only after interaction with 
appropriate protein binding partners. Reliable predictive algorithms 
based on expression and characterization databases are therefore needed 
to predict disorder and binding partners.
    Areas in which improvements are sought include:
    [sbull] Optimization of cloning and clone validation techniques to 
support the protein production process.
    [sbull] Optimization of cell-free and cellular expression methods.
    [sbull] Optimization of protein purification protocols.
    [sbull] Improved strategies for increasing the fraction of proteins 
that can be synthesized by automated methods. This may include 
sequence-based predictions of methods most likely to succeed and 
insights for optimization of expression protocols.
    High-throughput, economical approaches for characterizing 
synthesized protein to assess product quality and to predict protein 
function are also solicited. A goal is to provide multiple benchmark 
biophysical characterizations for each protein under several 
conditions. These approaches are expected to include:
    [sbull] Biophysical techniques, e.g., mass spectrometry circular 
dichroism, calorimetry, partial proteolysis, deuterium exchange, 
surface plasmon resonance, neutron scattering, nuclear magnetic 
resonance.
    [sbull] Improved techniques for predicting, from protein sequence, 
ordered and dis-ordered domains and for predicting solubility 
properties of proteins and protein domains.
    [sbull] Integrated data acquisition and management tools for 
tracking all steps of the production and characterization process and 
for supporting detailed QC/QA procedures.
    [sbull] Improved high-throughput methods to predict, then rapidly 
test, and finally to confirm binding partners for proteins so that the 
nearly infinite number of potential interactions is reduced to 
experimentally testable subset.

(3) Molecular Tags To Identify Individual Proteins and To Characterize 
Multi-Protein Complexes in Microbial Cells

    This solicitation seeks advances in technology needed to mass-
produce molecular tags for proteins and protein complexes, as tools to 
be used for determining function. As a top priority, technologies are 
sought for mass-producing specific protein recognition tags capable of 
functioning as:
    [sbull] Capture reagents in affinity extraction and purification 
protocols, and as.
    [sbull] Labeling reagents for intracellular and `in situ' 
localization and mapping studies.
    These technologies must be scalable to permit tens of thousands of 
successful tags to be produced and characterized per year at affordable 
costs. It is recognized that none of the many approaches under 
development to address this problem have yet demonstrated compelling 
promise--even as generally effective laboratory-scale methods. Yet for 
the purposes of

[[Page 69211]]

Genomes to Life and for modern biology altogether, very high-
throughput, industrially robust methods to address this problem are 
required.
    For the purposes of this solicitation, it is assumed that purified 
protein `targets' will be provided to the researchers in micro-gram to 
milli-gram quantities so that tags can be optimized and characterized. 
Tags that interfere with function as well as those that do not 
interfere with protein function are both needed to help better define 
the biological roles of proteins. Areas in which technological 
improvements are sought include:
    [sbull] Scalable methods for producing `epitope-directed' affinity 
reagents of high specificity and affinity for proteins capable of 
functioning either as affinity extraction and capture reagents or as 
intra-cellular labeling reagents. High success ratios (fraction of 
protein epitopes yielding useful reagents) are essential.
    [sbull] Improvements in protein-directed affinity tag design to 
improve tag utility, e.g., to facilitate subsequent purification and 
or/imaging, to facilitate release of the tagged protein, to image with 
and without disrupting activity, etc.
    [sbull] Improved methods for developing tags directed specifically 
to protein complexes as distinct from their component proteins. 
Labeling complexes with and without disrupting interactions amongst 
protein components will provide important functional insights.
    [sbull] Improved strategies for predicting, from sequence data, 
what potential protein epitopes are likely to be successful targets for 
tagging with and without interfering with function, and for predicting 
what tag development methods are likely to work for a particular 
protein/epitope.
    [sbull] Imaging and labeling methods for multiplex mapping of 
proteins within cells. Simultaneously monitoring multiple labeled 
proteins will provide more comprehensive views of multi-protein 
complexes and their activities.
    [sbull] Informatics tools both for managing tag production 
processes and for managing the data resulting from their use.

(4) High Resolution, Quantitative Microbial Biochemistry

    As noted above, the initial focus of Genomes to Life is on microbes 
(including fungi) directly relevant to DOE mission needs in energy 
(cleaner energy, biomass conversion, carbon sequestration) or the 
environment (cleanup of metals and radionuclides at DOE sites). To this 
end, development of novel technologies are encouraged to support the 
characterization of the internal environment and organization of 
prokaryotic microbes relevant to DOE missions and the Genomes to Life 
program and to explore how the characteristics of a microbe's internal 
environment affect its metabolism and physiology.
    Very little is known of the internal ``milieu'' of any cell. A 
microbial cell is not likely to be a ``bag of dilute salt water'' 
within which metabolites and gene products freely diffuse. There is 
internal organization due to structural cytoskeletal components, 
partitioning of gene products in different parts of the cell so that 
they can efficiently mediate their appropriate pathways, concentration 
gradients of proteins and small molecules across the volume of the 
cell, and physical effects caused by the cell membrane and 
intracellular constituents including the viscosity of a cell's 
cytoplasm.
    A protein's localization within a cell, its relationships with 
other proteins, concentrations, and subcellular dynamics are critically 
important parameters in determining its function, for identifying 
functional networks of proteins in a morphological context, and for 
expanding our understanding of whole-cell function. Thus, studies on 
the topological, physical, and chemical properties of cellular 
cytoplasm, their effects on protein dynamics, on flux rates of 
metabolites, on protein-protein and protein-ligand interactions, and 
ultimately, on protein function are needed.
    Research is needed that furnishes information on the dynamic 
behavior of these various molecules as the ``molecular machines'' 
perform their functions and on the distribution, localization, 
movement, and temporal variations of the molecules and complexes inside 
individual microbes as they carry out reactions of relevance to DOE 
missions and the Genomes to Life Program. Research is also needed to 
characterize topological, physical, and chemical characteristics 
underlying cellular responses to external stimuli, e.g., nutrients, 
toxins, or changes in environmental conditions. Similarly, 
computational algorithms designed to recognize regulatory networks or 
patterns of gene expression under different circumstances are needed 
that can provide insights into co-regulated genes.
    New methods that accomplish any of several aims are solicited:
    [sbull] Techniques to map the spatial distribution and 
concentrations of proteins and metabolites within prokaryotes.
    [sbull] Techniques to assess fluxes and changes in concentrations 
of metabolites as a function of intracellular parameters and spatial 
location.
    [sbull] Techniques to effectively map the immediate environment 
surrounding specific proteins, protein complexes, or other structural 
components within prokaryotes.
    [sbull] Techniques to measure changes in enzyme-catalyzed reaction 
rates (catabolic and anabolic) and fluxes, as a function of the 
internal cell milieu, e.g., distance from the inner membrane surface, 
proton concentration, temperature, etc.
    [sbull] Techniques to quantitate intracellular protein-protein 
association/dissociation rates as a function of ion concentrations, 
dielectric constants, protein concentrations, small molecule 
(metabolite, cofactor, ligand, etc.) concentrations, or temperature.
    [sbull] Techniques to link data from experiments addressing the 
above aims to the broader goals of the Genomes to Life Program.
    [sbull] Techniques to exploit computational methods to interrogate 
resulting datasets in order to suggest experimental priorities and 
derive insights into the underlying biology.

(5) New Genomic Strategies and Technologies for Studying Complex 
Microbial Communities

    Microorganisms are the largest reservoir of genetic and biochemical 
diversity on earth. New methods for examining microbial communities 
have revealed that uncultured microbes make up more than 99% of many 
natural microbial communities. DNA isolated directly from environmental 
samples is a tremendous resource for examining the structure and 
function of microbial communities. The science of microbial ecology 
will be advanced by understanding the distribution, diversity, relative 
abundance, and interactions of the microorganisms in these communities.
    A goal of the Genomes to Life Program (Goal 3) is to dramatically 
extend current scientific and technical understanding of the genetic 
diversity and metabolic capabilities of microbial communities in the 
environment, especially those related to remediation, biogeochemical 
cycles, climate changes, energy production, and biotechnology. A 
challenge to achieving this objective, however, is the difficulty in 
characterizing the complexity of microbial communities in nature. For 
example, it has been estimated that there may be thousands of different 
species in surface soils. Thus, new

[[Page 69212]]

strategies and technologies are needed to help define and assess the 
repertoire of metabolic capabilities as embodied in the collective 
community's genomic sequence.
    We need new technologies that enable us to:
    [sbull] Determine whole-genome sequences of dominant uncultured 
microorganisms to estimate their genetic diversity and 
interrelationships. Novel technologies and strategies are needed to use 
the genome sequence to identify the genes, metabolic pathways, 
regulatory network and proteins needed for survival, growth and 
adaptation to the environment.
    [sbull] Identify the extent, patterns and spatial distribution of 
genetic diversity in microbial communities of interest to the DOE 
mission areas. In particular, we need to understand how microbial 
diversity supports community structure and function, and the 
relationship of genetic diversity to key environmental parameters. For 
example, one strategy for understanding the extent and pattern of 
genetic diversity in microbial communities is to sequence bacterial 
artificial chromosome (BAC) clones from individual microbial 
communities by the shotgun approach. Comparing BAC clone sequences 
should lead to insights into community genetic diversity and metabolic 
capacity.
    [sbull] Understand the ecological functions of the uncultured 
microorganisms. We need to identify the metabolic functions that these 
genomes encode and to understand how those functions contribute to the 
community's ecological role in the environment. Of particular interest 
is the unique role of novel uncultured microorganisms in ecosystems 
relevant to DOE's missions in bioremediation, carbon sequestration, 
global climate change, energy production, and biotechnology.
    [sbull] Determine cellular and biochemical functions of genes 
discovered in uncultured community members. This includes determining 
the protein complexes unique to uncultured microorganisms in ecosystems 
of DOE relevance, and whether their unique characteristics can be used 
for protein engineering.
    [sbull] Understand the genetic basis of microbial community 
functional stability and adaptation in environments important to DOE 
missions. We need to understand the relationship between genetic 
diversity and microbial community stability. For example, the genetic 
basis and factors controlling microbial community stability and 
adaptation is of great importance in managing microbial communities to 
bioremediate contaminated sites, sequester carbon from the atmosphere, 
and contribute to sustainable energy production.
    Key technologies needed to achieve these goals include, but are not 
limited to:
    [sbull] New approaches for recovering RNA and high-molecular-weight 
DNA from environmental samples.
    [sbull] New approaches for isolating single cells of uncultured 
microorganisms.
    [sbull] New parallel comparative approaches that allow unique 
microbial community DNA fragments to be identified and the community to 
be characterized in automated high-throughput ways.
    [sbull] Novel technologies and approaches for defining the patterns 
of expression and functions of genes from microbial communities with 
large numbers of uncultured microorganisms, under different 
environmental conditions.
    [sbull] Advanced methods for community genome sequence assembly, 
genome comparison, microarray data analysis, and data management.
    In addition, there are many computational challenges to 
characterizing the composition and functional capabilities of microbial 
communities. New algorithms for DNA sequence assembly and annotation 
will be required to analyze the multiorganism sequence data, and new 
modeling methods will be required to predict the behavior of microbial 
communities. Computational methods needed include the ability to 
deconvolute mixtures of partial genomes sampled in the environment and 
to identify individual organisms; to facilitate multiple-organism 
shotgun-sequence assembly; to improve comparative approaches to 
microbial sequence annotation and gene finding; to reconstruct pathways 
from sequenced or partially sequenced genomes; and to evaluate the 
combined metabolic capabilities of heterogeneous microbial populations. 
Importantly, computational methods are needed to correlate genomic, 
physiological, and biogeochemical site parameters, as well as their 
spatial and temporal distribution. Finally, methods to integrate 
regulatory-network, pathway, and expression data into integrated models 
of microbial community function are needed.

(6) Pathway Inference in Prokaryotes

    Many of the future solutions to the problems of supplying energy 
without net greenhouse gas emissions, managing the atmosphere's carbon 
budget, and remediating environmental contamination from metals, 
radionuclides, and toxic chemicals, will be based on biotechnology. 
Most of the new biotechnologies will almost certainly arise from 
fundamental advances in our understanding the ``microbial world''. This 
is primarily due to two facts. First, the metabolism of naturally 
occurring microorganisms plays a major role, often a dominant one, in 
many of the key chemical and energy fluxes of the planet. Second, 
virtually all of the biochemical transformations needed for safe energy 
production, carbon management, and environmental cleanup are part of 
the natural repertoire of one or more microorganisms. The challenge 
therefore is to explore and understand the immense chemical processing 
power that the microbial world possesses and uses. Achieving the needed 
understanding will require a nearly complete predictive mastery of the 
microbial cell from a `systems' point of view--including their 
metabolic and signaling pathways, their regulatory networks, their 
material and energy flow constraints, etc. Data sets of considerable 
size and complexity must be obtained, managed, and mined. In addition, 
entirely new realms of modeling and simulation must be mastered.
    The research requested in this section builds on advances in both 
computation and data base management as well as the extraordinary 
increase in the speed and capacity--and a corresponding reduction in 
the cost--of genome sequencing. Most fundamentally, it builds on the 
new and massive investment in the systems-level genomic-style study of 
microbial cells and microbial communities being undertaken as part of 
the Genomes to Life initiative.
    The research requested in this section will facilitate the use of 
data obtained from the genomic and `systems-level' experimental study 
of microbes (primarily prokaryotes) and microbial communities. It will 
in particular assist in using these data to predict the role played by 
each of the proteins encoded in the microbe's genome, the microbe's 
signaling and metabolic pathways, its regulatory mechanisms, and its 
biochemical capacities. This research will help enable the re-
annotation of incorrectly annotated genomes, the prediction of 
functions for unknown genes, and discovery of known functions for which 
no genes have been identified. Biochemical capacities with direct 
relevance to DOE missions, such as energy production, carbon fixation, 
bioremediation, etc. are of particular interest.
    Pathway Inference: Information on regulatory, metabolic, and 
signaling

[[Page 69213]]

pathways in prokaryotes is growing rapidly. Just as the use of 
similarity searches, such as Basic Local Alignment Search Tool, across 
genomes of multiple organisms has provided extraordinarily useful 
information regarding the imputed function of the target gene 
sequences, the research requested in this section is intended to 
facilitate similar inferences through probes of pathways in other 
organisms, primarily microbes. Although, some new knowledge may be 
required experimentally, the emphasis is on providing a computational 
infrastructure for this homology searching. Investigators may propose 
the construction of specific databases, research on knowledge 
representation, and/or tools to measure similarity or provide 
inference. Any proposed databases should contain references to the 
source of the data, including measures of presumed accuracy, based 
partly on whether annotations were derived from experimental results or 
computational analogy. Research may be proposed on data structures and 
data access tools for the integrative storage of pathway, signaling, 
and regulation information needed to support `knowledge' extraction and 
in particular the computation of inferences about pathway structure and 
function. This goal presents questions concerning the types of data 
that should be stored and how they are to be interrelated, queried, 
presented, etc. Research also may be proposed to develop tools and 
resources that will support computational methods for inferring the 
existence and function of signaling, regulatory, and metabolic 
pathways. The research in this element initially may be conducted on 
organisms chosen for their utility to the research rather than for 
their importance to DOE, but the proposed research should show that it 
will be transferable to prokaryotes and pathways of DOE interest.

(7) Implications for Society, the Law, Education, and Technology 
Transfer

    Scientific research takes place in a context of ongoing societal 
concerns and expectations. Headlines about DNA, genes, and the new 
powers of science to analyze and manipulate fundamental elements of 
life vie for our attention daily. The dazzling diversity of 
applications of DNA science to fields ranging from medicine and 
agriculture to forensics and environmental restoration are having and 
will continue to have profound impacts on society and the lives of our 
citizenry. Many recent discoveries stem from data and tools generated 
by the Human Genome Project, whose goal is to describe in intricate 
detail the DNA from humans and other selected organisms by 2003. DNA is 
the information molecule that carries instructions for creating and 
maintaining all life. Resources and analytical technologies generated 
by the Human Genome Project and other genetic research can be applied 
to the DNA of all other organisms including those that are currently 
centerpieces of Genomes to Life research. Thus, it is important for the 
Genomes to Life program to address some of the ethical, legal, and 
social issues that may arise from the project.
    The Genomes to Life program initially focuses on nonpathogenic 
microbes of environmental importance and those that have potential to 
address DOE missions such as bioremediation, energy production, global 
climate change processes and biotechnology. To this end, research is 
solicited into the Implications for Society, the Law, Education, and 
Technology Transfer from the research being conducted under the Genomes 
to Life program. Investigations are encouraged that focus on:
    [sbull] Defining the range, nature and scope of issues raised by 
Genomes to Life research or the applications of that research;
    [sbull] Exploring legal issues such as intellectual property 
protection and commercialization practices that may be relevant to 
advances in the Genomes to Life program;
    [sbull] Exploring potential economic sequelae to the introduction 
of Genomes to Life scientific developments into the marketplace, e.g., 
impacts on the biotechnology sector and other industries;
    [sbull] Educational challenges from the Genomes to Life mediated 
``paradigm shift'' from reductionist science to a more 
``reconstructionist'' science, e.g., the need to present science as 
more of a synthetic activity requiring insights from different 
scientific disciplines.
    The scope of research on the Implications for Society, the Law, 
Economics and Education is a work in progress and emphases will evolve 
as opportunities are identified to explore the consequences of Genomes 
to Life science for society.

(8) Other Novel and Innovative Technologies and Research Strategies To 
Address the Core Goals of the Genomes to Life Research Program

    Many different technologies, research strategies, and data 
resources will be required to successfully address the core goals of 
the Genomes to Life program. Applications will be accepted that propose 
to develop additional tools, research strategies, or resources that 
will help speed success in reaching the core goals of the Genomes to 
Life program. In most cases, these new technologies and research 
strategies should be scalable and automatable for genome-scale 
analyses. A strategy for or demonstration of scalability and 
automatability should be described. The relevance to Genomes to Life 
goals should be clearly described.

Program Funding

    Up to $10 million is available in Fiscal Year 2003, contingent upon 
availability of appropriated funds. It is anticipated that individual 
research grants will be funded at a level of $250,000 to $1,000,000 per 
year.

Merit and Relevance Review

    Applications will be subjected to scientific merit review (peer 
review) and will be evaluated against the following evaluation criteria 
listed in descending order of importance as codified at 10 CFR 
605.10(d):
    1. Scientific and/or Technical Merit of the Project;
    2. Appropriateness of the Proposed Method or Approach;
    3. Competency of Applicant's Personnel and Adequacy of Proposed 
Resources;
    4. Reasonableness and Appropriateness of the Proposed Budget.
    The evaluation will include program policy factors such as the 
relevance of the proposed research to the terms of the announcement and 
the Department's programmatic needs. External peer reviewers are 
selected with regard to both their scientific expertise and the absence 
of conflict-of-interest issues. Non-federal reviewers may be used, and 
submission of an application constitutes agreement that this is 
acceptable to the investigator(s) and the submitting institution.

Applications

    Information about the development and submission of applications, 
eligibility, limitations, evaluation, selection process, and other 
policies and procedures may be found in the Application Guide for the 
Office of Science Financial Assistance Program and 10 CFR Part 605. 
Electronic access to the Guide and required forms is made available via 
the World Wide Web at: http://www.science.doe.gov/production/grants/grants.html. DOE is under no obligation to pay for any costs associated 
with the preparation or submission of applications if an award is not 
made.

[[Page 69214]]

    The application must contain an abstract or project summary, 
letters of intent from collaborators, and short curriculum vitas 
consistent with NIH guidelines for all Principal and co-Principal 
Investigators.
    Adherence to type size and line spacing requirements is necessary 
for several reasons. No applicants should have the advantage, or by 
using small type, of providing more text in their applications. Small 
type may also make it difficult for reviewers to read the application. 
Applications must have 1-inch margins at the top, bottom, and on each 
side. Type sizes must be 10 point or larger. Line spacing is at the 
discretion of the applicant but there must be no more than 6 lines per 
vertical inch of text. Pages should be standard 8\1/2\'' x 11'' (or 
metric A4, i.e., 210 mm x 297 mm).
    As noted above, color images should be submitted in IIPS as a 
separate file in PDF format and identified as such. These images should 
be kept to a minimum due to the limitations of reproducing them. They 
should be numbered and referred to in the body of the technical 
scientific application as Color image 1, Color image 2, etc.
    Applicants are expected to use the following ordered format to 
prepare Applications in addition to following instructions in the 
Application Guide for the Office of Science Financial Assistance 
Program. Applications must be written in English, with all budgets in 
U.S. dollars.
    [sbull] Face page (DOE F 4650.2 (10-91))
    [sbull] Project abstract (no more than one page) including the name 
of the applicant, mailing address, phone, Fax, and e-mail
    [sbull] Budgets for each year and a summary budget page for the 
entire project period (using DOE F 4620.1)
    [sbull] Budget explanation
    [sbull] Budgets and budget explanation for each collaborative 
subproject, if any
    [sbull] Project description (includes goals, background, research 
plan, preliminary studies and progress, and research design and 
methodologies) not to exceed 20 pages.

--Goals
--Background
--Research plan
--Preliminary studies and progress (if applicable)
--Research design and methodologies

    [sbull] Literature cited.
    [sbull] Collaborative arrangements (if applicable).
    [sbull] Biographical sketches (limit 2 pages per senior 
investigator).
    [sbull] Description of facilities and resources.
    [sbull] Current and pending support for each senior investigator.
    The Office of Science, as part of its grant regulations, requires 
at 10 CFR 605.11(b) that a recipient receiving a grant to perform 
research involving recombinant DNA molecules and/or organisms and 
viruses containing recombinant DNA molecules shall comply with the 
National Institutes of Health ``Guidelines for Research Involving 
Recombinant DNA Molecules'', which is available via the world wide Web 
at: http://www.niehs.nih.gov/odhsb/biosafe/nih/rdna-apr98.pdf, (59 FR 
34496, July 5, 1994), or such later revision of those guidelines as may 
be published in the Federal Register.
    DOE policy requires that potential applicants adhere to 10 CFR part 
745 ``Protection of Human Subjects'' (if applicable), or such later 
revision of those guidelines as may be published in the Federal 
Register.

    The Catalog of Federal Domestic Assistance Number for this 
program is 81.049, and the solicitation control number is ERFAP 10 
CFR part 605.


    Issued in Washington, DC, on November 7, 2002.
Ralph H. De Lorenzo,
Acting Associate Director of Science for Resource Management.
[FR Doc. 02-29022 Filed 11-14-02; 8:45 am]
BILLING CODE 6450-01-P