[Federal Register Volume 66, Number 15 (Tuesday, January 23, 2001)]
[Notices]
[Pages 7475-7478]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-2053]


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DEPARTMENT OF ENERGY


Office of Science; Office of Science Financial Assistance Program 
Notice 01-20; Microbial Cell Project

AGENCY: U.S. Department of Energy (DOE).

ACTION: Notice inviting grant applications.

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SUMMARY: The Offices of Biological and Environmental Research (OBER), 
Basic Energy Sciences (BES), and Advanced Scientific Computing Research 
(ASCR) of the Office of Science (SC), U.S. Department of Energy, hereby 
announce their interest in receiving applications for research grants 
in support of the Microbial Cell Project (MCP), an effort to build on 
information from completely sequenced microbial genomes to achieve a 
more comprehensive understanding of the functioning of a prokaryotic 
microbial cell. This notice encourages applications from 
interdisciplinary scientific partnerships or teams that include such 
disciplines as microbiology, molecular biology, applied mathematics, 
biochemistry, structural and computational biology, as well as physics, 
chemistry, engineering and computer science. The MCP is focused on 
fundamental research to understand those reactions, pathways, and 
regulatory networks that are involved in environmental processes of 
relevance to the DOE, specifically the bioremediation of metals and 
radionuclides, cellulose degradation, carbon sequestration, and the 
production, conversion, or conservation of energy (e.g. fuels, 
chemicals, and chemical feedstocks). Research areas of particular 
interest that should be integrated into an interdisciplinary approach 
can include studies of: (1) Functional analysis of the microbial 
proteome; (2) biochemical and physiological characterization; (3) 
intracellular localization; and (4) cell modeling. This announcement 
represents a planned first step in an ambitious effort to understand 
the functions of all the macromolecular components in a microbial cell, 
to understand all their interactions as they form pathways and 
processes that are related to DOE-relevant activities, and to 
eventually build predictive models for microbial activities that 
address DOE mission needs.

DATES: Preapplications referencing Program Notice 01-20 should be 
received by February 21, 2001. Earlier submissions will be gladly 
accepted. A response to timely preapplications will be communicated to 
the applicant by March 9, 2001.
    Formal applications in response to this notice should be received 
by 4:30 p.m., E.D.T., April 24, 2001, to be accepted for merit review 
and funding in FY 2001.

ADDRESSES: Preapplications referencing Program Notice 01-20 should be 
sent to Dr. Daniel W. Drell, Office of Biological and Environmental 
Research, SC-72, Office of Science, U.S. Department of Energy, 19901 
Germantown Road, Germantown, MD 20874-1290; e-mail is encouraged (but 
not required) for submitting preapplications using the following 
address: [email protected].
    Formal applications referencing Program Notice 01-20, should be 
forwarded to: U.S. Department of Energy, Office of Science, Grants and 
Contracts Division, SC-64, 19901 Germantown Road, Germantown, MD 20874-
1290, ATTN: Program Notice 01-20. This address must be used when 
submitting applications by U.S. Postal Service Express Mail or any 
commercial mail delivery service, or when hand-carried by the 
applicant.

FOR FURTHER INFORMATION CONTACT:
Dr. Daniel W. Drell, SC-72, Office of Biological and Environmental 
Research, Office of Science, U.S. Department of Energy, 19901 
Germantown Road, Germantown, MD 20874-1290, telephone: (301) 903-4742; 
e-mail: [email protected]
Dr. Gregory L. Dilworth, SC-143, Energy Biosciences Program, Office of 
Basic Energy Sciences, Office of Science, U.S. Department of Energy, 
19901 Germantown Road, Germantown, MD 20874-1290, telephone: (301) 903-
2873; e-mail: [email protected]

    The full text of Program Notice 01-20 is available via the World 
Wide Web using the following web site address: http://www.sc.doe.gov/production/grants/grants.html.

SUPPLEMENTARY INFORMATION: The Microbial Cell Project (MCP) supports 
key DOE missions by building on the successful DOE Microbial Genome 
Program that has furnished microbial DNA sequence information on 
microbes relevant to environmental remediation, global carbon 
sequestration (e.g. CO2 fixation), complex polymer degradation (e.g. 
cellulose and lignins), and energy production (fuels, chemicals, and 
chemical feedstocks). These microbial genome sequences provide a finite 
set of ``working parts'' for a cell; the challenge now is to understand 
how these parts are assembled into functional pathways and networks to 
accomplish activities of interest to the DOE (specifically those 
identified in the preceding sentence.) The traditional reductionist 
experimental approach has defined specific steps or stages within many 
physiological processes; however, the availability of whole genomes 
affords the opportunity to integrate these individual pathways into a 
larger physiological or whole organism framework. The MCP seeks to 
integrate available information about individual processes and 
regulatory complexes to understand the intracellular environment in 
which these pathways and networks exist and function. The DOE Microbial 
Cell Project is part of a coordinated Federal effort called the Microbe 
Project involving elements from several other Federal agencies.
    This notice strongly encourages interdisciplinary teams that 
assemble a range of expertise into an integrated approach to 
characterizing the structure and function of a prokaryotic cell. The 
purpose of encouraging interdisciplinary teams is to combine diverse 
scientific talents into a coordinated program and thus it is very 
important that a coordination plan describing how the whole exceeds the 
sum of the parts be included in the application. In addition, the MCP 
seeks to promote research on the internal organization and complex 
control systems that allow microbial cells to respond to their 
environment, to make unique products, and to carry out specialized 
functions relevant to DOE missions in the bioremediation of metals and 
radionuclides, cellulose degradation, carbon sequestration, and the 
production, conversion, or conservation of energy. This effort will 
exploit a range of approaches, among them: (1) Functional analyses of 
proteins and protein interactions; (2) metabolic and flux measurements; 
(3) intracellular imaging technologies for

[[Page 7476]]

the localization and quantitation of proteins and other cellular 
constituents; and (4) computational modeling to represent the 
activities of a cell in ways that permit testable predictions of 
microbial cell functions.
    Preference will be given to those applications selecting 
prokaryotic microbes that satisfy all of the following criteria: (a) 
The chosen microbe is of DOE mission-relevance, i.e., can bioremediate 
metals and radionuclides, sequesters environmental carbon, e.g., can 
fix CO2, degrades significant biopolymers such as celluloses 
and lignins, or generates energy sources, fuels, chemicals, and 
chemical feedstocks. Strict pathogens or parasites will not be 
considered; (b) complete or near-complete genomic sequencing 
information from the chosen microbe exists in the public domain; (c) 
the chosen microbe grows sufficiently in culture to enable experimental 
work; d() the chosen microbe can easily be genetically transformed; and 
(e) expression vectors are available. Of particular importance will be 
a clear description of a coherent plan for making efficient use of the 
available sequence information. (See http://www.ornl.gov/microbialgenomes/organisms.html for a current list of microbes that 
have been and are being sequenced.) If a group proposes to carry out 
work under this notice on a specific microbe, it should be prepared to 
justify the merits of the chosen target organism to the peer review 
process. It is expected that each project supported by the MCP will be 
focused on an energy-related or environmentally relevant microbe (or 
group of microbes) for which extensive sequence information is known, 
although applicants may take advantage of relevant information derived 
from other microbes that are not considered DOE targets, e.g. E. coli 
or yeast. While integrated and multidisciplinary consortia are strongly 
encouraged, exceptional applications from individual investigators 
focused on more confined aspects or areas may be considered.
    This program notice encourages research applications that integrate 
the following highly interrelated thrusts, using a single, sequenced, 
DOE-relevant microbe as the unifying cornerstone. For the purposes of 
this notice, the interests of DOE are the bioremediation of metals and 
radionuclides, cellulose degradation, carbon sequestration, and energy 
production, conversion, or conservation. Integrated applications should 
include a careful description of how the project's proposed 
interdisciplinary research team will integrate all or most of the 
following components into a single research project. These components 
are:
    (1) Functional analysis of the microbial proteome. It is presently 
difficult, and in many instances impossible, to predict biological 
function from microbial genomic sequence data, even when the entire 
genome has been sequenced and is available for inspection. Applications 
should discuss better ways to exploit sequence data from novel open 
reading frames, and even whole genomes, to characterize the pathways 
and networks that mediate microbial physiology and function, and how 
they are regulated under different environmental conditions. This 
effort can take place at different levels of resolution: A medium-
resolution (less detailed) analysis of novel or unannotated genes and 
open reading frames across an entire sequenced microbial genome or a 
higher-resolution (more comprehensive) analysis of novel or unannotated 
genes and open reading frames that participate in one or a few 
processes supporting the stated interests of DOE. The research emphasis 
should be on whole genome approaches to functional prediction, 
functional regulation, functional categorization (at medium 
resolution), or on specific systems, e.g., redox enzymes, metal 
reductases, or hydrogen or methane production components (at high 
resolution). Applications may include the use of new high-throughput 
technologies/tools to better understand expression patterns and protein 
profiles, as well as the exploitation of functional manipulations to 
better understand pathways relevant to the DOE. Identification of 
domains in gene sequences that mediate protein-protein interactions 
that are part of these kinds of pathways are also of great interest. An 
explicit intention of this notice is to promote research on DOE mission 
relevant protein complexes, pathways, and processes and their 
biochemistry, physiology and regulation as a basis for understanding 
function. Studies on individual proteins are not encouraged.
    (2) Biochemical and physiological characterization. The MCP seeks 
to go beyond identifying discrete genes and proteins that participate 
in a few isolated enzymatic reactions; the interest is in defining the 
global interactions among multiple cellular components. How do these 
proteins, metabolites, or cellular biomolecules interact with each 
other to form functional networks or linkages between the constituents 
of traditionally described modular pathways? There is an acute need to 
know more about the quantitative intracellular physiology and 
biochemistry of a microbial cell's constituents, e.g., assembly 
dynamics, kinetics, and fluxes of relevant proteins and cytoplasmic 
components under in vivo conditions. Applications may include the use 
of new high-throughput technologies/tools to better quantify protein 
biochemistry inside a cell in response to different conditions and to 
better understand regulatory molecules and noncoding regulatory 
sequences that affect pathways relevant to the DOE. Of particular 
interest, are explorations of the physical mechanisms of intracellular 
communication and information exchange that underlie the DOE mission 
relevant processes listed earlier in this notice. This notice does not 
encourage research applications directed toward microarray or ``gene-
chip'' development or construction; however, such arrays or chips may 
be used to address the aims of this notice.
    (3) Intracellular localization. A microbial cell is not a simple 
``bag of dilute saline'' in which proteins freely diffuse and interact 
in ways solely governed by simple diffusion. Although this assumption 
(of simplicity) has proven useful in studying protein biochemistry and 
reaction kinetics at the level of single enzymes, it does not represent 
the internal reality of even a simple microbial cell. This notice 
encourages research on the intracellular physico-chemical environment, 
including the intracellular distribution, localization, movement, 
temporal variations, and topological or mechanical constraints on 
physiological function of microbial proteins involved in reaction 
pathways and networks that are of interest to DOE. Technologies for 
imaging microbial cell constituents in real time are also of interest.
    (4) Cell Modeling. It is not presently possible to model every 
single interaction in a cell, much less represent its overlapping but 
distinct networks and pathways in sufficient detail to capture most its 
complexity. This notice encourages research applications to develop and 
explore computational models of those networks and pathways of interest 
to the DOE. Computational models are sought to simulate the 
intracellular environment at different levels of resolution: (a) At 
medium resolution, i.e., modeling most of a cell's proteome, to 
generate a rough or approximate predictive understanding of the 
``minimal metabolic scaffold'' for processes such as methanogenesis, 
photosynthesis, or metal reduction, or (b) at higher resolution: i.e. 
for a detailed quantitative representation of a relevant physiological 
process to optimize or manipulate a particular reaction, and to 
accurately predict

[[Page 7477]]

responses to environmental perturbations. It is important that any 
proposed software development activities be based on modular design, 
which enables upgrades and expansions to the predictive modeling 
capability as more quantitative data about protein biochemistry, 
physiology, and intracellular topology becomes available. Of particular 
importance is that modeling efforts not be conducted in isolation from 
the biological ``reality'' derived from experimental research. Of 
special interest will be computational models that would effectively 
utilize investments made by the Office of Science in massively 
parallel, high-performance computing hardware and software libraries. 
It is expected that computational tools developed under these awards 
will be widely distributed to the scientific community (e.g. via a WWW 
site) and that some level of user support will be available. Applicants 
with an interest in this thrust area are strongly encouraged to explore 
the companion Program Notice 01-21, Advanced Modeling and Simulation of 
Biological Systems, which encourages the submission of research 
applications that emphasize the applied mathematics and computer 
science advances needed to provide the computational modeling 
foundation upon which this notice is focused.

Preapplications

    Potential applicants are strongly encouraged to submit a brief 
preapplication that consists of two to three pages of narrative 
describing the research objectives, the technical approach(s), and the 
proposed team members and their expertise. The intent in requesting a 
preapplication is to save the time and effort of applicants in 
preparing and submitting a formal project application that may be 
inappropriate for the program. Preapplications will be reviewed 
relative to the scope and research needs of the Microbial Cell Project, 
as outlined in the summary paragraph and in the SUPPLEMENTARY 
INFORMATION. The preapplication should identify, on the cover sheet, 
the title of the project, the institution, principal investigator name, 
telephone, fax, and e-mail address. No budget information or 
biographical data need be included, nor is an institutional endorsement 
necessary. A response to timely preapplications will be communicated to 
the Principal Investigator by March 9, 2001.

Program Funding

    It is anticipated that up to $6 million will be available for all 
MCP awards in Fiscal Year 2001. It is anticipated that at least 4 
awards will be made to interdisciplinary scientific teams, contingent 
on satisfactory peer review, the availability of funds, and the size of 
the awards. Multiple year funding is expected, also contingent on 
availability of funds and progress of the research; pending the 
availability of future funding, it is anticipated that this initiative 
will reflect a long term commitment to understanding the workings of a 
microbial cell. Awards to interdisciplinary teams are expected to range 
from $0.5 million to $1.5 million per year, total costs, with terms of 
one to three years. (A number of awards in the $100-200 thousand range, 
total annual costs, may be made to exceptional individual investigator 
applications). The DOE is under no obligation to pay for any costs 
associated with the preparation or submission of an application. DOE 
reserves the right to fund, in whole or in part, any, all, or none of 
the applications submitted in response to this Notice. Applications 
received by the Office of Science under its normal competitive 
application mechanisms may also be deemed appropriate for consideration 
under this announcement and may be funded under this program.

Merit Review

    Applications will be subjected to scientific merit review (peer 
review) and will be evaluated against the following evaluation criteria 
which are listed in descending order of importance 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.
    In addition to the above evaluation criteria, applications will 
also be evaluated on the following:
    5. The robustness of the organizational framework and its 
coordination plan if a consortium is proposed.
    The evaluation will include program policy factors such as the 
relevance of the proposed research to the terms of the announcement and 
the agency's programmatic needs. Note, external peer reviewers are 
selected with regard to both their scientific expertise and the absence 
of conflict-of-interest issues. Non-federal reviewers will often be 
used, and submission of an application constitutes agreement that this 
is acceptable to the investigator(s) and the submitting institution.

Submission Information

    The Project Description must be 25 pages or less, exclusive of 
attachments. It must contain an abstract or project summary on a 
separate page with the name of the applicant, mailing address, phone 
FAX and E-mail listed. The application must include letters of intent 
from collaborators (briefly describing the intended contribution of 
each to the research), and short curriculum vitaes, consistent with NIH 
guidelines, for the applicant and any co-PIs.
    To provide a consistent format for the submission, review and 
solicitation of grant applications submitted under this notice, the 
preparation and submission of grant applications must follow the 
guidelines given in the Application Guide for the Office of Science 
Financial Assistance Program, 10 CFR part 605. Access to SC's Financial 
Assistance Application Guide is possible via the World Wide Web at: 
http://www.sc.doe.gov/production/grants/grants.html.
    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 Office of Science, as part of its grant regulations (10 CFR 
605.11(b)) requires that a grantee funded by SC and performing research 
involving recombinant DNA molecules and/or organisms and viruses 
containing recombinant DNA molecules shall comply with the NIH 
``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.
    Other useful web sites include:

MCP Home Page--http://microbialcellproject.org
Microbial Genome Program Home Page--http://www.er.doe.gov/production/ober/microbial.html
DOE Joint Genome Institute Microbial Web Page--http://www.jgi.doe.gov/JGI_microbial/html/
GenBank Home Page--http://www.ncbi.nlm.nih.gov/
Human Genome Home Page--http://www.ornl.gov/hgmis

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

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    Issued in Washington, DC on January 16, 2001.
John Rodney Clark,
Associate Director of Science for Resource Management.
[FR Doc. 01-2053 Filed 1-22-01; 8:45 am]
BILLING CODE 6450-01-U