NIH Guide: PILOT PROJECTS FOR THE PROTEIN STRUCTURE INITIATIVE (STRUCTURAL GENOMICS)

PILOT PROJECTS FOR THE PROTEIN STRUCTURE INITIATIVE (STRUCTURAL GENOMICS)

Release Date: June 3, 1999

RFA NUMBER: GM-99-009

P.T.

National Institute of General Medical Sciences (NIGMS)

Letter of Intent Receipt Date: October 15, 1999
Application Receipt Date: February 11, 2000

PURPOSE

The National Institute of General Medical Sciences encourages
applications for research centers that will serve as pilots to examine
the best approach for developing subsequent integrated, large-scale
research networks in structural genomics. This is part of the
Institute's Protein Structure Initiative (PSI), whose goal is the
understanding of protein structural families, structural folds, and the
relationship of structure and function. These research centers should
include all the constituent tasks of structural genomics and should
test strategies for large-scale high throughput structure determination
by X-ray crystallography and/or NMR.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000," a
PHS-led national activity for setting priority areas. This Request for
Applications (RFA), Pilot Projects for the Protein Structure Initiative
(Structural Genomics), is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary
Report: Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325
(telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of state and local governments, and
eligible agencies of the Federal government. Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators. Foreign institutions are not
eligible for research center grants. However, subcontracts to foreign
institutions are allowable, with sufficient justification.

MECHANISM OF SUPPORT

Support of this program will be through research center grants (P50).
Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant. The total
project period for an application submitted in response to this RFA may
not exceed five years. Awards will be administered under the NIH
Grants Policy Statement (1998), that can be found at:
https://grants.nih.gov/grants/policy/nihgps/ Awards will be made prior to
September 29, 2000.

FUNDS AVAILABLE

The NIGMS expects to consider funding 3 to 6 research centers, each
ranging in cost no greater than 3 million dollars direct costs per
year. Only applications found to be responsive to this announcement
and of high scientific merit will be considered for funding. Not all of
the funds will be spent if there are not enough highly meritorious
applications. Funding in future years is subject to the availability
of funds.

RESEARCH OBJECTIVES

Background

Following the completion of the sequence of the human genome, a crucial
step in understanding living systems is the determination of the
structure and function of the entire set of gene products. Data from
the genome project have led to comparative protein sequence analyses
and numerous efforts to develop methodologies for the identification of
protein families. Utilization of these computational analyses with
structural determinations by X-ray crystallography and NMR techniques
to study protein structural families constitutes the new field of
structural genomics and is the goal of the NIGMS Protein Structure
Initiative (PSI). These studies should lead to an understanding of
structure/function relationships and the ability to obtain structural
models of all proteins identified by genomics. This project will
require the determination of a large number (perhaps 10,000) of protein
structures in a high throughput mode. Recent and anticipated
technological developments in protein structural determinations make
this formidable task feasible. The availability of comparative
sequence analyses and methodological improvements now make such a
large-scale structural project appropriate.

Three recent workshops sponsored by NIGMS have focussed on the
practicality, constituent tasks, goals, and planning of this project.
There was general agreement on technical feasibility due to advances in
the development of high throughput expression systems, protein
purification, and sample preparation (crystallization for X-ray
crystallography and isotopic labeling for NMR). All of these likely
can be organized on the large scale required. Methods for the
structure determination of proteins have also improved significantly in
recent years. The identification of protein families and target
selection proved to be the most controversial topic and was the focus
of the third workshop. A summary of these meetings can be found on the
NIGMS web site at:
http://www.nih.gov/nigms/funding/psi.html . Following the workshops
and discussions by the National Advisory General Medical Sciences
Council, it was concluded that the necessary tasks for the PSI project
are feasible and that the goal of this initiative is an important
scientific endeavor. The resulting basis set of protein structures and
structure folds will be crucial in understanding protein structure and
evolution, will contribute to the solution of the protein folding
problem, and will provide insights into the relationship of structure
and function.

Objectives and Scope

The purpose of this RFA is to announce support for research centers in
the new and emerging field of structural genomics. These research
centers are intended to serve as pilots that will lead to subsequent
large-scale research networks in structural genomics and high
throughput structural determination of proteins by X-ray
crystallography and NMR methods. They should contain all of the
constituent tasks of structural genomics and should demonstrate the
ability to accomplish the computational and experimental facets as an
integrated and high throughput operation. Effective plans for
management and administration of the research centers are crucial.
Attention should be paid to costs and efficiency, as well as technology
development. Rapid release of data into the public databases will be
required, as described below.

Applicants should include the following components:

1) Family Classification and Target Selection: There are several
schemes of comparative protein sequence analysis for parsing genomes
into protein families and for choosing protein targets for structural
genomics projects. These have been discussed in the scientific
literature and at several recent scientific meetings and workshops (for
example, see the NIGMS Structural Genomics Targets Workshop, referenced
above). Examples for targeting schemes to choose or prioritize
proteins for structural determination include: many of the proteins of
single organisms with a completed genome; putative proteins of unknown
function; protein families of known functions or medical relevance; and
clusters of orthologous groups (COGs) spanning the three domains of
life and perhaps corresponding to "ancient conserved regions." Since
no single scheme has emerged as a consensus choice, this decision is
left to applicants. Their experience and results in choosing an
approach are expected to be one of the outcomes of these pilot
projects. Applicants are expected to determine their own target
selection schemes and to present detailed plans and preliminary results
for this stage of their structural genomics project.

2) Generation of Protein for Biophysical Analyses: There is now
considerable experience in the generation of expression systems to
produce large quantities of most proteins in a form suitable for
biophysical studies. Applicants for the research centers should
present evidence of their capability to generate protein expression
systems, to overexpress proteins, and to purify protein samples.
Emphasis should be on high throughput, efficiency, and cost savings.

3) Sample Preparation for Structural Studies: This crucial experimental
task has seen significant progress recently. There has been greater
understanding of the basic mechanisms of crystallizations by various
physical approaches. These advances have significantly improved the
ability of structural biologists to crystallize proteins, especially
for soluble globular proteins. NMR studies will require isotopic
labeling of protein samples. The applicant's experience and plans for
the preparation of samples for structure determinations in a high
throughput mode should also be presented. Crystallization of membrane
proteins and a number of other classes of proteins are still very
difficult and not yet amenable to high throughput operations, but
innovative projects in this area as part of a larger effort are
encouraged.

4) Structure Determination: With many major technical advances in
recent years, X-ray crystallography for high-resolution structure
determination has become straightforward for many protein samples. The
major breakthrough has been the almost universal use of synchrotron
beamlines, which produce high fluxes and variable wavelengths. In
addition, major improvements have come from new detectors,
cryocrystallographic techniques, multiple-wavelength anomalous
diffraction techniques, and advanced computational systems for rapid
data collection, processing, and model building. New NMR methods and
higher field instruments have increased the size of proteins that can
be solved by this technique. The structure determination component
should be the nucleus of a structural genomics research center and
applicants should have considerable expertise and resources in either
or both of these techniques. The research centers should have plans
for structural determinations in a high throughput mode, with emphasis
on efficiency, cost reductions, and extensions to large-scale
operation. The research centers are expected to demonstrate their
access to state-of-the-art synchrotron and/or NMR facilities. The
NIGMS is currently planning the development of additional beamlines at
several synchrotron facilities, and will likely be able to make
additional beamtime available to general users and research centers
funded by this RFA within the next few years. However, the structural
genomics research centers are expected to demonstrate their own plans
for data collection and structure determinations.

5) Analyses and Dissemination of Results: With several disparate
components that are interdependent, management and administration are
crucial. In addition to the usual administrative details, the
leadership of the research centers must have plans for directing the
research, e.g., making decisions about which proteins to study first,
determining when to pursue a structure and when to discontinue,
coordination between different groups, etc. Since the goal of this
initiative is to add to the body of knowledge of protein structure and
to enable the NIGMS and scientific community to plan and prepare for
large-scale operations in structural genomics, release and
dissemination of results are crucial. In addition to the structure
factors and coordinates, this includes information on strategies for
target selections, status of research on these proteins, technological
and methodology findings, high throughput approaches, efficiency, and
cost analyses. The pilot research centers will be required to have
plans for timely deposition of coordinates and related data into the
public database and for handling intellectual property issues. They
should also address their plans for analyses of results relative to
understanding protein structure and the field of structural genomics.
The NIGMS plans to hold annual meetings at the NIH for grantees in
structural genomics to discuss their progress and results.

Summary

The purpose of this RFA is to call for applications supporting research
centers in structural genomics. These research centers are intended to
provide information to the NIH and the scientific community that will
lead to subsequent development of large-scale research networks in
structural genomics. Both computational and experimental aspects are
essential, as well as a comprehensive and integrated research plan.
Emphasis should be placed on protein structural determinations in a
high throughput mode.

There are two related program announcements:

1) A program for R01 and P01 grants to support research on the
development of methodology and technology underpinning the emerging
field of structural genomics. Projects related to high throughput
structure determination by X-ray crystallography and NMR, as well as
those addressing other constituent tasks of structural genomics, are
relevant. This PA will be published in the near future.

2) A similar program to the above for structural genomics methodology
and technology development for Small Business Innovation Research/Small
Business Technology Transfer (SBIR/STTR) applications. The SBIR/STTR
PA will be published in the near future.

POST-AWARD MANAGEMENT

During the course of the grant period, both computational and
experimental technologies will improve, and the rate of progress and
focus of work supported by the grant may change. It is expected that
the Principal Investigator will make any necessary adjustment in
scientific direction to accommodate the expected scale-up and changing
environment, keeping the NIGMS staff informed if significant changes
are made. In order to ensure that the project remains focused on
appropriate goals, incorporates new technological advances and makes
sufficient progress, scientific and programmatic visits to the grantee
will be conducted at a frequency to be negotiated with the awardee. In
addition, benchmarks for progress may be changed annually.

The NIGMS may include outside consultants in the annual progress review
and reduce or withhold funds for failure to meet milestones agreed upon
by grantees and NIH staff. A report by the NIGMS program director on
each research center's progress and any recommendations to modify
funding will be made annually to the National Advisory General Medical
Sciences Council.

LETTER OF INTENT

Prospective applicants are asked to submit, by Oct. 15, 1999, a letter
of intent that includes a descriptive title of the proposed research,
the name, address, and telephone number of the Principal Investigator,
the identities of other key personnel and participating institutions,
and the number and title of the RFA in response to which the
application will be submitted. Although a letter of intent is not
required, is not binding, and does not enter into the review of
subsequent applications, the information that it contains allows
Institute staff to estimate the potential review workload and to avoid
conflict of interest in the review..

The letter of intent is to be sent to:

John C. Norvell, Ph.D.
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
45 Center Drive, Room 2AS.13B
Bethesda, MD 20892-6200
Telephone: (301) 594-0533
FAX: (301) 480-2004
Email: norvellj@nigms.nih.gov

SPECIAL REQUIREMENTS

The NIGMS has adopted several polices that are applicable to these
structural genomics research centers. Applicants must present plans to
adhere to the policies, where appropriate.

Research Training. In most cases, the research projects envisioned at
this stage of the PSI will involve extensive data collection with
limited hypothesis-driven aspects. Therefore they may not be
appropriate as research training projects. Applicants planning to
employ graduate students and/or postdoctoral research assistants on
their project should address this issue.

Intellectual property. The results of the structural genomics projects
should be freely available for use by the entire research community
and, therefore, must be released into the public domain. Applicants
should present plans related to intellectual property rights. The
NIGMS will monitor its grantees' activities with respect to patenting
the structural results and technology developments.

Data Release and Sharing of Results and Materials. Structural results,
including protein coordinates and structure factors should be deposited
promptly into the Protein Data Bank (PDB). Guidelines developed by NIH
do not permit holds on deposited coordinates
(https://grants.nih.gov/grants/guide/notice-files/not99-010.html). In
addition, dissemination of results of the structural genomics research
centers is crucial and applicants should plan on sharing findings and
the experiences at the annual meetings for structural genomics grantees
and in other appropriate forums. This includes information on
strategies for target selections, status of research on these proteins,
technological and methodology findings, high throughput approaches,
efficiency, and cost analyses. Grantees will be required to provide
the information listed above in their annual progress report. The
NIGMS is supporting the development of a database (contact Dr. Norvell
at NIGMS for updated information) to facilitate this sharing of
information and the coordination of the research projects undertaken by
the research centers. In some cases, the proteins and samples
generated by these research centers will need to be pursued by detailed
functional studies by scientists both within and outside the research
centers and beyond the scope of these awards. Thus, the research
centers should have plans both for timely deposition of coordinates and
related data and for sharing results and materials.

Management Plan. The management of a structural genomics research
center requires a significant commitment by the P.I. Accordingly, he
or she is expected to devote a substantial effort to the project. The
applicant must propose a management plan that takes into account the
changes that will occur over the 5-year term of the award.

External Scientific Advisory Committee. Each research center should
have an external advisory committee of research scientists not involved
in the consortium to provide independent assessment and advice to the
principal investigator and staff. This committee should be appointed
by the principal investigator and meet at least twice each year. In
order to maximize the pool of possible reviewers, the potential members
of the advisory committee should not be contacted or selected until
after an award has been made.

Annual Meeting. Grantees in the PSI program will be expected to attend
an annual meeting at the NIH to discuss their progress and results.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398
(rev. 4/98) and will be accepted only at the deadline of Feb. 11, 2000.
Application kits are available at most institutional offices of
sponsored research and may be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701
Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, email: grantsinfo@nih.gov.

The RFA label available in the PHS 398 (rev. 4/98) application form
must be affixed to the bottom of the face page of the application.
Failure to use this label could result in delayed processing of the
application such that it may not reach the review committee in time for
review. In addition, the RFA title, and number, must be typed on line
2 of the face page of the application form and the YES box must be
marked.

Potential applicants are strongly urged to contact the program staff
listed under INQUIRIES for guidance in the preparation of the
application. Responsibility for the planning, direction, and execution
of the proposed project will be solely that of the applicant. The
total project period for an application submitted in response to this
RFA may not exceed five years.

Special application requirements:
The research center should be an integrated, coordinated project, with
various interdependent subprojects that comprise structural genomics as
described above. It must be fully described and justified.
Collaborations and consortia are encouraged. In such collaborations,
the respective contributions should be well integrated into the design
of the application. The application should have a face page; abstract;
project summary; plans for administrative management; plans for project
management with annual milestones and evaluations; subproject
descriptions; consolidated budget; key personnel listing; biographical
sketches; investigators' other support; institutional support,
resources and facilities; letters of collaboration; plans for sharing
results and materials; plans for handling intellectual property issues;
etc. An overview section should be prepared that includes an overall
description which defines the scope and objectives. The budget should
be no greater than $3 million direct costs for the first year, with
annual cost-of-living increases in subsequent years. It should be
fully justified and should include funds for attending the annual
meeting. The page limit for the research plan (including specific
aims, background and significance, preliminary studies, and research
design and methods) is increased to 60 pages total.

The title and number of RFA must be typed on line 2 of the face page of
the application form ("Protein Structure Initiative," GM-99-009) and
the YES box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed photocopies in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

At the time of submission, two additional copies of the application and
any appendix material must be sent to:

Helen R. Sunshine, Ph.D., Chief
Office of Scientific Review
National Institute of General Medical Sciences
Building 45, Room Number 1As.13
National Institutes of Health
Bethesda, MD 20892

Applications must be received by February 11, 2000. If an application is
received after that date, it will be returned to the applicant without
review. The Center for Scientific Review (CSR) will not accept any
application in response to this RFA that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application. The CSR will not accept any application that is
essentially the same as one already reviewed. This does not preclude the
submission of substantial revisions of applications already reviewed, but
such applications must include an introduction addressing the previous
critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and
for responsiveness to the RFA by the NIGMS program staff. Incomplete
and/or nonresponsive applications will be returned to the applicant
without further consideration. Those applications that are complete
and responsive will be evaluated in accordance with the criteria stated
below for scientific/technical merit by an appropriate peer review
group convened by the NIGMS. Site visits or applicant interviews may
or may not be performed as part of the initial review. Applicants
should not assume they will occur and therefore must present a complete
and well-justified written proposal. As part of the initial merit
review, all applications will receive a written critique and may
undergo a process in which only those applications deemed to have the
highest scientific merit will be discussed, assigned a priority score,
and receive a second level review by the National Advisory General
Medical Sciences Council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.
In the written comments reviewers will be asked to discuss the
following aspects of the application in order to judge the likelihood
that the proposed research will have a substantial impact on the
pursuit of these goals. Each of these criteria will be addressed and
considered in assigning the overall score, weighting them as
appropriate for each application.

1. Significance: Will this research project make an important
contribution to the field of structural genomics? If the aims of the
application are achieved, how will scientific knowledge be advanced?
What will be the effect of these studies on the concepts or methods
that drive this field? What is the likelihood that the research center
will be able to evolve into a successful large-scale high throughput
structure determination research network?

2. Approach: Are the conceptual framework, design, methods, and
analyses adequately developed, well integrated, and appropriate to the
aims of the project? Does the applicant acknowledge potential problem
areas and consider alternative tactics? Is the management and
administrative framework adequate? Are the milestones and plans for
evaluations appropriate?

3. Innovation: Does the project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does the project
challenge existing paradigms or develop new methodologies or
technologies? How exportable are these strategies and technologies?
Is there a plan for incorporating new technologies at reasonable costs?

4. Investigator: Is the investigator appropriately trained and well
suited to carry out this work? Is the work proposed appropriate to the
experience level of the Principal Investigator and other researchers?
Does the Principal Investigator have the appropriate management and
administrative skills?

5. Environment: Does the scientific environment in which the work
will be done contribute to the probability of success? Do the proposed
research centers take advantage of unique features of the scientific
environment or employ useful collaborative arrangements? Is there
adequate institutional support?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o plans for protein family classification and target selection,
including plans for testing this strategy and its applicability to
subsequent large-scale research networks.

o plans and previously demonstrated success in increasing throughput
and decreasing costs;

o plans for handling intellectual property issues, for sharing
results and materials generated by this research, and for prompt
placement of data in the public domain, including deposition of
coordinates in the Protein Data Bank;

o the reasonableness of the proposed budget in relation to the
proposed research; and

o the adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the
project proposed in the application.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications assigned to the NIGMS. Awards will be made prior to
September 29, 2000. The following will be considered in making funding
decisions:

o quality of the proposed project as determined by peer review;

o program priority of research in this area and other areas of
Institute interest;

o plans for rapid dissemination of the results and information on
technological developments, including rapid deposition and release of
all protein coordinates and structure factors into the PDB, i.e., holds
on release are not permitted;

o overall contribution of the project to knowledge and experience
required to meet the long range goals of the structural genomics
project; and

o availability of funds.

INQUIRIES

Inquiries are encouraged. The opportunity to clarify any issues or
questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Direct inquiries regarding fiscal matters to:

Ms. Phyllis Finch-Smith
Grants Management Office
National Institute of General Medical Sciences
45 Center Drive, Room 2AS.55H
Bethesda, MD 20892-6200
Telephone: (301) 594-5243
FAX: (301) 480-2554
Email: finchp@nigms.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.821. Awards are made under authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public
Law 99-158, 42 USC 241 and 285) and administered under NIH Grants
Policy Statement (October 1, 1998) and Federal Regulations 42 CFR 52
and 45 CFR Part 74. This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products. In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, and
portion of a facility) in which regular or routine education, library,
day care, health care or early childhood development services are
provided to children. This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.

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