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: 
http://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 
(http://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 301-435-
0714, 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:

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

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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