ADVANCED INSTRUMENTATION FOR HIGH RESOLUTION ELECTRON MICROSCOPY

Release Date:  April 3, 2000

PA NUMBER:  PA-00-083

National Institute of General Medical Sciences

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

PURPOSE

The National Institutes of Health (NIH) and the National Institute of General 
Medical Sciences (NIGMS) support the application of electron microscopy (EM) 
to a broad range of problems in molecular and cellular biology.  Current 
research efforts aim at extending the capabilities of EM for determining the 
atomic structures of isolated macromolecular assemblies and analyzing spatial 
arrangements of macromolecules in cells.  The next generation of EM 
instrumentation and associated infrastructure will be required to achieve 
these capabilities.  The purpose of this Program Announcement (PA) is to 
describe the types of support that NIGMS will provide for advanced 
instrumentation in conjunction with its ongoing and new research projects.  
For its projects that require advanced EM instrumentation, NIGMS will provide 
support for upkeep and operation and assist in the acquisition of equipment.
 
HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a PHS 
led national activity for setting priority areas.  This Program Announcement 
(PA), Advanced Instrumentation for High Resolution Electron microscopy, is 
related to one or more of the priority areas.  Potential applicants may 
obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, 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.

MECHANISM OF SUPPORT

This PA will use existing NIH research project grant (R01) award and program 
project grant (P01) award mechanisms.  Foreign institutions are not eligible 
for Program Project grants.  Applications for competing supplements to 
existing grants will also be accepted, if there will be at least one year 
remaining in the project period at the time of supplement funding.  
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 PA may not exceed five years. 

NIGMS does not offer shared instrumentation grants, but shared 
instrumentation may be requested from other agencies through a variety of 
mechanisms, including the NIH National Center for Research Resources (NCRR) 
Shared Instrumentation Grants (PA number PAR-99-031, 
http://grants.nih.gov/grants/guide/pa-files/PAR-99-031.html) and the National 
Science Foundation (NSF) Grants for Multi-user Equipment and Instrumentation 
Resources for Biological Sciences (NSF-98-137, 
http://www.nsf.gov/pubs/1998/nsf98137/nsf98137.txt).  In accordance with 
NIGMS guidelines, requests for dedicated equipment items may be incorporated 
into NIGMS R01, P01, or competing supplemental applications.  NIGMS is 
willing to provide continuing support for upkeep and operation of advanced 
instrumentation and associated infrastructure (e.g., service contracts and 
support personnel), requests may be incorporated into R01, P01, or competing 
supplemental applications. 

For most research efforts the Research Project (R01) is the preferred grant 
mechanism.  For complex multi-investigator research efforts which meet the 
objectives of NIGMS Program Project (P01) grants, 
(http://www.nih.gov/nigms/funding/pa/progproj.html), the P01 may be the 
preferred mechanism. Investigators planning to apply for P01 grants should 
contact staff listed in the NIGMS P01 announcement.   

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm
 
RESEARCH OBJECTIVES

Background 

In April 1998, a special Cell Biology and Biophysics Subcommittee of the 
National Advisory General Medical Sciences Council examined research trends 
in the areas of molecular cell biology, structural biology and biophysics.  
Among the challenges and opportunities identified by the panel were better 
methods for structural analysis of large macromolecular assemblies and for 
imaging macromolecules in cells.  In the area of EM, the subcommittee cited a 
need for support for the acquisition of the next generation of electron 
microscopes and their operation by especially high-caliber personnel. To 
examine these issues, NIGMS and NCRR convened a workshop in November 1998 to 
evaluate instrumentation and technology development needs for high resolution 
EM.

NIH supports a number of projects that utilize EM for high-resolution 
molecular imaging and cellular tomography.  Progress in these areas depends 
on access of investigators to electron microscopes capable of producing high-
resolution images and the highest possible fraction of usable images.  The 
next generation of electron microscopes incorporates advanced features that 
enhance capabilities for high-resolution imaging of biological specimens.  
Examples include field emission electron sources, liquid helium cold stages, 
energy filters, higher accelerating voltages, and detectors with large active 
areas.  For optimal progress, many research projects involving high 
resolution EM will soon require access to microscopes with these advanced 
features.  However, instruments with the required capabilities have become 
too expensive for single groups.  Their cost exceeds the award limits for the 
NIH and NSF shared instrumentation grants programs.  Operation and upkeep are 
also beyond the resources of most laboratories, which must rely on R01 grants 
and local funds.

This PA is issued in response to the findings and recommendations of the 
workshop, as endorsed by the National Advisory General Medical Sciences 
Council at its May, 1999 meeting.  It addresses needs of ongoing and new 
NIGMS research programs for access to advanced instrumentation for high-
resolution EM.  An accompanying PA addresses technology development for high-
resolution electron microscopy.

Scientific Objectives

NIGMS is willing to incorporate support for advanced instrumentation for 
high-resolution electron microscopy into its ongoing or new research 
projects.  This PA is not intended as a lead mechanism for acquisition of 
shared instrumentation, for user facilities, or for regional or national 
centers, these are supported by NCRR through its Shared Instrumentation and 
Biomedical Technology Resource Grants 
(http://www.ncrr.nih.gov/biotech/SIG_Fact_Sheet.pdf).
  
Scope

For the acquisition of instrumentation through a variety of mechanisms of 
NIH, NSF, and other Federal agencies, NIGMS may provide a substantial 
contribution (up to $1 million), when the equipment is justified as part of 
an NIGMS supported research effort.  In all cases, the cost of the instrument 
and associated operating support must be consistent with the scope of the 
research project(s) with which it is associated.  NIGMS will provide support 
for operation and upkeep of microscopes and ancillary equipment (e.g., 
service contracts and support personnel), in conjunction with its support for 
associated ongoing or new NIGMS research projects.  Because of the level of 
experience and skill required, support personnel may include career track, 
senior postdoctoral scientists. 

Summary

This PA addresses the need of basic research in molecular cell biology for 
more effective application of EM for the structural analysis of large 
macromolecular assemblies and for the imaging of macromolecules in cells.  To 
meet this need, investigators will require the next generation of EM 
instrumentation and associated infrastructure.  This PA is intended to ensure 
that ongoing and new research projects that develop and/or apply advanced (3-
D and high-resolution) EM methods are equipped with the instruments that are 
needed to achieve the required data throughput and image resolution.  

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their subpopulations must be included in all NIH supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification is provided that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of 
the research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the 
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical 
Research," which have been published in the Federal Register of March 28, 
1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 
23, No. 11, March 18, 1994 available on the web at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects" that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev. 
4/98) and will be accepted at the standard application deadlines as indicated 
in the application kit.  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: [email protected].

Applicants planning to submit an investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended/revised 
version of the preceding grant application types requesting $500,000 or more 
in direct costs for any year are advised that he or she must contact the 
Institute or Center (IC) program staff before submitting the application, 
i.e., as plans for the study are being developed.  Furthermore, the applicant 
must obtain agreement from the IC staff that the IC will accept the 
application for consideration for award.  Finally, the applicant must 
identify, in a cover letter sent with the application, the staff member and 
Institute or Center who agreed to accept assignment of the application.  

This policy requires an applicant to obtain agreement for acceptance of both 
any such application and any such subsequent amendment.  Refer to the NIH 
Guide for Grants and Contracts, March 20, 1998 at 
http://grants.nih.gov/grants/guide/notice-files/not98-030.html

Because of the anticipated complexity of applications responding to this 
Program Announcement, potential applicants are strongly advised to contact 
staff before preparing applications.

Individual Research Project (R01) Grants Requesting $250,000 Direct Costs Per 
Year or less.

For the R01 mechanism, specific application instructions have been modified 
to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being 
examined by the NIH. Complete and detailed instructions and information on 
Modular Grants can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

R01 applications that request more than $250,000 direct costs per year should 
follow the instructions in the PHS Form 398.

The title and number of the program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the 
Checklist, and five 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)

SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only 
when there is a possibility for an award. It is anticipated that these 
changes will reduce the administrative burden for the applicants, reviewers 
and Institute staff.  The research grant application form PHS 398 (rev. 4/98) 
is to be used in applying for these grants, with the modifications noted 
below.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $250,000 per year. (Applications that 
request more than $250,000 direct costs in any year must follow the 
traditional PHS 398 application instructions.)  The total direct costs must 
be requested in accordance with the program guidelines and the modifications 
made to the standard PHS 398 application instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular 
Total Direct plus Facilities and Administrative (F&A) costs] for the initial 
budget period.  Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 
of the PHS 398. It is not required and will not be accepted with the 
application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the 
categorical budget table on Form Page 5 of the PHS 398. It is not required 
and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for 
sample pages.) At the top of the page, enter the total direct costs requested 
for each year.  This is not a Form page.

o Under Personnel, List key project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the 
nearest $1,000. List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of key personnel, 
and the role on the project. Indicate whether the collaborating institution 
is foreign or domestic. The total cost for a consortium/contractual 
arrangement is included in the overall requested modular direct cost amount.  
Include the Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by  
reviewers in the assessment of each individual"s qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team. A biographical sketch is required for 
all key personnel, following the instructions below. No more than three pages 
may be used for each person. A sample biographical sketch may be viewed at: 
http://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page,
- List position(s) and any honors,
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations,

o CHECKLIST - This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the 
type of agreement and the date. All appropriate exclusions must be applied in 
the calculation of the F&A costs for the initial budget period and all future 
budget years.

o The applicant should provide the name and telephone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review. 
 
REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral 
guidelines.  Applications will be evaluated for scientific and technical 
merit by an appropriate scientific review group convened in accordance with 
the standard NIH peer review procedures.  As part of the initial merit 
review, all applications will receive a written critique and undergo a 
process in which only those applications deemed to have the highest 
scientific merit, generally the top half of applications under review, will 
be discussed, assigned a priority score, and receive a second level review by 
the appropriate national advisory council or board.

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.  Note that the 
application does not need to be strong in all categories to be judged likely 
to have major scientific impact and thus deserve a high priority score.  For 
example, an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

(1) Significance:  Does this study address an important problem?  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?

(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?

(3) Innovation:  Does the project employ novel concepts, approaches or 
method? Are the aims original and innovative?  Does the project challenge 
existing paradigms or develop new methodologies or technologies?

(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 (if any)?

(5) Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of 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  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

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.

The initial review group will also examine the provisions for the protection 
of human subjects and the safety of the research environment.

Additional scientific/technical merit review information is included. For the 
research component of applications, reviewers will apply the standard NIH 
review criteria (explained above).  For instrumentation with advanced 
capabilities, the reviewers will be asked to evaluate whether the requested 
equipment will allow the PI to attain important goals not otherwise 
practicable, for example to achieve substantially better resolution and 
interpretability.  In the case of a competing supplement, the reviewers will 
be asked to evaluate whether the requested equipment will provide a critical 
enhancement of the goals and outcome of the parent project.
 
AWARD CRITERIA

Applications will compete for available funds with all other recommended 
applications.  The following will be considered in making funding decisions: 
quality of the proposed project as determined by peer review, availability of 
funds, and program priority.  

For acquisition and support of advanced instrumentation, cost effectiveness 
will be evaluated in terms of (1) scope of the associated ongoing or new 
research programs and (2) benefits to the associated groups of investigators 
and research programs.

INQUIRIES

Inquiries are strongly encouraged.  We welcome the opportunity to clarify any 
issues or questions from potential applicants.

Direct inquiries regarding programmatic issues to:

James F. Deatherage, Ph.D. 
Division of Cell Biology and Biophysics 
National Institute of General Medical Sciences 
Building 45, Room 2AS.13J 
Bethesda, MD  20892-6200 
Telephone:  (301) 594-3828   
Fax:  (301) 480-2004  
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Ms. Phyllis Y. Smith
Grants Management Office 
National Institute of General Medical Sciences 
Building 45, Room 2AN.55H 
Bethesda, MD  20892-6200 
Telephone:  (301) 594-5243 
Fax:  (301) 480-2554 
Email:  [email protected]

AUTHORITY AND REGULATIONS 

This program is described in the Catalog of Federal Domestic Assistance No. 
93.821.  Awards are made under authorization of sections 301 and 405 the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  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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