Full Text PA-93-091


NIH GUIDE, Volume 22, Number 20, June 4, 1993


P.T. 34

  Human Genome 
  Nucleic Acid Sequencing 
  Molecular Genetics 

National Center for Human Genome Research


The purpose of this program announcement is to solicit new or renewal
applications for large-scale projects in genomic research.  The
announcement describes a reformulated, flexible program for support of
research efforts designed to complete the initial five-year goals of
the research program of the National Center for Human Genome Research
(NCHGR) and to progress beyond them toward the ultimate goal of
determining the complete sequence of human DNA.  The new program, which
is called the Genome Science and Technology Centers (GESTEC) program,
will support large-scale, multidisciplinary genomic studies under the
P50 and P01 grant mechanisms.

The GESTEC program is intended to develop the technologies needed to
accomplish the goals of the Human Genome Program and to apply them to
the large-scale generation of mapping and sequencing information.
Improved informatics solutions to data management will be a vital
component to realizing success in these efforts.  While primary focus
will be on the mapping and sequencing objectives, it is also
appropriate to address the need for better methods of annotating the
maps and sequences, e.g., techniques for identifying and mapping all of
the genes and/or other functional elements in a large genomic region.


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.  While a single
institution must be the applicant, multi-institutional arrangements
(consortia) are possible if there is a compelling reason for them and
if there is clear evidence of close interaction among the participants.
Applications from foreign institutions will not be accepted.  However,
subcontracts to foreign institutions are allowable, with sufficient
justification.  Applications from minority individuals and women are

Industrial/academic collaborations are also encouraged.  In such
collaborations, the respective contributions should be well-integrated
into the design and operation of the center, to encourage
cross-fertilization of ideas and rapid application of the research to
practical purposes.


Grants in the GESTEC program may be supported by specialized center
grants (P50) or program project grants (P01).  The P50 mechanism will
be used for broad, complex, multidisciplinary programs that address the
goals of the Human Genome Project.  The P01 mechanism will be used for
programs that support a minimum of three research components with a
well-defined central research focus.



The National Institutes of Health (NIH) is currently engaged, along
with several other federal, private, and international organizations,
in a 15-year research program designed to characterize the human genome
and the genomes of selected model organisms.  This research program,
the Human Genome Project (HGP), has the following interrelated goals:

(1) the construction of high-resolution genetic linkage maps;
(2) the development of physical maps;
(3) the determination of the complete nucleotide sequence of the
genomes of selected organisms, including the human;
(4) the development of the capability to collect, store, distribute and
analyze the data and materials produced;
(5) the development of appropriate new technologies to achieve these
goals; and
(6) the identification of major issues related to the ethical, legal
and social implications (ELSI) of genome research, and the development
of policy options to address them.

The product of the Human Genome Project will be a set of information
and material resources available to the entire research community that
will facilitate further research as to the prevention, diagnosis, and
therapy of disease, as well as a further understanding of human

In 1990, the NCHGR and the Department of Energy (DOE) jointly published
a plan "Understanding Our Genetic Inheritance - The U.S. Human Genome
Project:  The First Five Years FY 1991-1995" that set out specific
goals to be achieved in the first five-year phase of the U.S. human
genome program.  As of October 1993, the NCHGR will begin the fourth
year of operation under that plan, with the prospect that many of the
goals will be achieved on schedule. Anticipating the attainment of the
initial set of goals, the NCHGR is currently engaged in developing
goals for the second five-year period.  At the same time, the NCHGR
centers program, which has supported several large-scale,
multidisciplinary projects that have made significant contributions to
recent achievements, is also in transition, and a number of the grants
awarded initially are scheduled for recompetition during the next year.

The NCHGR intends to build upon the success of the current program and
the lessons that have been learned from it, by establishing a
reformulated centers program, the Genome Science and Technology Centers
(GESTEC) program.  This announcement solicits applications for new and
continuing projects that propose to finish the goals of the first
five-year component of the HGP and to address the further needs of the
project, leading toward complete sequencing of the human genome and the
genomes of selected model organisms.

Progress and Future Needs in Mapping

For the genetic linkage map, several current efforts, both genome-wide
or on an individual chromosome level, are expected to achieve the
timely completion of the 2 to 5 centimorgan genetic map called for in
the Five-year Plan.  Similarly, recent progress in physical mapping has
been very rapid, with contiguous for long genomic regions, including
two human chromosomes and parts of many others, having been assembled.
While much work remains to be done in order to complete physical maps
of the resolution called for in the Five-Year Plan (with a
"sequence-tagged site" (STS) every 100 kb across most of the genome and
with much of the genome in large physical contiguous of cloned DNA),
there is a good possibility that this goal also will be largely
attained by 1995.

Even after the goals set forth for the first five years have been
completed, however, continued technology development will be necessary
to ensure progress toward sequencing the entire human genome.  For
example, it has not yet been convincingly demonstrated that any of the
currently available cloning vectors allow reliably faithful cloning of
mammalian genomic DNA.  Thus, new techniques or strategies will be
needed to generate "sequence-ready" physical maps, comprised of DNA
that can be readily sequenced.  In the next several years, strategies
for creating maps and reducing them to nucleotide sequences will have
to be thoughtfully and carefully integrated.  Better methods of
annotating genetic and physical maps, e.g., with genes and other
functional elements, on a genomic scale are also needed.

Progress and Future Needs in DNA Sequencing

Progress has also been rapid toward the long-term goal of the Human
Genome Program, i.e., determining the complete sequence of the DNA of
certain model organisms and the human.  In 1990, the cost of sequencing
in laboratories devoted to DNA sequencing was estimated to be about $5
per finished base.  At the same time, the rate at which finished
sequence could be generated was relatively low.  Since its inception,
the NCHGR has supported several efforts designed to test and refine
current methods in large-scale projects or develop entirely new
approaches to DNA sequencing that offer substantial improvements over
current methods.

Through these efforts, a number of advanced sequencing laboratories are
within reach of being able to generate contiguous finished sequence at
a rate of megabases per year and the cost is now projected to be
approximately $1 per finished base pair.  Several interesting regions
of both non-human and human DNA have been sequenced in these projects.

To build on this significant progress, multidisciplinary centers will
be needed to develop and implement visionary, integrated strategies
that will optimize the several aspects of DNA sequencing, including
sample preparation, band resolution and detection, sequence assembly
and finishing, and annotation.  The efforts in the GESTEC centers will
need to be carefully balanced between technology development and actual
testing in a production mode in order that the new technology developed
is effective and well-suited to achieving the ambitious goals of the
Human Genome Program.  It is expected that, through previous
feasibility studies, applicants for GESTEC program grants will have
demonstrated their ability to sequence at high throughput in a cost
effective manner and to manage a large-scale sequencing effort.

Objectives and scope

The GESTEC program is intended to foster and support innovative
projects in which technology development and cost effectiveness are
expected to push the limits of current capabilities.  The GESTEC
program is NOT intended to fund projects in which existing technology
is simply applied to large-scale production or projects that involve a
consortium of investigators whose research interests are only loosely
united by a common theme.

To achieve the ambitious goals that this program is intended to attain,
it is anticipated that a Genome Science and Technology Center must be:

o mission-oriented, addressing in a highly integrated way, a major,
quantifiable goal(s) of the HGP, including completion of the initial
genome program goals and/or going beyond those by addressing the
ultimate goal of the HGP --  the first complete sequence of a human

o creative and innovative in terms of the proposed strategy and
development of new technology for achieving its goal(s);

o readily adaptable to new technology and new scientific developments;

o focused, on an on-going basis, on issues of increased efficiency as
evidenced by a plan for improvements in the rate of output of data and
materials; at the same time, attention must be paid to maintaining or
improving the quality of the techniques, data, and materials developed;

o attentive to the needs of the larger scientific community, as
demonstrated by the inclusion of an outreach program that will allow
the center to act as a hub for collaboration and as a source for
materials and information; the study of ELSI issues and outreach to the
general public through education programs can be a component of such an
outreach activity.

Allowable Components of Gestec Grant Applications

Genomic research is defined, in part, by its emphasis on technology
development and on a high rate of data production.  Because of these
inherent characteristics, investigators in the field have occasionally
found standard organizational structures other than those prescribed by
traditional multi-component grant mechanisms, i.e., research projects
and technical cores each managed by a differed principal investigator,
to be more effective in managing and effecting large-scale genome
research projects.  In order to facilitate the most rapid progress and
efficient use of limited resources, applicants will not be required to
use the standard organizational format.  Rather, each applicant is
encouraged to divide the program into units that will best accomplish
the scientific goals of the proposed project.

Each proposed organizational component must have an identified leader,
although no minimum number of different leaders is required.  For
example, the Principal Investigator of the entire grant may also serve
as leader of several, or even all, of the components, if such an
arrangement is scientifically justified and adequate supervision of the
project can be assured.  The selection of the leader for each component
should be justified in terms of the scientific and management needs of
that component and the experience of the proposed leader.

The following is a discussion of the activities most frequently found
in multicomponent, genome research projects.  Each of these will, in
some way, be integral to GESTEC programs and the organizational plan
developed by the applicant must address each of these activities.
Thus, while the form of the components may differ dramatically among
grants in the GESTEC program, it is essential that the scientific and
management structure (organizational plan) be clearly presented in the
application, both for the overall program and for the individual
activities.  It is also essential that the requested budget correspond
directly to the organizational plan.  The proposed plan will be
considered as an indication of the quality of the management of the

Research activities

There are four primary activities that are usually part of a GESTEC
grant:  scientific research, technology development, technical support
of either of the preceding, and outreach to the scientific community.
Additionally, a GESTEC grant may have administrative and management
elements as well as request alterations and renovations.  In a
traditionally organized program project or center, research and
technology development activities are normally organized as individual
"research projects", while technical support and outreach activities
are presented as "technical cores."  It has been the experience,
however, in some large-scale genome projects that it is more efficient
and productive to organize and manage efforts in others ways, for
example, by combining certain research and support activities into a
single unit.  In a proposal for a GESTEC project, the applicant may
design activities to accomplish the scientific objectives most

Technology development

The development of new and better technology needed to achieve the
objectives of the Human Genome Project is considered to be one of the
most important aspects of a GESTEC project.  Funds for technology
development may be requested to support (1) the design and development
of prototypes for equipment needed to increase the rate and efficiency
of data production and analysis, (2) pilot projects to take advantage
of scientific opportunities that present themselves during the course
of the project, and (3) the development of technology to meet
unanticipated needs of the research and support activities of the

In some cases, it may be possible to present, in the application, a
detailed description of plans and justification for the particular
technology development projects envisioned.  Applicants are encouraged
to fully describe and justify plans to the extent possible.  However,
it is also recognized that unanticipated needs may arise as the project
develops and, thus, a complete description of all technology
development plans may not be possible.  In the latter case, the request
for technology development funds must be justified by the inclusion of
a strategy for making decisions about the use of such funds, e.g., the
planning process for the use of the funds, alternative logistical plans
for development of a variety of technologies, and the process for
evaluating projects to be supported by technology development
activities.  In an application for renewal of currently-funded NCHGR
grants, the justification for technology development funds must include
a description of the use(s) to which such funds were put during the
previous grant period.

Technical support activities

An applicant may request shared facilities or equipment that will be
required by more than one element of the proposed research program.
Each applicant should examine the needs of the proposed program and
request those technical facilities that would be required to support
the proposed research in the most efficient and cost-effective manner.

Outreach Activities

GESTEC projects are expected to have an interest in and a sense of
responsibility for outreach to the greater scientific community.   At
a minimum, effective and rapid distribution of data and/or materials
generated by a GESTEC project to external investigators is an essential
and expected activity of each center.  Accordingly, the proposal must
include a full description of plans for accomplishing this goal.  The
joint NIH-DOE Advisory Committee on the Human Genome has recently
issued a set of Guidelines for Access to Data and Material Resources,
which is available from the program administrators listed below and
which would form the basis of an acceptable plan, although
investigators are encouraged to go beyond these guidelines whenever
possible.  Funding to support data and materials distribution may be
requested in a GESTEC grant application.  Other means of distribution,
such as through a commercial vendor are also acceptable.

Beyond such distribution activities, GESTEC projects are also
encouraged to provide outreach to the larger community by acting as a
hub of genomic collaboration through activities such as providing
additional services to the community, for example, visitor laboratories
or library screening services.  Beyond outreach to the scientific
community, development of public education outreach programs and
demonstration of interest in ELSI issues are also desirable.
Applications for renewal of currently-funded NCHGR center grants must
document their accomplishments in the outreach area as part of their
justification for continued support.

Administrative and Management Activities

Funds to support overall management of the GESTEC grant may be
requested.  As the GESTEC program allows for flexibility in management
to fit the scientific purpose of the application, it is essential that
the applicant adequately describe and justify both the overall
management strategy proposed, as well as a plan for the management of
each of the activities.

Management of a scientific enterprise as complex as a GESTEC center
will require a significant amount of attention and effort.  Therefore,
the proposed center director must serve on a full-time or significant
part-time basis.  He or she should have authority over appointments and
space within the center.  The portion of the salaries of the principal
investigator and other key individuals corresponding to the percentage
of time devoted to center administration can be included as an
allowable cost.

Costs of advisory committees, steering committees, and/or consultants
can also be included as an administrative activity.  Such committees
are not required, but it is strongly recommended that an effective
mechanism be proposed for obtaining independent advice to ensure
guidance of the center toward the attainment of its stated goals.  In
some cases, and at the request of the investigator, NCHGR may appoint
an oversight committee for the center in order to monitor progress and
the appropriate funding level.  It will not be necessary for applicants
to identify external advisory committee members before review of the

Alterations and Renovations

Funds needed for renovation of existing space may be requested, if such
space is needed to house core facilities or new or expanded research
activities. According to the Public Health Service (PHS) Grants
Management Policy Statement, detailed justification of the need, and
plans for, the use of the renovated space must be provided in the
application and renovation plans must be approved by NIH before funds
for this purpose can be released.  In order to ensure that any
renovations or alterations are done in a timely manner, (1) the request
for alterations and renovations must include a timetable, (2) the
renovation plans must be received by NCHGR no later than three months
after the date of funding of the grant, and (3) the work must be
finished within one year from the date of NIH approval of the plan.
The application must also outline any plans for accommodating the
project during the expected renovation period.  Such a plan should take
into account any need for accommodation of the program in temporary
space while the renovations are being done.  The University
administration's commitment to the proposed plan must be well

PHS policy also limits the dollar amount for alterations and
renovations to the lesser of $150,000 or 25 percent of total direct
costs over a three year period. Waivers to exceed this amount may be
sought by the NCHGR in exceptional cases. Costs of equipping renovated
laboratories may be included in the request if the items are directly
related to the research being conducted in the center.

Term of Support

The term of support for GESTEC programs is normally five years.

Post Award Management

During the course of the grant period and as progress toward the goals
of the Human Genome Project is made, the focus of the GESTEC grant will
likely change.  In order to ensure that GESTEC projects funded for five
years remain focused on appropriate goals and make sufficient progress,
frequent scientific and programmatic reviews will be conducted.  Yearly
meetings of the Directors of GESTEC projects and NCHGR staff will be
held to discuss recent achievements and expected future directions.  It
is expected that Pis of GESTEC grants will make the necessary
adjustments in scientific direction and management structure to
accommodate to changing requirements.  In the case of five-year awards,
applications for competitive renewal of support will be due at the
first submission date after the beginning of the fourth year.  In the
event that the review of this application is not favorable, this will
allow sufficient time for submission and review of a revised
application or for orderly phase-out of the grant.  Further support
will be for a three- to five-year period.

As noted above, GESTEC projects are encouraged to use advisory
committees as a means to obtain independent advice.  In renewal
applications, continued support of this activity must be justified by
the demonstration that the advisory committee mechanism has been used



NIH and policy requires that applicants for NIH clinical research
grants and cooperative agreements include minorities and women in study
populations so that research findings can be of benefit to all persons
at risk of the disease, disorder, or condition under study; special
emphasis must be placed on the need for inclusion of minorities and
subjects of appropriate gender in studies of diseases, disorders, and
conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear,
compelling scientific rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of the
study.  This information must be included in the form PHS 398 (rev.
9/91) in Sections 1-4 of the Research Plan AND summarized in Section 5,
Human Subjects.  Applicants are urged to carefully assess the
feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
(i.e., Native Americans (including American Indians or Alaskan
Natives), Asian/Pacific Islanders, Blacks, Hispanics).  Rationale must
be provided for studies on single minority population groups.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of diseases,
disorders, or conditions including, but not limited to, clinical

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include tissue from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including

If the required information is not contained within the application,
the review will be deferred until the information is provided.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be reflected in
assigning the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.


Applications are to be submitted on the grant application form PHS 398
(rev. 9/91) and will be accepted at the standard application deadlines
as indicated in the application kit.  Application kits are available
from most institutional offices of sponsored research from the Office
of Grants Inquiries, Division of Research Grants, National Institutes
of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
301/710-0267.  The title and number of the announcement must be typed
in Section 2a on the face page of the application.  The completed
original and three legible copies must be sent or delivered to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Additionally, two copies of the application must also be sent to:

Office of Scientific Research
National Center for Human Genome Research
Building 38A, Room 604
Bethesda, MD  20892


Upon receipt, applications will be reviewed for completeness by DRG
staff.  Incomplete applications will be returned to the applicant
without further consideration.

The regular NIH receipt dates for center grant and program project
applications and renewals are:  February 1, June 1, and October 1.
Applications will be evaluated for scientific merit by the Genome
Research Review Committee (GRRC) or an appropriate NCHGR review
committee constituted for the purpose of evaluating GESTEC grant
applications.  Site visits may be conducted as part of the review
process.  However, applicants should present a complete and
well-justified written proposal and not depend on site visits to
amplify their application.

Review criteria will include:

o Significance and originality of the research and methodological
o Feasibility of the research and adequacy of the experimental design;
o Training, experience, research competence and commitment of the
o Adequacy of the facilities and resources;
o Provisions for the protection of human subjects, the humane care of
animals and biosafety conditions.

Subsequent to evaluation by the initial review group, applications will
be reviewed by the appropriate National Advisory Council.


The following will be considered in making funding decisions:

o Quality of the proposed project as determined by peer review;
o Value of the proposed research and of the proposed technology
development for achieving the goals of the Human Genome Program;
o Adequacy of the proposed management structure;
o Nature and extent of the outreach program, including the adequacy of
any plans proposed for sharing and distributing data and resources in
a timely manner;
o Balance among projects within the NCHGR's grant portfolio;
o Availability of funds.


Written and telephone inquiries are strongly encouraged.  The GESTEC
grant proposal guidelines should be requested before preparing the
grant application.  The opportunity to clarify any issues or questions
from potential applicants is welcome.

Inquires regarding the GESTEC program may be directed to:

Jane L. Peterson, Ph.D.
Research Centers Branch
National Center for Human Genome Research
Building 38A, Room 610
Bethesda, MD  20892
Telephone:  (301) 496-7531

Specific questions regarding DNA sequencing/technology development may
be directed to:

Robert L. Strausberg, Ph.D.
Technology Development Program
National Center for Human Genome Research
Building 38A, Room 610
Bethesda, MD  20892
Telephone:  (301) 496-7531

Inquiries regarding fiscal matters may be directed to:

Ms. Jean Cahill
Grants Management Officer
National Center for Human Genome Research
Building 38A, Room 613
Bethesda, MD  20892
Telephone:  (301) 402-0733


This program is described in the Catalog of Federal Domestic Assistance
No. 93.172.  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 PHS grants
policies 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.


Return to PA Index

Return to NIH Guide Main Index

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.