[Federal Register Volume 62, Number 115 (Monday, June 16, 1997)]
[Notices]
[Pages 32621-32625]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-15744]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


National Human Genome Research Institute; Notice

    Request for application, low-cost, high-accuracy DNA sequencing 
technologies.

    NIH GUIDE, Volume 26, Number 16, May 16, 1997.
    RFA: HG-97-002.
    P.T. 34; K.W. 1215018, 0755045.
    National Human Genome Research Institute.
    Letter of Intent Receipt Date: August 1, 1997.
    Application Receipt Date: October 16, 1997.

Purpose

    The purpose of this Request for Applications (RFA) is to stimulate 
research on next-generation technologies that have the potential to 
reduce the cost of high-accuracy genomic DNA sequencing by at least an 
order of magnitude.

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 
RFA, Low-Cost, High-Accuracy DNA Sequencing Technologies, is related to 
several priority areas including cancer, heart disease and stroke, 
diabetes and chronic disability conditions, and maternal and infant 
health. Potential applicants may obtain a copy of ``Healthy People 
2000'' (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock 
No. 017-001-00473-1) through the Superintendent of Documents, 
Government Printing Office, Washington, DC 20402-9325 (telephone 202-
512-1800).

Eligibility Requirements

    Applications may be submitted by domestic for-profit and non-profit 
organizations, public and private, such as universities, colleges, 
hospitals, laboratories, companies, 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. Applications from 
foreign institutions will not be accepted. However, subcontracts to 
foreign institutions are allowable, with sufficient justification.

Mechanism of Support

    This RFA will use the National Institutes of Health (NIH) research 
project grant (R01), First Independent Research Support and Transition 
(FIRST) (R29) award, exploratory/developmental grant (R21), and program 
project (P01) mechanisms. The total project period for an R01 or P01 
application submitted in response to this RFA may not exceed three 
years. R29 grants are subject to the usual conditions for the FIRST 
awards. Exploratory/developmental (R21) grants will be limited to 
$100,000 direct cost per year for a maximum of three years (one year 
longer than NHGRI's standard R21 grant). The R21 grant mechanism is 
used to support highly creative approaches for which substantial 
preliminary data are not yet available. Specific information about the 
R21 grant mechanism can be found in the NHGRI Program Announcement PA-
97-045, ``Pilot Projects or Feasibility Studies for Genomic Mapping, 
Sequencing and Analysis'' (available from http://www.nhgri.nih.gov/
Grant____info/Funding/Research/pilotpa.html). The R21 grants are not 
renewable, but future project continuation is possible through other 
grant mechanisms such as the R01 or P01. Responsibility for the 
planning, direction, and execution of the proposed project will be 
solely that of the applicant. Awards will be administered under PHS 
grants policy as stated in the Public Health Service Grants Policy 
Statement. The anticipated award date is July 1, 1998. It is 
anticipated that another RFA related to DNA sequencing

[[Page 32622]]

technology will be issued by NHGRI next year.

Funds Available

    It is anticipated that approximately $5 million (total costs) will 
be available for this initiative in Fiscal Year 1998. NHGRI anticipates 
that projects at very different stages of development will be submitted 
in response to this RFA. Therefore, the size of awards may vary 
substantially; accordingly the number of grants funded may be as few as 
five or as many as 20, depending on the quality and scope of the 
applications received. Awards pursuant to this RFA are contingent upon 
the availability of funds for this purpose. The amount of funding for 
this solicitation may be increased if a large number of highly 
meritorious applications is received and if funds are available. Only 
applications found to be of high scientific merit will be considered 
for funding and all of the funds will not be spent if there are not 
enough highly meritorious applications. Any applicant planning to 
submit an application for more than $500,000 direct cost in any one 
year MUST contact the NHGRI staff listed under inquiries in order for 
the application to be accepted by NIH.

Research Objectives

Background

    NHGRI is currently engaged, along with several other federal, 
private, and international organizations, in a fifteen year research 
program called the Human Genome Project (HGP). The goals are to 
characterize the genomes of human and selected model organisms, to 
develop technologies to analyze the human genome, to examine the 
ethical, legal, and social implications of human genetics research, and 
to train scientists who will be able to utilize the tools and resources 
developed through the HGP to pursue biological studies that will 
improve human health.
    Significant progress toward completing these goals has been made in 
the past seven years, with several having already been achieved. The 
genetic mapping goals for both the human and the mouse have been met. 
Progress toward the human and mouse physical mapping goals is steady, 
with sufficient support in place to allow the achievement of these 
goals ahead of schedule. There has also been good progress toward 
meeting the sequencing goals. The genomic sequence of both E. coli and 
S. cerevisiae have been determined, the sequence of C. elegans is 
expected to be finished by 1998, and the complete sequence of D. 
melanogaster is expected to be finished shortly after the end of this 
century.
    As a result of recent improvements in sequencing technology and 
strategies, confidence is high that current technology, enhanced by 
foreseeable improvements, will be sufficient to complete a reference 
human genomic DNA sequence by the target date, 2005. To this end, pilot 
projects for large-scale production of human genomic DNA sequence were 
initiated in 1996. However, even with anticipated improvements, DNA 
sequencing is likely to remain too expensive to meet the scientific 
demand for sequence information. For example, additional sequencing 
will be needed to understand the sequence variation between individuals 
that is associated with individual differences in inherited 
susceptibility to disease. Such studies may require obtaining the 
sequence of much of the genomic DNA from large numbers (tens to 
possibly thousands) of individuals. Similarly, the utility of the 
initial complete genomic sequence of a few organisms for understanding 
their biology will increase the incentive to collect genomic sequence 
information for many other organisms to study their biology and 
evolutionary and symbiotic relationships. DNA sequencing of that 
magnitude can only be contemplated when sequencing techniques have been 
made considerably more cost-effective and robust than they are today, 
or will be in the foreseeable future. The purpose of this RFA is to 
stimulate the development of the technologies needed to achieve these 
goals.

Objectives and Scope

    Technologies for de novo sequencing and re-sequencing are needed. 
It should be noted that the conceptual distinction between these DNA 
sequencing technologies is not fundamental, but is instead a function 
of the limitations of the technologies as currently implemented. As 
novel methods are introduced and sequencing technologies mature, 
throughput and accuracy will increase and cost will decrease, and the 
distinction may not persist. However, at least for the present, the 
capabilities of these approaches and their potential near-term 
applications are sufficiently different to justify distinguishing 
between them for the purpose of this RFA.
    De novo sequencing involves determining DNA sequence without any 
prior knowledge of that sequence. The initial reference human sequence 
will be determined by de novo sequencing, as were the sequences of 
yeast, H. influenzae, M. genitalium, M. jannaschii, and E. coli. 
Technology for de novo sequencing will continue to be needed to 
determine the complete sequence of the genomes of numerous other 
organisms including pathogens, agriculturally important organisms, and 
those that have utility as model organisms and sources of 
pharmaceutical products.
    Technology is also needed for re-sequencing or rapidly comparing 
sequences to identify differences. Re-sequencing takes advantage of 
sequence information obtained from one sample, to design a more 
efficient approach to determining the sequence of another, similar 
sample. Today's re-sequencing technologies are effective for samples 
that are extremely similar (e.g., for identifying single-base 
differences in a particular gene isolated from two individuals). With 
additional development, however, the data quality and throughput of re-
sequencing technology my be improved, and expanded to allow 
determination of sequence in cases such as insertions or deletions 
relative to a reference sequence. Re-sequencing technology may be the 
most cost-effective way, for example, to collect the large amounts of 
sequence data from large numbers of individuals that is needed to 
understand the sequence variations associated with individual 
differences in inherited susceptibility to disease.
    This RFA seeks to stimulate research on next-generation 
technologies (including those for de novo sequencing, re-sequencing, or 
both) that have the potential to reduce the cost of high-accuracy 
genomic DNA sequencing by at least an order of magnitude. State-of-the-
art technology can currently generate de novo sequence data containing 
less than 1 error per 10,000 base pairs at a total cost (including 
machines, personnel, supplies, and overhead) of approximately $0.50 per 
base pair. The goal of research under this RFA will be to drive the 
total cost of obtaining accurate (<1 error in 10,000 bp) de novo 
sequence to well below $0.05 per base pair; re-sequencing should cost 
considerably less.
    Applications responsive to this RFA will include those designed to:
    Conduct research on novel scientific or engineering principles 
which have promise for being applicable to the development of cost-
effective DNA sequencing technologies;
    Study the application to DNA sequencing of principles that are well 
established in other fields of science or engineering, and that have 
strong potential for application to DNA sequencing, but for which such 
application may not have been demonstrated; and

[[Page 32623]]

    Further develop technologies for which proof of principle for DNA 
sequencing may already have been demonstrated, but for which 
substantial additional work is required to achieve high throughput and 
low cost for genomic sequencing (examples include mass spectrometry, 
sequencing by hybridization, and micromachined and micro-electro-
mechanical systems [MEMS]).
    This list is not intended to be all-inclusive, but instead to 
provide examples of responsive projects. Potential applicants who have 
questions about the responsiveness of specific ideas are encouraged to 
contact NHGRI staff listed under Inquiries before submitting an 
application.
    Applicants should directly address the advantages of the proposed 
approach over existing approaches, and justify their assertion that 
successful development of the technology will result in a ten-fold 
decrease in the cost of sequencing. Applicants proposing to develop 
technologies for which proof of principle for DNA sequencing has not 
yet been demonstrated should describe clearly the manner in which the 
proposed technology might be applied to sequencing. For such projects, 
it will be difficult to predict with confidence the cost of sequencing 
using the technology. It is therefore particularly important to present 
a clear conceptual overview of the entire system in which the 
technology would be used and if possible to estimate the cost of 
developing, producing, and using such a system.
    Current DNA sequencing approaches require some combination of 
steps, including the isolation of DNA from biological samples, 
biochemical amplification of the DNA within the sample, incorporation 
of fluorescent label into the sample, determination of the nucleotide 
sequence of each sample, ``assembly'' of data from numerous overlapping 
and redundant determinations into a continuous dataset, and analysis of 
the sequence data. As new technologies are developed, some or all of 
these steps may still be required. Research on all of these steps, and 
particularly on the integration of steps into a continuous process, 
will be supported under this RFA. For projects whose aim is to develop 
integrated systems, applicants should address the throughput of the 
various system components, and how the entire system will support the 
achievement of the cost and quality goals of this RFA.
    The RFA will also accept applications to develop computational 
tools needed in support of systems or in conjunction with components 
eligible for funding under this RFA. Support for development of 
computational tools may be included as part of the technology 
development application. An application to develop computational tools 
that is submitted independently of a proposal to develop hardware 
systems should describe how the results of the independent research 
will be integrated with existing or planned technology.
    The following types of research will NOT be supported under this 
RFA: projects to improve slab gels, microchannels, and capillary array 
electrophoresis, in systems in which the well-to-read distance is 
measured in tens of centimeters. This type of research is currently 
receiving support from NHGRI as a result of recent RFAs. However, NHGRI 
continues to encourage this type of technology development for DNA 
sequencing; applications for such studies should be submitted under the 
Program Announcement PA-97-044 ``Technologies for Genomic Mapping, 
Sequencing, and Analysis'' (available from http://www.nhgri.nih.gov/
Grant__info/Funding/Research/techpa.html).

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 sub-populations 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, Volume 23, Number 11, March 18, 1994.

Special Requirements

    Statement of milestones: It has been the experience of NGHRI that 
technology development projects that establish a clear statement of 
their milestones, and benchmarks by which attainment of those 
milestones can be measured, make more rapid progress toward achieving 
their short- and long-range goals. Therefore, applicants should present 
a clear timetable for the achievement of specific milestones, and 
should define the benchmarks by which progress toward those milestones 
will be measured. Both the milestones and benchmarks should be stated 
as quantitatively as possible.
    Dissemination of the results of technology development research: 
Proposals should address the issue of access by groups other than the 
developers to any instruments or software developed through this 
program.
    Post-award management: During the course of the grant period, 
technologies will improve and the rate of progress and focus of work 
supported by the grants may change. It is expected that the principal 
investigators will make any necessary adjustments in scientific 
direction to accommodate the changing environment. During the award 
period, the principal investigators may be invited to meet with NIH 
program staff in Bethesda, MD, or at the grantee site, to review 
scientific progress. Other scientists external to and knowledgeable 
about these studies may also be invited to participate. Applicants 
should include travel funds for the P.I. to meet annually with NIH 
staff in the Washington, D.C. area, should such meetings be advisable.
    Special human subjects issues: Recently, it has become evident that 
special human subjects issues are raised by the large-scale sequencing 
of human genomic DNA because large amounts of DNA sequence information 
from single individuals may be generated. Similar issues can be 
anticipated in projects in which sequence variations are identified in 
individuals. The NHGRI and the DOE have recently issued a document, 
``Guidance on Human Subjects Issues in Large-Scale DNA Sequencing'' to 
address these issues. This document can be found on the NHGRI web site 
at (http://www.NHGRI.nih.gov/Grant__infor/Funding/Statements/
large__scale.html). Any application submitted in response to this RFA 
that includes a plan to sequence at least 1 megabase of human DNA 
during the period of the grant, or to determine a large number of human 
sequence polymorphisms, in the context of testing the technology under 
development, should address these special human subjects issues.

Letter of Intent

    Prospective applicants are asked to submit, by August 1, 1997, 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

[[Page 32624]]

other key personnel and participating institutions, and the number and 
title of the RFA in response to which the application may be submitted. 
Although a letter of intent is not required, is not binding, and does 
not enter into the review of a subsequent application, it can help 
establish an early dialogue with NHGRI staff, and the information that 
it contains allows NHGRI 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: Jeffery A. Schloss Ph.D., 
Division of Extramural Research, National Human Genome Research 
Institute, Building 38A, Room 614, Bethesda, MD 20892-6050, Telephone: 
(301) 496-7531, FAX: (301) 480-2770, E-mail: Jeff__S[email protected].

Application Procedures

    The research grant application form PHS 398 (rev. 5/95) is to be 
used in applying for these grants. These forms are available at most 
institutional offices of sponsored research; 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, e-mail: [email protected]; and from 
the program administrator listed under Inquiries.
    The RFA label available in the 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.
    Submit a signed, typewritten original of the application, including 
the Checklist, and three signed photocopies, in one package to: 
Division of Research Grants, National Institutes of Health, 6701 
Rockledge Drive, Room 1040, Bethesda, MD 20892-7710, Bethesda, MD 20817 
(for express/courier service).
    At the time of submission, two additional copies of the 
application, including appendices, must also be sent to: Rudy Pozzatti, 
Ph.D, Office of Scientific Review, National Human Genome Research 
Institute, Building 38A, Room 613, Bethesda, MD 20892-6050.
    Applications must be received by October 16, 1997. If an 
application is received after that date, it will be returned to the 
applicant without review. The Division of Research Grants (DRG) 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 DRG 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. The applicants should 
also ensure that their revised applications respond to the review 
criteria by which applications received in response to this RFA will be 
evaluated.

Review Considerations

    Upon receipt, applications will be reviewed for completeness by DRG 
and for responsiveness to the RFA by NHGRI program staff. Incomplete 
applications will be returned to the applicant without further 
consideration. If the application is not responsive to the RFA, NIH 
staff will contact the applicant to determine whether to return the 
application to the applicant or submit it for review in competition 
with unsolicited applications at the next review cycle.
    Those applications that are complete and responsive will be 
evaluated for scientific and technical merit in accordance with the 
criteria stated below by an appropriate peer review group convened by 
the NHGRI. 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 and assigned a priority score. All applications will receive 
a second level of review by the National Advisory Council for Human 
Genome Research.
    Review criteria will include:
    Scientific and technical merit of the proposed research;
    Potential of the proposed technology to achieve the cost and 
quality goals of this RFA;
    Appropriateness and adequacy of the experimental approach and 
methodology proposed to carry out the research;
    Adequacy with which critical technical issues have been identified, 
and solutions proposed;
    Appropriateness of the timeline and milestones established by the 
investigator to ensure continued progress toward the specific aims, and 
adequacy of the specific benchmarks proposed for measuring progress 
toward the milestones;
    Adequacy of plans to integrate the proposed technology with other 
components of a process required to accomplish DNA sequencing;
    Qualifications and research experience of the principal 
investigator and staff in the area of the proposed research;
    Availability of the resources necessary to perform the reseach;
    Adequacy of plans for dissemination of technical advances and 
software tools developed under grant support:
    Appropriateness of the proposed budget and duration in relation to 
the proposed research; and
    Adequacy of plans to protect human subjects and to include women 
and minorities, if applicable.
    For R21 applications, preliminary data are not required. However, 
the applicant does have the responsibility for developing a sound 
research plan and for presenting any other information that can be 
considered as evidence of feasibility.

Award Criteria

    Factors that will be used to make award decisions are:
    Quality of the proposed project as determined by peer review:
    Balance among the projects received in response to the RFA in 
addressing different experimental approaches and their complementarity 
to other ongoing efforts, and value of the proposed research for 
achieving the goals of the National Human Genome Research Institute;
    Adequacy of plans to manage and share data, resources and 
technology in a timely manner; and
    Availability of funds.

Inquiries

    Inquiries concerning this RFA are encouraged. The opportunity to 
clarify any issues or questions from potential applicants is welcome.
    Direct inquiries regarding programmatic issues to: Jeffery A. 
Schloss, Ph.D., Division of Extramural Research, National Human Genome 
Research Institute, Building 38A, Room 614, Bethesda, MD 20892-6050, 
Telephone: (301) 496-7531, FAX: (301) 480-2770, E-mail: 
Jeff__S[email protected].
    Direct inquiries regarding fiscal matters to: Ms. Jean Cahill, 
Grants Management Office, National Human Genome Research Institute, 
Building 38A, Room 613, Bethesda, MD 20892-6050, Telephone: (301) 402-
0733, FAX: (301) 402-1951, E-mail: Jean__C[email protected].

[[Page 32625]]

Authority and Regulations

    This program is described in the Catolog of Federal Domestic 
Assistance No. 93.172. Awards are made under authorization of the 
Public Health Service Act, Title IV, Part A (Pub. L. 78-410, as amended 
by Public Law 99-158, 42 U.S.C. 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.
    The PHS strongly encourages all grant 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, any 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.

(Catalogue of Federal Domestic Assistance Program No. 93.172, Human 
Genome Research)
Elke Jordan,
Deputy Director.
[FR Doc. 97-15744 Filed 6-13-97; 8:45 am]
BILLING CODE 4140-01-M