ADVANCED X-RAY DETECTORS FOR SYNCHROTRON-BASED STRUCTURAL BIOLOGY

Release Date:  January 26, 1999

PA NUMBER:  PAR-99-052

P.T.

National Center for Research Resources
National Institute of General Medical Sciences

Application Receipt Date:  March 11, 1999

PURPOSE

It is the purpose of this Program Announcement (PA) to stimulate advanced
detector development, particularly for synchrotron-based X-ray crystallography
applications, and their effective integration into high throughput macromolecule
structure-determination systems.  The Small Business Innovation Research (SBIR)
program has supported such development efforts; however, the extent of such
support has been limited.  Recently, the NIH has announced that applicants may
request a larger budget and period of support if necessary for completion of the
project (see NIH Guide for Grants and Contracts, February 13, 1998, at
http://www.nih.gov/grants/guide/notice-files/not98-014.html).  This PA provides
a means within the SBIR program to more fully accommodate the high expenses
involved in such detector development, particularly multidisciplinary staffing,
custom-fabrication, and long-term project support through the prototype
development stage.

Both the 1992 and 1997 BioSync reports
(http://www.ornl.gov/hgmis/biosync/intro.html) identified fast, efficient X-ray
detectors as the most critical technological need for effective utilization of
synchrotron radiation resources.  Charge coupled device (CCD) area detectors are
rapidly infiltrating synchrotron-based X-ray crystallography facilities because
of their readout time and resolution advantages over imaging plates.  As larger
CCD arrays become available the storage-phosphor imaging plate system's large
sensing area advantage will erode as well.  However, even current CCD detectors
cannot keep up with the prodigious diffraction data flow from today's synchrotron
X-ray sources.  Detector linearity and readout times are limiting data
acquisition at a time when the most efficient utilization of costly beamtime is
essential.  Therefore, the development of new generations of detectors must be
pursued with the intention of their rapid commercialization.  In addition to
advances in CCD detector technology, two technologies currently in the
development stage, pixel-array detectors (PAD) and detectors based on amorphous
silicon, appear to offer millisecond readout times, wide dynamic range, well-
characterized statistical characteristics, and stability during long exposure
times.  Other types of detectors, perhaps based on superconductor technology may
also become competitive.

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 PA, Advanced X-ray Detectors for
Synchrotron-Based Structural Biology, is related to several of the priority
areas.  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

Eligibility requirements are described in the OMNIBUS SOLICITATIONS.  Any small
business, independently owned and operated by United States citizens or permanent
resident aliens may apply.  The business must be organized for-profit, cannot be
dominant in its field of expertise, and must have its principal place of business
in the United States.  Including any affiliates, the company can be the employer
of no more than 500 people.

MECHANISM OF SUPPORT

Support for this PA is through the SBIR mechanism, which is a set-aside program.

Applications can be submitted for support as Phase I SBIR (R43) or Phase II SBIR
(R44) grants; or under the SBIR FAST-TRACK option as described in the OMNIBUS
SOLICITATIONS.  Phase II applications in response to this PA will only be
accepted as competing continuations of previously funded NIH Phase I SBIR awards. 
The Phase II proposal must be a logical extension of the Phase I research.

Information on the FAST-TRACK process and the OMNIBUS SOLICITATIONS are available
at: http://www.nih.gov/grants/funding/sbir.htm.

Awards will be administered under NIH grants policy as stated in the NIH Grants
Policy Statement, issued October 1, 1998, available at
http://www.nih.gov/grants/policy/nihgps/.

It is expected that two to four awards will be made in FY99, and $2 million from
the SBIR set-aside will be designated for this purpose.  The number of awards
will be dependent upon receipt of a sufficient number and diversity of
applications with high scientific merit.

RESEARCH OBJECTIVES

X-ray crystallography provides the structural foundation of biomedical science. 
Our understanding of the catalytic, structural, and control roles of proteins and
nucleic acids is based on our ability to relate, at atomic levels of detail,
macromolecular structure to function.  X-ray crystallography research is now
making an important transition from the use of laboratory systems to synchrotron-
based X-ray facilities, driven by the higher data quality, the capability of
producing complete data sets from microcrystals, and by high data acquisition
rates.  Recent efforts to acquire phasing and time-dependent structural
information have absolute requirements for synchrotron X-ray sources.  The demand
for synchrotron beamline time has increased enormously since 1992 which has led
to substantial over-subscription of these facilities.  It is therefore essential
that all aspects of synchrotron crystallography research be optimized.  Numerous
reports have emphasized that detectors, their readout characteristics, and
associated data storage are weak links in the crystallographic data acquisition
process.

The objective of this PA is to support the development of advanced detectors for
synchrotron X-ray research, their implementation in functioning prototypes, and
their ultimate commercialization and integration into high throughput
synchrotron-based X-ray crystallography beamlines.  Such advances in detector
technology will, for example, enable acquisition of extensive series of
anticancer drug-protein target structures.  This PA recognizes that such
technology development efforts require a sustained effort by multidisciplinary
groups and involve utilization of expensive fabrication processes.

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 has 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.

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

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 clear and compelling 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://www.nih.gov/grants/guide/notice-files/not98-024.html.

APPLICATION PROCEDURES

This PA must be read in conjunction with the OMNIBUS SOLICITATION OF THE PUBLIC
HEALTH SERVICE FOR SMALL BUSINESS INNOVATION RESEARCH GRANT (SBIR) APPLICATIONS. 
All of the instructions within the omnibus solicitation apply with the following
exceptions:

o Special Receipt Date
o Initial review convened by the Center for Scientific Review
o Additional review considerations
o More flexible time and budget specifications

Applications received in response to this PA are to be prepared as described in
the OMNIBUS SOLICITATIONS for the SBIR program.  OMNIBUS SOLICITATIONS are
available electronically through the NIH, Office of Extramural Research "Small
Business Funding Opportunities" website:
http://www.nih.gov/grants/funding/sbir.htm.  Hard copies, subject to
availability, may be obtained from the PHS SBIR Solicitation Office, phone (301)
206-9385; FAX (301) 206-9722; email a2y@cu.nih.gov.  Information helpful for the
preparation of the application can be obtained at:
http://www.nih.gov/grants/funding/sbirsttradvice.htm.

Applications in response to this PA are to be submitted on the applicable grant
application forms as follows:

SBIR Phase I þ PHS 6246-1 (1/98)
http://www.nih.gov/grants/funding/sbir1/SBIR.htm

SBIR Phase II þ PHS 6246-2 (1/98)
http://www.nih.gov/grants/funding/sbir2/index.htm

The application forms are also located in the back pages of the OMNIBUS
SOLICITATIONS.  Applications will be accepted on March 11, 1999.  The PA title
and number must be typed in line 2 on the face page of the application form.

If an application is received after the application receipt 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 PA that is essentially the
same as one currently pending review, unless the applicant withdraws the pending
application.  This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an introduction
addressing the previous critique.

SBIR projects submitted for Phase II support in response to this PA must contain
a successful Phase I feasibility prior to a Phase II award.  Applications can be
submitted for Phase I or Phase II support, or as a combined Phase I and II (Fast
Track).  Phase II applications will only be accepted as continuations of
previously funded Phase I grants.  The Phase II proposal must be a logical
extension of the Phase I research, but not necessarily a Phase I supported in
response to this PA.

PHASE I:  Demonstration of feasibility for the next step in the detector
development process.  It would be expected, but not required, that Phase I would
support relatively early discovery and evaluation projects.  Phase I projects
should focus on research required to advance to the next stage in the development
process and present a plan and time line outlining accomplishments and milestones
to be achieved at each stage.  Applicants should emphasize innovative aspects of
the detector design and its probable capabilities.  Applicants should include a
general plan for the complete development project and clearly state how the
proposed Phase I fits into this plan.

For this PA, projects normally will be supported in Phase I for up to two years
with a budget of up to $750,000, total costs, per year.  Larger budgets could be
considered if required for conduct of the research and appropriately justified
in the application.  The second year of support will be contingent upon NCRR
programmatic evaluation to ensure that investigators are accomplishing milestones
and time lines presented in the original application.

PHASE II: Full prototype development leading to Phase III commercialization. 
Support can be requested for development work leading to full-scale prototypes,
their testing at synchrotron beamlines, development of electronics and software
for data transfer, and evaluation of user interfaces.

It is not possible for the SBIR program to provide full funding for the
commercialization of advanced detectors.  Thus, a co-funding partner or other
sources of support should be identified prior to a Phase II award.  The funds
and/or resources to be dedicated to activities directly related to the
commercialization of detectors by the partner/company, including details of the
commitment contingencies, must be clearly specified in the application. 
Appropriate documentation of the commitment must be provided.

Phase II awards can be for up to four years and $750,000 total costs, per year. 
As with Phase I, requests for larger budgets may be considered, and support for
years two to four is dependent upon NCRR programmatic review of progress
including achievement of proposed milestones and evaluation of additional
information not required in the original application.

FAST TRACK: Applications may be submitted for combined Phase I and Phase II FAST
TRACK consideration as described in the OMNIBUS SOLICITATIONS.  However, due to
the complex nature of detector technology development, it is recommended that
only well defined and more advanced projects be proposed for support through this
mechanism.

Phase I, FAST TRACK applications must specify clear, measurable goals that should
be achieved prior to Phase II funding.  Failure to provide measurable goals in
the Phase I application and/or sufficient detail in the Phase II application may
be sufficient reason for the peer review committee to exclude the Phase II from
consideration.  Special provisions described in this PA pertaining to Phase I and
Phase II also apply to FAST TRACK applications.

An additional requirement of the FAST TRACK mechanism is the commitment of funds
and/or resources for commercialization of the product to ensure a rapid
transition to the market.  These funds are in addition to the funds required for
research support in Phase II described above.  A Commitment Appendix to the Phase
II application must be included which specifies the amount of funds and/or nature
of resources that will be dedicated to the SBIR project and must describe those
activities.  If such commitment is from an investor or partner organization, a
copy of the agreement or a letter describing the details of the agreement must
be provided.  The small business concern must also submit a concise Product
Development Plan (limited to five pages) as an Appendix to the Phase II
application addressing the four areas described in the instructions for FAST
TRACK applications in the OMNIBUS SOLICITATIONS.

Potential applicants are encouraged to contact program staff for guidance and to
read the advice and information on the web sites.  However, responsibility for
planning, direction, and execution of the proposed research will be solely that
of the applicant.

The completed original application and two legible copies must be sent or
delivered 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)

The submission, review, and award schedule for this Program Announcement is:

Application Receipt Date:  March 11, 1999
CSR Committee Review:      June/July 1999
NCRR Council Review:       September 1999
Earliest Funding:          September 1999

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the CSR for completeness and by
NCRR for responsiveness.  Applications not adhering to application instructions
described above and those applications that are incomplete or non-responsive will
be returned to the applicant without review.

Applications will be reviewed for scientific and technical merit and the
documented ability of the investigators to meet the RESEARCH OBJECTIVES of this
PA by an initial review group convened by the CSR, 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 the applications under review, will be discussed, assigned a priority
score, and receive a second level review by the appropriate national advisory
council.

Review Criteria

Review criteria are essentially as described in the OMNIBUS SOLICITATIONS with
the additional considerations specified for this PA.

o  The soundness and technical merit of the proposed approach.

o  The qualifications of the proposed principal investigator, supporting staff,
and consultants.

o  The scientific, technical, or technological innovation of the overall detector
development project.

o  The potential of the proposed research for commercial application.

o  The appropriateness of the budget requested.

o  The adequacy and suitability of the facilities and research environment.

o  Where appropriate, the adequacy of assurances detailing the proposed means for
(a) safeguarding human or animal subjects and/or (b) protecting against or
minimizing any adverse effect on the environment.

o  Potential impact of the developed technology on structural biology research.

Phase I applications should specify clear, measurable goals (milestones) that
should be achieved prior to initiating Phase II.  Failure to provide clear,
measurable goals may be sufficient reason for the initial review group to judge
the application non-competitive.

The initial review group will also examine the adequacy of plans to include both
genders and minorities and their subgroups as appropriate for the scientific
goals of the research, plans for the recruitment and retention of subjects; the
adequacy of plans for including children as appropriate for the scientific goals
of the research, or justification for exclusion; the provisions for the
protection of human and animal subjects and the safety of the research
environment.

AWARD CRITERIA

Funding decisions for Phase I or Phase II applications will be based on the
quality of the proposed project as determined by peer review, program priority,
potential impact on structural biology research, and availability of funds.

FAST TRACK, Phase II applications may be funded following submission of the Phase
I progress report and other documents necessary for continuation.  Phase II
applications will be selected for funding based on the initial priority score,
NCRR's assessment of the Phase I progress and determination that Phase I goals
were achieved, the project's potential for commercial success, and the
availability of funds.

INQUIRIES:

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

Direct inquiries regarding programmatic issues to:

Dr. Karl A. Koehler 
Biomedical Technology
National Center for Research Resources
6705 Rockledge Drive, Room 6160, MSC 7965
Bethesda, MD 20892-7965
Telephone: (301) 435-0755
FAX: (301) 480-3659
Email:  Karlk@ep.ncrr.nih.gov
Email:  BTAdir@ep.ncrr.nih.gov

Dr. John Norvell
National Institute of General Medical Sciences
Building 45, Room 2AS-13B
Bethesda, MD  20892-6200
Telephone: (301) 594-0533
FAX: (301) 480-2004
Email:  jn18a@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Joellen Harper
Office of Grants and Contracts Management
National Center for Research Resources
6705 Rockledge Drive, Room 6086, MSC 7965
Bethesda, MD 20892-7965
Telephone (301) 435-0844
Email:  harperj@ncrr.nih.gov

Ms. Marcia Hahn
Grants Administration Branch
National Institute of General Medical Sciences
Building 45, Room 2AN-24C
Bethesda, MD  20892
Telephone (301) 594-5135
Email:  hahnm@nigms.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.371.  Awards are made under authorization of the Public Health Service Act,
Title III, 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 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, 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.

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