PAR-99-052: ADVANCED X-RAY DETECTORS FOR SYNCHROTRON-BASED STRUCTURAL BIOLOGY

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