Charles J. Arntzen charles.arntzen@asu.edu

1. Case studies of NIH-funded Collaborative Research Programs • Charles J. Arntzencharles.arntzen@asu.edu

2. Biotech Information Technology Sputnik

3. What national factors are driving large projects in government agencies? • 1. Less industry work in basic science; more focus on development. • 2. More complex outcome needs; technology is more sophisticated. • 3. Universities are learning more about team research (led by a few universities)

5. New Molecular Entities “Biotech drugs”

6. NIH funding trends

7. LARGE-SCALE COLLABORATIVE PROJECT AWARDS Release Date: February 28, 2001 RFA: RFA-GM-01-004 National Institute of General Medical Sciences The purpose of this RFA is to reannounce the National Institute of General Medical Sciences (NIGMS) program of “Large-Scale Collaborative Project Awards”, (commonly called large Glue Grants) • What is a “Large Scale Project” in government/academic terms? • Complex • Poorly defined project tasks, task relationships, project environment and outcomes. • New technologies or new integration of existing technologies. • Large number of stakeholders and institutions. • Long timelines.

8. National Human Genome Research InstituteNational Institutes of Health 
U.S. Department of Health and Human ServicesApplicantsWanted:Funding Now Available for New Phase of NHGRI Large-Scale Sequencing ProgramThe National Human Genome Research Institute (NHGRI) has started the new year with a bang, offering about $90 million in new funding opportunities to continue its support of large genome sequencing and analysis centers that are the hallmark of its flagship Large-Scale Sequencing Program. The new grants place greater emphasis on the health and clinical applications of DNA sequencing and the creation of software tools that researchers can use to analyze immense data sets made possible by new sequencing platforms.Applications are due March 3, 2011, and awards for up to four years of funding will be made in the fall of 2011.Over the last decade, the NHGRI Large-Scale Sequencing Program has been an engine for historic scientific discovery. In addition to successfully completing the human genome sequence, the program has also sequenced the genomes of bacteria, fungus, mice, rats and chimpanzees, humans' closest living relative. Sequencing the genomes of these organisms provides researchers critical insights into human biology.The program has provided researchers with resources to better understand DNA changes in health and disease. These include detailed maps of genetic variation, efforts to identify the parts of the genome that affect the function of genes and medical sequencing projects to uncover genome changes that lead to inherited disease and common diseases such as cancer. Thanks to more efficient and cheaper next generation sequencing methods, the program has also contributed a great deal to understanding the human microbiome, the genomes of the microbes that live in and on the human body and changes in the epigenome, chemical marks that contribute to how the human genome may function and contribute to disease."We still have much to learn. These grants target efforts to understand the genomic basis for disease and ways to make sequence data relevant to individual patients and their doctors," said Adam Felsenfeld, Ph.D., program director for NHGRI's Large-Scale Sequencing Program. "At the same time, the program will continue to define state-of-the-art, large-scale sequencing and be a major contributor to the knowledge base that scientists need to make future advances in biomedicine and basic biology."Currently, NHGRI's Large-Scale Sequencing Research Network, a major component of the sequencing program, is comprised of three sequencing centers: the Broad Sequencing Platform, The Broad Institute, Cambridge Mass.; the Human Genome Sequencing Center, Baylor College of Medicine, Houston; and The Genome Center, Washington University School of Medicine, St. Louis.NHGRI has issued Request for Applications (RFA) for the Large-Scale Sequencing Program in four areas:Three awards will be made to Large-scale Genome Sequence and Analysis Centers, which will address the genomic basis of complex disease. During the next four to five years, for example, such centers will sequence thousands of human genomes from individuals in specific disease cohorts and continue efforts to catalog all the genetic mutations involved in cancer. The Genome Sequencing and Analysis Centers RFA is available at Genome Sequencing and Analysis Centers (U54) [grants.nih.gov]. 
Up to two centers for Mendelian disorders will be established to find genes responsible for the majority of rare, single-gene (Mendelian) disorders. It is now feasible to find these genes located in the one percent of the genome that code for proteins, known as the exome. The center(s) will identify appropriate samples in the research community, obtain the proper informed consent for genomic sequencing and coordinate analysis efforts among disease research communities. The Mendelian Disorders Genome Centers RFA is available at Mendelian Disorders Genome Centers (U54) [grants.nih.gov].
Clinical Sequencing Exploratory Research Projects will be investigator-initiated efforts that apply what has been learned from NHGRI medical sequencing activities to the care of individual patients. This program will stimulate the use of DNA sequence information in the clinic to bridge the gap between discovery and patient care. The Clinical Sequencing Exploratory Research RFA is available at Clinical Sequencing Exploratory Research (U01) [grants.nih.gov].
The Informatics Tools for High-throughput Sequence Analysis funding opportunity will support the creation of robust, well-documented and well-supported computer software programs that act as informatics tools to analyze DNA sequence data. The biomedical research community needs new tools to overcome bottlenecks they encounter while analyzing genomic data. There are two RFA's for Informatics Tools for High-Throughput Sequencing Analysis, one for academic institutions and one for small businesses. They are available at Informatics Tools for High-Throughput Sequence Data Analysis (U01) [grants.nih.gov] and Informatics Tools for High-Throughput Sequence Data Analysis (SBIR) (R43/R44) [grnats.nih.gov]. 
The shared deadline to apply for the RFAs above is March 3, 2011.Posted: January 10, 2011Comments:Libby Hikinf (January 10, 2011, 18:50) Have you visited grantwatch.com and clicked Health on the left side. Be sure to choose your state of interest on the home page. Grants are described in full detail. To see how grants are posted Tour the Archives. To view current grants, subscribe. 
Name or alias (optional):Comment (required):5000 characters remaining. NIH research centers often have a singular objective (example: Human genome project)

9. Small projects: fit the “university style.” Take a piece of a large problem and probe it deeply using graduate students, technicians, postdocs. The discovery paradox – we can define efforts on small projects for 1-2 years, but not longer. But, big projects need milestones and decision gates. Need rewards for faculty/groups who are successful. Problems: defining the project and managing it. Project risk = complexity, innovativeness, projet definition, management experience, regulatory environment, budget uncertainty.

10. NIH funding trends ASU average project is $254,704 for 23 months.

11. NIH funding trends

12. Five factors for success in large projects: • Get an idea • Sell the idea • Ramping a project up • Steady state mode management • Close down management • Need different people for each, and incentives for each….

13. Our STI CRC has three projects and two cores (administrative and production). The Central Theme is to use plant biotechnology as a very cost-effective manufacturing platform to biomanufacturemicrobicides and subunit vaccines. ASU. Mucosal immunization using lectin fusions and VLPs with epitope display. Focus on achieving vaginal immune responses. Mapp. Monoclonal antibody expression in plants, formulation for vaginal delivery. University of Maryland. Human clinical trials Kentucky Bioprocessing, Inc.mAB manufacturing; final GMP “polish to fill” for VLP vaccines.

14. The idea: plants can produce vaccines that elicit mucosal responses. • Tacket, C.O., Mason, H.S. , Losonsky, G., Estes, M.K., Levine, M.M. , Arntzen, C.J. . 2000. Human immune responses to a Novel Norwalk virus vaccine delivered in transgenic potatoes. The Journal of Infectious Diseases. 182:302-305.

15. Idea 2: Plant can produce monoclonal antibodies www.research.bayer.com

16. Concept 3: Plant Made Therapeutics can be made at commercial scale.

17. CVD Close Down Phase Validate the idea in a clinical trial. Close collaboration between: • Carol Tacket (University of Maryland Center for Vaccine Development) • Melissa Herbst-Kralovetz (ASU, with assistance from Brooke Hjelm and DaaimahLaVigne) • Preclinical studies: • A panel of TLR agonists (TLR3, 5, 7, 7/8 and 9 agonists) was evaluated in conjunction with Norwalk virus capsid protein (NVCP) virus-like particles (VLP) • Following intranasal (IN) immunization, significant levels of serum IgG, IgG1 and IgG2a production are induced in response to NVCP co-delivered with several TLR agonists relative to controls. • Significant levels of vaginal IgA was only produced in IN immunization with GARD and CpG-ODN • GARD and CpG-ODN agonists were the only adjuvants to induce significant levels of IgA at nasal, bronchoalveolar, salivary and gastrointestinal surfaces • IL-2 secretion was observed following recall stimulation in all of the IN immunization groups These results have lead to a plan to use intranasal imunization using VLPs plus TLR agonist in human trials.

18. Specific Aim 1: Administrative oversight Project 1 Specific Aim 2: Prepare INDs for Project 3 Project 2 Specific Aim 3: Assemble a portfolio of intellectual property and develop a freedom to operate strategy for plant-made microbicides and mucosal vaccines. Project 3 Specific Aim 4: Create a design and development team for plant-made microbicides and mucosal vaccines. Production Core Specific Aims The long-range objective of the AzBio Center is to develop safe and effective plant-made microbicides and mucosal vaccines that prevent transmission in the vagina. The Center’s hypothesis is that sufficient concentrations of mucosal antibodies can exclude sexually transmitted pathogens in the vagina, resulting in prevention of transmission. Goals of the Administrative Core are: (a) provide scientific support to the AzBio Center's cores and projects to enable evaluation of the hypothesis; (b) provide regulatory, intellectual property and product development expertise for plant made microbicides and mucosal vaccines. Although the data collected by the Center are surrogate measures of protection in humans, this information (when coupled with active and passive immunization studies in animals) will enhance the likelihood of success in human efficacy trials. Functional relationships of the Administrative Core

19. The “Big Picture” on large projects…. • How do you develop effective management plans that cover all the key issues (financial, training and supervision, compliance)? • How do you encourage interdisciplinary research in academia where one field of research seems to be a natural way of moving forward? • What steps should be taken when a collaborative project comes to an end? How do you plan to end a “big project”…..