Principal Investigator/Program Director (Last, First, Middle): (BERWICK, William Herllly RESOURCES FOR MARINE ALGAL CONSULTANT VALERIE PAUL FACILITIES: Specify the facilities to be used for the conduct of the proposed research. indicate the performance sites and describe capacities, pertinent capabilities, relative proximity, and extent of availability tothe project. Under "Other," identify support services such as machine shop, electronics shop, and specify the extent to which they will be available to the project. Use continuation pages if necessary. Laboratory: The Smithsonian Marine Station is a research facility located on the intracoastal waterway in Fort Pierce, FL. Laboratory space is available in a laboratory/office building (8000 sq ft). My individual research space is available in a laboratory (220 sq ft) that houses chemical instrumentation, computers, analytical balances and all supplies for isolating and quantifying marine natural products. A multi-user chemistry laboratory (420 sq ft) is available for additional chemical research, and another shared laboratory houses freezers, freeze drier, speed-vac, ovens and other laboratory equipment. A multi- user molecular laboratory and facilities for microscopy (confocal, light, SEM, TEM) are also available. Clinical: N/A Animal: A wet laboratory is available with filtered, recirculating sea water supply for holding marine organisms. Temperature-controlled aquaria and incubators are also in the wet laboratory. Computer: My personal and laboratory computers and a general use computer laboratory with 6 computers and printers are available. All are of recent vintage and have the normal complement of software (Microsoft Office and necessary statistical, graphics and other software packages). All computers are connected to dedicated ink-jet/laserjet printers and are networked to color laser printers within the computer laboratory. Office: I have sufficient office space (200 sq ft) for computer, administrative and research files, books, and other research materials. Additional office space within the main laboratory/office building provides appropriate desk and computer environments for students, postdoctoral associates, and research assistants. Other: Administrative support is available (one administrative assistant). Research boats, SCUBA gear, and trucks and vans for collection of organisms from the field are available. The Marine Station has a small machine shop to support the research and field work and five full time research assistants to support field and laboratory research. Major Equipment: Chemical laboratory: Two HPLC systems (Waters Breeze system with UV/Vis detector and Perkin Elmer system with PDA detector and autosampler), Shimadzu GC/MS, rotary evaporators, freeze drier, speed-vac, analytical balances. Molecular and other laboratories: electrophoresis equipment for the analysis of DNA, RNA, and isozymes; gel imager; thermal cyclers for DNA amplification; ultra-, high- and low-speed centrifuges and microcentrifuges for molecular, cellular, and tissue separations; compound and dissecting microscopes for analyzing specimens, ultra-cold freezer, dewar flask and dry-shipper for preserving samples; freezers and refrigerators; sonicator and several types of homogenizers for preparing samples; incubators, ovens and water baths; fume hoods, shakers, pH meters; UV/VIS spectrometer; Dissecting and compound microscopes with photographic and video capabilities; confocal microscope; scanning and transmission electron microscopes. PHS 398 (Rev. O5/01) Page Resources Format Page Principal investigator/Program Director (Last, First, Middle): GERWICK, William þÿH ¬l`l[y A. SPECIFIC AIMS The over-arching goal of this work is to discover new lead compounds from Panamanian plants and algae for the treatment of several tropical diseases and cancer, employing a spectrum of innovative as well as traditional bioassays. This pursuit will be inextricably connected to the development of scientific training and capacity building in a biodiversity-rich yet economically~developing country, and will foster tangible results in biodiversity conservation and infrastructure development. The specific aims of this proposal which will allow us to reach these goals are: l. To use ecological concepts to guide the collection of terrestrial plants and marine algae within the biodiversity- rich country of Panama. 2. To produce extracts of these collected plant and algae samples and prefractionate these by appropriate techniques to produce reduced complexity screening units which have active ingredients in increased titer. 3. To evaluate these extracts and prefractionated samples for activity to several tropical diseases, including malaria, Chagas' disease, and leishmaniasis. 4. To evaluate these extracts and prefractionated samples for activity against cancer using i) a 3-cancer cell line Screen, and ii) a range of innovative mechanism-based targets through collaboration with the Novartis Institute for Biomedical Research. 5 _ To evaluate these extracts and prefractionated samples for activity to a panel of insects, plant pathogenic fungi, and weeds through collaboration with Dow AgroSciences. 6. To utilize an integrated approach of taxonomy, computer databases, and comparison to our Diode Array Detected HPLC database of known compounds to rapidly and efficiently dereplicate known and nuisance compounds at an early stage in the discovery process. 7. To isolate active compounds identified in the above assay areas using bioassay-guided approaches, and to detemrine the structures of these substances using efficient and modem spectroscopic methods. 8. To inventory the biodiversity of terrestrial plants and marine algae in Panama, and to continue to build the permanent floral collections in Panama. 9. To continue conservation efforts around the island of Coiba on the Pacific coast of Panama, including the inscription ofthe Coiba National Park to the list of World Heritage Sites, community outreach, delineation ofthe park's boundaries and enhanced enforcement. 10. To evolve and maintain the formal contracts between all of the participants in this program to address intellectual property rights, promote equitable sharing of benefits, and to facilitate broad access to the data and results of these research endeavors. l 1. To help build the scientific infrastructure and expertise necessary to support a sustainable drug discovery program based in Panama. 12. To integrate our drug discovery and conservation efforts to innovatively develop new economic products from the biodiverse marine and terrestrial habitats of Panama. B. BACKGROUND B.1. History of this Application This proposal is a request to continue an ICBG Program located in Panama that has been in existence since 1998. The original proposal was an outgrowth of a long-standing involvement in Panama of the previous Principal Investigator (P.I.), Dr. Phyllis Coley, an internationally recognized plant ecologist, and the two co-P.I.'s, Drs. Todd Capson and Thomas Kursar. Under their combined leadership, a new model of drug discovery was implemented with the goals of providing Panama with the technology and training necessary to conduct drug discovery research in situ. Thus, the project has demonstrated that, even if royalties are never realized, the emphasis on strong host- country involvement has provided immediate and guaranteed benefits to Panama from the non-destructive use of their natural resources. Panamanian scientists and governmental institutions are committed to such research (ag. see letters of support in Appendices l, 2 and 4), and are convinced that it has demonstrated, and continues to demonstrate, the value of conserving Panama's biodiversity. In addition, this model has been effective in discovering medicinally active compounds, thus forging a practical link between drug discovery and conservation. This exciting approach addresses the widely perceived and pressing need for society to find ways to recognize the true value ofthe conservation of biodiversity. The project also constructively addresses issues such as access to biodiversity, benefit sharing, and defining intellectual property rights that are highlighted by the Convention on ___ PHS 398/2590 (Rev. O5/01) Page § 3 Continuation Format Page Principal investigator/Program Director (Last, First, Middle): GERWICK, William þÿH ¬|'[y Biological Diversity, and that represent major areas of concern in both developed and developing countries. The applicant organization of this original program was the Smithsonian Tropical Research Institute (STRI). ln its 80-year history, STRI has become one of the world's leading centers for basic research on the ecology, biology and evolution of tropical organisms. The Panama ICBG provided an unprecedented opportunity for STRI to form new bridges with Panamanian research institutions. STRl's prestige and lengthy history in Panama has greatly facilitated the relationship between the Panama ICBG and the Panamanian government, in particular, the National Authority of the Environment (known as "ANAM" for its acronym in Spanish). ANAM regulates access to biological resources in Panama, and is the institution with which STRI developed the appropriate agreements for intellectual and property rights related to drug discovery. ANAM also issues all permits for plant collections and exports in Panama. The Panama ICBG has a productive relationship with ANAM (see letter of support from Ricardo Riguera, Appendix 1), which is evident by the approval of40 permits forthe