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 H€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 H€|'[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 collection, transfer and export of samples forthe ICBG program. Plant collections in the biodiversity-rich Panamanian tropical forests have been guided by ecological principles which indicate that fresh, young leaves are richest in natural products. All plant collections, extractions, initial fractionations for bioassays, and database record keeping were conducted by Panamanian students, professionals and technicians, with oversight from the P.I. and Thomas Kursar in Utah and Todd Capson in Panama. Bioassays were largely conducted in Panama by Panamanian scientists, and featured host country relevant diseases such as malaria, Chagas' disease and leisinnaniasis. Additional in-country bioassays were for cancer cell toxicity and HIV, and agrochemical bioassays with whitefly and aphids. Midway in the previous grant cycle, a strong connection was made with the mechanism-based oncology bioassay program of the Novartis Biomedical Research Institute (NIBR), and thus started a productive evaluation ofpre-fractionated plant extracts for anticancer activities by this sophisticated approach. Two natural product chemistry programs at the University of Panama, all utilizing Panamanian scientists and students, have provided chemistry isolation and structure elucidation support to these efforts, and over the past 2 years, have productively isolated both new and known compounds with promising medicinally-relevant activities. Indeed, a landmark PATENT PENo|Nc Slmultaneously an exceptional development in conservation and outreac! !as been pioneered by this ICBG program in the Coiba'National Park, a 2,700 kmz park encompassing Coiba Island, a 503 kmz island that is 15 km from the southwest shore of Panama. The initiative in the Coiba National Park involves numerous host-country organizations as well as international NGO's and private citizen support, and is working with ANAM to have the park designated a UNESCO World Heritage Site. In mid-2001, contact between the ICBG participants and Bill Gerwick was made with specific interest to add additional chemical isolation and structure elucidation expertise, as well as a strong marine natural products program to the ICBG. Ensuing discussions, two visits by Gerwick to Panama, one to Utah, and numerous scientiiic and organizational interactions led to Gerwick joining the ICBG group to develop preliminary results for this application, and has generated a strong track record of interaction. With the maturing ofthe Panama ICBG program over the past 4 years, it also became appropriate for a chemistry~oriented scientist to assume overall leadership of the ICBG, and Gerwick accepted this responsibility. This ICBG renewal application has been developed over the last 8 months, and represents numerous interactions between the new P.I. and the ICBG participants. As detailed below, the majority of the proposed effort will continue to occur in the host-country [at the University of Panama, the Institute of Advanced Scientitic Research and High Technology Services (INDICASAT) and STRI] and the only "out of Panama" financial support will go to the Oregon marine natural products portion of AP3. A streamlining and partial re- organization ofthe ICBG in Panama is proposed, based on a critical self-review of accomplishments over the past 4 years, the need to support newly established laboratories, as well as budgetary restraints. Key to this proposal is a strong focus on the most successful features of the program: o Strong host-country involvement and in-country participation and training » Ecologically guided collections 0 Development of innovative Panama-based tropical disease assays 0 Whole cell as well as mechanism-based anticancer assays 0 Bioassay-guided isolations of constituents with medicinally relevant activity 0 Innovative approaches to tangible conservation goals, such as the Coiba project l_l___ PHS 398/2590 (Rev. 05/01) Page Q0 Continuation Format Page Principal investigator/Program Director (Last, First, Middle): GERWICK, William HSD!!

A combination of strategic and budgetary issues have led to the decision not to continue several aspects of the original proposal, including an inventory of beetles, the Shaman's apprentice program, HIV and agrochemical screening in Panama, and one of the chemistry laboratory programs (Dr. M. Gupta). The extremely difficult decision to not continue this Panama-based chemistry laboratory for budgetary reasons was compensated by recognition that this laboratory has other sources of funding, has extensive intemational collaborations, actively pulishes non-ICBG studies and will continue to be a productive natural products laboratory even without ICBG support. In this regard, the ICBG program has served its purpose well by enhancing the intemational recognition of a laboratory that will be self-sustaining even after the conclusion of ICBG involvement.

B.2. Brief Overview of the Participants and Their Institutions In Panama the project will take place at three principle institutions: the University of Panama, INDICASAT, and the Smithsonian Tropical Research Institute. While the principle STRI campus is in Panama City, a number of field laboratories and associated facilities will be used as a part of the plant and algae collections program, including the field stations in Bocas del Toro (providing access to the Caribbean) and facilities near the Coiba National Park (providing access to the Pacific, see map Figure 7, APl). Elsewhere, facilities at the University of Utah, Oregon State University, and the Smithsonian Institution's Fort Pierce Marine Laboratory will be used in ways appropriate to the work plan for the project, as described below. Dr. Gerwick will lead the Panama ICBG in its renewal period as a Research Associate of STRI based at Oregon State University. He is an internationally renowned scientist in marine natural products and bioorganic chemistry, President of the American Society of Pharrnacognosy and an Associate Editor of the Journal of Natural Products. The current P.I., Dr. Phyllis Coley is a world-renowned plant ecologist and is a Research Associate of STRI who is based at the University of Utah. She has over 25 years of field and research experience in Panama. She will be API for collections and extractions and database with Dr. Thomas leader of , responsible management together Kursar, an experienced plant physiologist who has worked in Panama for over 20 years. Together, Drs. Kursar and Coley have designed an innovative collection strategy for terrestrial plants. For the last two years, Dr. McPhail's work has focused on the collection of marine algae and the purification and characterization ofbioactive algal compounds. She will direct the marine portion of API' under the auspices of Dr. Gerwick, and with input from Dr. Valerie Paul, an irrternationally-recognized chemical ecologist based at the Smithsonian Marine Laboratory in Fort Pierce, Florida. Dr. Maria Heller has been director of the ICBG collection and extraction laboratory for the last 4 in this years. She was instrumental in helping to design the ICBG data management system and will continue capacity at STRI under APl. The laboratory of Dr. Eduardo Ortega-Barria, a physician and recognized parasitologist, has played a key role in the ICBG by establishing novel bioassays for activity against tropical diseases. The techniques developed are ideal for developing countries and stand to have a significant impact on finding treatments for these diseases. Dr. Ortega-Barria's colleague, Dr. Luz Romero, a physician and expert on the cell biology of leishmaniasis, has played an important research role in this laboratory, which has recently moved from Florida State University - Panama to INDICASAT. The P.I. Dr. Gerwick is also the designated leader of AP3, focusing on the purification and structure elucidation of bioactive terrestrial and marine natural products. Dr. Luis Cubilla, a natural products chemist with expertise on terrestrial plants, has become an important figure in leading research at the University of Panama, where he first established a research laboratory under the current ICBG two in AP3. Dr. and a half years ago. He will continue to direct chemical investigations of the terrestrial plant samples McPhail will be responsible for the processing of marine algae samples in the Gerwick laboratories at Oregon State University. Dr. Todd Capson has been the Panama-based coordinator of the ongoing ICBG since its inception. As such he has had direct input in many aspects of this multifaceted project. He has been instrumental in promoting biodiversity conservation in Panama, and will continue his pioneering efforts as leader of the proposed conservation in D.4. and D.5. and outreach program, AP4. A more detailed description of the participants is found Sections below. B.3. Panama, A Biodiversity "Hotspot" B.3.1. Panama has a Unique Biogeography As the southern-most portion of the Central American bridge between North and South America, Panama has two has blended been described as ". . .the crossroads of the Americas, where the plant and animal life of continents 100 km wide and diversified in an incredible display" (Hubbuch and Craft 1995). The Isthmus of Panama is merely PHS 398/2590 (Rev. 05/01) Page Qll Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERW|CK, William H€I`l[y 2 with a land area of 75,990 km . Developing southwards from North America as an enlarging chain of islands around 4_6 million years ago (I-laug and Tiedemann 1998), the isthmus enabled an exchange of flora and fauna between the Americas known as the "Great American Interchange" approximately 2.7 million years ago (Webb 1985). Today Panama is the northernmost range of many South American mammals and also plants. Seed dispersal associated with the movement of mammals facilitated an intercontinental mingling of terrestrial plants species, which, together with the physical geography of Panama, has resulted in an unsurpassed floristic biodiversity (Baithlott et al. 1996). Large gradients in altitude and rainfall are created by a fonnidable backbone of mountain range reaching 3,475 m, which extends along the length of Panama (Figure 1) and generates contrasting climates between the Atlantic and Pacific slopes. 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1 .,,_ . __ iQ __ _. and the Gulf of Panama (from Glynn and Maté 1997). See Appendix 5 for the color version. Figure 1: The Republic of Panama. The Coiba National Park is located within the Gulf of Chiriqui and its borders are indicated by solid lines. See Appendix 5 for the color version. The barrier posed by Panama has caused significant differences in ocean chemistry and climate between the Atlantic and Pacific Oceans, and changes in the Atlantic and Pacific surface-ocean circulation have likely affected global climate since the early Pliocene (Haug et al. 2001). In Central and South America the weather pattems (SW- trending trade winds) result in high evaporation in the Caribbean, making this body of water more saline (about 1 ppm) than the Pacific. The prevailing winds cause upwelling of cool nutrient rich waters in the Pacific (Haug et al. 2001). As a result, Pacific waters are generally more turbid and slightly cooler, with more abundant nutrients, chlorophyll and plankton than the Caribbean. Within the Panamanian Pacific, there is a marked contrast between Gulf of Chiriqui (in the southwest) and the Gulf of Panama (southeast). In the canal zone of central Panama, a break in the mountains results in unimpeded passage for the trade winds to the Gulf of Panama. The resultant surface flow causes upwelling of cold nutrient-laden water, producing a marked drop in temperature, which dips below 20 °C during upwelling phases (Glynn and Maté 1997). In contrast, the Central Cordillera blocks the flow of the trade winds in westem Panama (Figure 1), such that the Gulf of Chiriqui experiences much less upwelling and much higher sea surface temperatures (Figure 2). The differing physical enviromnents of the two oceans, as well as between the Gulfs of Panama and Chiriqui, are thought to be manifest in the high marine biodiversity observed in Panamanian waters (2,210 kmz), which embrace an impressive 2490 km of coastline.

B.3.2. Panama has High and Accessible Biological Diversity Panama is a "biodiversity hotspot" at the center ofthe region with the greatest concentration of terrestrial plant species in the world (Barthlott et al. 1996, Myers et al. 2000, see Figure 3). It is the northern-most extent for approximately 4,000 South American species, and endemic species account for 14% of its flora. It is estimated that there are over 13 life zones in Panama and over 8,500 species of flowering plants with over 8,400 already identified by taxonomic experts (Tosi 1971, D'Arcy 1987, M. Correa pers. comm.) This extraordinary regional (beta) diversity in a country slightly smaller than South Carolina results from an unusual mosaic of habitat types and

C0l\fif\U3ti°" F°|'ma\ PHS 39812590 (Rev. 05/01) Page ¢ P399 Principal Investigator/Program Director (Last, First, Middle): GERW|CK, William HS|"|[y comprises plant species from both Central and South America (D'Arcy 1987, Condit et al. 1996, Condit et al. 2002). As described in Section B.3.1., the small land mass of Panama with its 2,490 km of coastline has unparalleled access to the flora and fauna of three distinct water bodies: the Caribbean Sea, the Gulf of Chiriqui and the Gulf of Panama. Subtidal limestone platfomis, sand and mud plains, diverse reefs, seagrass meadows and mangroves are typical of the Caribbean coastline, which has a minimal tidal flux (<0.5 m). In contrast, the Pacific coast experiences a tidal amplitude of up to 6 m and comprises rocky outcrops with numerous tide pools and diverse algal turfs. The more protected shorelines have extensive sand and mud flats and mangrove forests. Corals are present but rarely develop into elaborate reefs, with the exception of the 1.6 kmz reef of Maria Ensenada in the Gulf of Chiriqui. Of all known genera of eastem Pacific reef-building corals, 91% occur in Panama, many of which are found in the relatively warm and protected waters of the Gulf of Chiriqui (Glynn and Maté 1997). Coral reefs constitute a comparatively trivial portion of coastal habitats in the eastern, more GLOBAL BIODIVERSITY SPECPES NUMBERS OF VASCULAR PLANTS

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~»_ - PHS 398/2590 (Rev. O5/01) Page cl Q Continuation Format Page Principal investigator/Program Director (Last, First, Middle): (BERWICK, William H€l'i[y B.3.4. Threats to Panama's Biodiverse Habitats Panama is unique in Central America in having 38.6% (29,000 kmz) of its land still in forest cover. Almost a quarter of Panama's land area is protected in the country's 43 parks and reserves. However, deforestation continues at a rapid rate: 1.6% or 519 kmz per year. At this rate, Panamanian forests will disappear within approximately 50 years (FAO 2001). Due to Pana1na's extraordinary yet threatened biodiversity, Panama is now considered a threatened biodiversity hotspot by Conservation International (Myers et al. 2000). For example, the remarkably diverse Darien region of eastern Panama has been designated a World Heritage Site and a World Biosphere Reserve, yet it lacks sufficient funds for protection against encroachment by colonists and illegal loggers. Darien National Park is meant to protect 5,700 krnz but there are only 11 people assigned to this formidable task. This is equivalent to 520 kmz of rugged terrain per park guard. The Darien province holds vast expanses ofprimary forests, yet also has the highest deforestation rate in the country, accounting for 93% of the area in Panama that has been given to logging concessions. Following completion of a road to Yaziva in 1985, large areas of Darien province adjoining the road have been and continue to be logged and converted to either agriculture or pasture. Similar habitat loss is occurring throughout Panama. Central Panama still contains large tracts of forest in the watershed of the Panama Canal that have been protected in the past. However, the future of these forests is uncertain, particularly since they lie adjacent to the major population center, Panama City. At present, very little of the biologically rich province ofBocas del Toro has been given any protection, yet mining exploration and newly planned roads pose serious threats to this pristine area. Several of Panama's ecosystems were recently acknowledged by the World Bank as being of global significance for conservation (Document ofthe World Bank, 1998). It is estimated that 30% of Caribbean coral reef systems are at high risk from overtishing as well as siltation and pollution from inland and coastal activities. A further 30% are being significantly threatened by human activities (Burke 2001). Notable also are the oil spills along the Caribbean coast of Panama (such as the Galeta spill of 1986: Guzman 1991), which are a chronic source of coral reef deterioration (Ballou et al. 1989). In the last decades, coral reef habitats have additionally been endangered by escalating outbreaks of disease (Cervino et al. 2001) and by coral bleaching events caused by the ElNif1o-La Niiia effect, such as that affecting the western Pacific coast of Panama in 1997-98 (Goreau et al. 2000). B.4. Natural Products in Drug Discovery B.4.l. Seminal Contributions of Natural Products to Modern Medicines Natural products have been and continue to be one of the most important sources ofpharmaceutical agents in use today. For example, it has been estimated that 37% of total pharmaceutical sales, and 45% of today's bestselling drugs, are from natural products and natural products derived molecules (Frormann and Jas 2002). Another analysis reported that 8 ofthe top 25 top selling drugs worldwide derive from microorganisms (Chicarelli-Robinson et al. 1997). Approximately 60% of the agents in clinical trial forthe treatment of cancer owe their origin to natural products (Cragg and Newman 2000). From a very recent analysis by Newman et al. (unpublished), which updates their earlier tally ofthe origins of clinically useful agents (Cragg et al. 2000), 697 agents are currently in use in the clinic. Of these, 30 (4.3%) are unmodified natural products, 155 (22.2%) are modified natural products, 77 (11%) have a natural products "ancestry" and 42 (6%) are "biologicals" (e.g. proteins). The remaining 393 (56.4%) are synthetic compounds. Hence, in raw numbers, natural products have played a critical role in the development of 262 (37.5%) ofthe agents in use today. The importance of natural products in drug discovery is even more evident when one considers the inherent structural diversity available in natural products versus synthetic materials. The point has been made in the literature and is widely appreciated by the pharmaceutical industry that the success of a drug screening program is not based on the raw numbers of compounds screened, but rather, on how well they explore "chemical diversity space" (Frorrnann and Jas 2002). An additional feature of importance for a natural products-based screening program, especially one guided by ecological insight, is the evolutionary history of the compounds. Because the molecular structures of natural products have been molded over eons in response to intense interactions among species (Harborne 1988), they are ideal for maximizing the success of screening for novel structures, for identifying previously unrecognized target proteins or activities (eng. microtubule stabilization by taxol), and even for identifying novel binding activity in proteins with well characterized binding sites. As a consequence, an ecologically-guided collection and bioassay program will take full advantage ofthe discoveries to be made in natural products.

_ It is estimated that 40% of the molecular scaffolds found in natural products are unrepresented among synthetic compounds yet synthetic compounds (>l0 million known) are more than 100 times more plentiful that natural

PHS 398/2590 (Rev. 05/01) Page Q lj; Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERW|CK, Wi||l8m |'|6H[y products (ca. 110,000 reported; Henkel et al. l999)! Natural products are of inherently greater chemical diversity and complexity than synthetic compounds because ofthe high frequency of asymmetric centers (which gives molecules a 3-dimensional topology which is difficult for synthetic chemists to mimic; Waterman 1998). They are also generally larger in molecular weight and have an increased oxygen content, a greater number of sp3-hybridized bridgehead atoms and ring structures, and a variety of functional groups that are unrepresented among synthetic compounds. Natural products have also played an enormous role as research biochemicals that are used in elucidating both normal cellular processes as well as those present in pathological states. In this regard, many ofthe essential tools of pharmacologists studying drug action are natural products, and these have been useful in identifying novel targets for treating human disease. For example, a number of natural products target various features ofthe cell cycle, and in doing so have elucidated a multitude of checkpoint controls that were not previously recognized. A number of natural products also bind to the ATP binding site of cyclin dependent kinases, yet show specificity for the different Cdk's, and thus have been useful for dissenting these fundamental control mechanisms of the cell cycle (Newman et al. 2002). Marine natural products such as didemnimide A (1) and isogranulatimide (2) function as checkpoint inhibitors and have been enormously useful tools in cell biology, as well as having high potential as cancer chemotherapeutics. A molecule previously characterized by one group of this ICBG proposal, the cyanobacteria] Proteau et al. is the first H H pigment scytonemin (3, 1993), N OH ° ° / Q described small molecule inhibitor of human polo-like ` _ Q ~N kinase, a serine/threonine kinase that plays an integral NH / NN / / Q G role in regulating the G(2)/M transition in the cell cycle §"'§°N N;/N 0 E H H0 Q /H Q (Stevenson er al. 2002). Scytonemin has potential in as as abnormal Didemnimide (1) isogfanuiaiimide (2) seyronemin (3) treating both inflammatory well proliferative diseases. B.4.2. High Biodiversity Equates with High Chemodiversity There is much debate on how many species exist on the planet, largely because ofuncertainty over the true extent of the microbial world; however, estimates as high as 30 million have been reported (Waterman 1998). Nevertheless, when one considers that for most species, and especially for microbes, each consists of multiple strains with their own unique metabolic profiles, the numbers of organisms to be examined for useful natural products is enormous. As illustrated inthe biodiversity map (Figure 3), the tropical belt is the richest zone for vascular plant diversity. The Indo-Pacific Regions and Caribbean-Pacific Juncttue are two of the most highly biodiverse regions on the planet. Inherent to high biodiversity is high inter-species interaction. Competition among co-habitating species for limiting resources (e.g. space, nutrients - Reigosa er al. 1999, Gross 1999) has been proposed as a key factor for why the percentage of species containing bioactive natural products is so high in biodiversity-rich areas, such as the tropics. As elegantly argued by Cragg and Newman (2002), in response to arguments put forth by Tulp and Bohlin (2002), chemical diversity is encountered as a function of biodiversity. Implicitly, the Panama and Indo- Pacific regions possess the greatest percentage and number of species which elaborate bioactive natural products. B.5. Ecology-Guided and Bioactivity-Enhanced Collections B.5.1. Rationale for Terrestrial Ecology-Guided Collections A key component of the collections Associate Program in the ongoing Panama ICBG project is the use of ecological insight to determine the collection strategy. Results from bioassays conducted during our ICBG project (Coley et al. submitted) have confirmed original hypotheses that young, fresh leaves are more likely than mature leaves to contain active compounds (Coley and Kursar 1996, Kursar and Coley 2003), and these are desciibed in detail in API (Section C.l.). B.5.2. Rationale for Marine Ecology-Guided Collections The expertise of Dr. Valerie Paul in the field of algal chemical ecology will aid us in the selection of marine algae most likely to use chemical defense strategies (see letter of support, Appendix 2). Macroalgae and cyanobacteria proliferate in the shallow subtidal zone, where shallow reefs accommodate a diversity of algal species, and cyanobacteria are the primary nitrogen fixers. Alternatively, mangrove forests and sea grass communities provide sheltered habitats for cyanobacteria in locations with high light intensity and temperature as well as low wave action. These locations also provide refuge for scores of small fishes and fish spat, as well as a variety of marine invertebrates, and yet algal and cyanobacterial species are conspicuously untouched by the myriad predators in this environment. Therefore, cyanobacteria] blooms and uncalcified macroalgal species are collected preferentially PHS 398/2590 (Rev. 05/01) Page 55 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERW|CK, William H€l1[y

onthe premise that they rely on chemical rather than physical defense mechanisms (Hay 1996). However, there are occasional reports of chemically-defended calcareous macroalgae (Hay 1997). B.6. Focused and Effective Drug Discovery Program B.6.1. Treatments for Tropical Diseases Although drugs remain the mainstay of control for most parasitic diseases, no new classes of antiparasitic drugs have been developed since the 1960s and few are pending (WHO Infectious Diseases Report, 2000), a critical situation for poor, developing countries where tropical diseases remain a crippling affliction. In the Panama-based laboratories of AP2, novel colorimetric and fluorimetric assays [American trypanosomiasis (Chagas' disease), leishmaniasis and malaria] developed in Panama will be used to test and then direct the isolation of active PATENT PENDWG com ounds trom terrestrial and marine lant crude extracts as well as some corals (AP3 Section C. 1. 1.1; Cubilla-Rios et al. 2002), a program was initiated in Panama to evaluate both toxicity and efficacy of our lead compounds. We will test the in vivo potential to cure both cutaneous and visceral leishmaniasis using mouse models. ICBG-leveraged funding was obtained from the Smithsonian by AP2 and AP3 scientists for this second stage of drug discovery within Panama (see AP2 and AP3). B.6.2. Anticancer Agents A broad-based strategy of anticancer drug discovery will use two complementary approaches. Firstly, the 3-cell line [H-460 (lung), SF-268 (central nervous system) and MCF7 (breast)] assay developed by the NCI (http://dtp.nci.nih.gov/branches/btb/ivclsp.html), which has been successfully run in Panama for the past 5 years, will continue to be used in Panama to detect cell cytotoxins. This mechanism-blind approach will be complemented by a mechanism-based screening method run in conjunction with our industrial partner, Novartis Pharmaceuticals (see letter of support, Appendix 3). As detailed in the AP2 application, Novartis is utilizing state-of-the-art knowledge of cancer cell biology along with high throughput screening (HTS) to iind mechanism-based anticancer lead compounds, with a primary focus on targets involving modulation of the activity of oncogenes, tumor suppressor genes, apoptosis, and various signal transduction pathways. This complement of assays will ensure a modem and focused approach, yet one which allows for the discovery of anticancer-type compounds that work by new mechanisms. B.6.3. Agrochemicals A strong partnership with a leader in the agrochemical industry, Dow AgroSciences (DAS), will capitalize on the samples and resources being developed by this ICBG program (see letter of support, Appendix 3). A broad- based herbicide, insecticide and fungicide screening program at DAS ofproven efficacy in discovering new agrochemicals will be applied to the Panama materials (see AP2, Section D.3). Additionally, cultures of endophytic of and in API will be to DAS for culture fungi produced during the past period ICBG support, continuing , provided and agrochemical screening. B.7. Strong Host Country Involvement and Close Interactions with Panama Governmental Agencies The majority of the scientific research for the current ICBG program, as well as that proposed in this renewal, occurs in host country institutions and is carried out by Panamanian scientists and students. This involves research programs at the University of Panama, INDICASAT, and the Smithsonian Tropical Research Institution. The close interaction between the Panama ICBG and the National Authority of the Environment (ANAM) is described in AP4 (Section C.2). ANAM has been the primary interface between the ICBG program and the Panamanian government, and collaborations include the development of Material Transfer Agreements, the design of databases for ANAM that enhance their ability to monitor and regulate the country's biodiversity, and the development of strategies forthe protection of national parks. Through the intemet-based ICBG database described in the API (Section D.l I .), ANAM has instant access to information on all of ICBG plant collections, including their GPS coordinates, the date of collection and ecological conditions. As described in AP4 (Section C.2.3.), we coordinated with a major, World Bank supported ANAM program for sustainable development, known as the Panama Atlantic Mesoamerican Biological Corridor, to provide information on our plant collections in the Omar Torrijos H National Park. B.8. Pioneering Conservation Initiatives A priority ofthe Panama ICBG over the past 4.5 years has been the design and implementation of initiatives that promote biodiversity conservation in Panama. Our extensive involvement with a range of Panamanian institutions from the government, NGO's and the scientitic community, combined with the wealth of information available through STRI, has provided insight into the fundamental causes ofbiodiversity loss in Panama. Therefore, _ PHS 398/2590 (Rev. 05/01) Page Z6 Continuation Format Page Principan Investigator/Program Direeror (Last, First, Middle); GERWICK, William Henry our three basic strategies are: community outreach, designing mechanisms to protect the Coiba National Park and institutional strengthening ofANAM (as described in Section C.1.4.). B.8.1. Outreach Activities We have engaged in consistent public outreach efforts that have taken the form of lectures, newspaper articles, and other activities (109 in 4.5 years) that have served primarily to emphasize the link between biodiversity and human health and to discuss the extraordinary potential of Panama's terrestrial and marine ecosystems for natural products drug discovery and benefits that may arise through a program based in the host country, such as strengthening scientific institutions and training students. B.8.2. Conservation Initiatives in the Coiba National Park In collaboration with ANAM, the ICBG has assembled a team of local and international NGOs, and donors and research institutions (see letters of support, Appendix 1) that will be involved in marking the park's boundaries with buoys and radars to detect the entry of boats, and in community outreach with marine resource users. Further, the Panama ICBG took the lead in coordinating with ANAM to submit to UNESCO an application for the inscription of Coiba National Park as a World Heritage Site.

C. PROGRESS REPORT AND PRELIMINARY RESULTS C.1. Progress Report C.1.1. Progress Towards Attaining Goals Our primary objectives during the previous funding period were to build the basis for a sustainable, natural products-based drug discovery program in Panama; to develop Panamanian scientific infrastructure; to promote technology-transfer to Panama; to discover novel treatments for human disease; to develop novel and appropriate technologies for developing countries to find treatments for parasitic diseases; to establish collaborations with the pharmaceutical industry; and to enhance biodiversity conservation in Panama. We have made substantial progress towards the goals listed above, exemplified by the following accomplishments: (i) In total, there are 22 Panamanian B.S.-level students currently working on the Panama ICBG program, in the disciplines ofbotany, tissue culture, microbiology, parasitology, bioassay-guided fractionation and structural elucidation. Taking into account undergraduate thesis projects, temporary assistants and personnel no longer working on the ICBG program, a total of 5 7 B.S.-level Panamanian scientists have been associated with the ICBG over the past 4.5 years. Of the 6 laboratories they worked in, 5 are in Panamanian institutions. (ii) Among the laboratories established and maintained by the Panama ICBG, is that of Eduardo Ortega-Barria (Associate Program 2), which has developed bioassays that detect activity against the parasites that cause malaria, Chagas' disease and leishmaniasis. For the first time in a Panamanian laboratory, Plasmodiumfalcmarum parasites have been cultured. The laboratory is currently staffed by 7 scientists, and visiting scientists from throughout Latin America as well as Africa have received training in Dr. Ortega-Barria's laboratory. His laboratory has tested samples from research programs based in the US, Africa and Latin America. A total of 889 plant species in addition to 191 pure compounds and partially purified fractions have been tested for antiplasmodial activity, 2,181 extracts and 268 pure compounds and partially purified fractions for activity against Trypanosoma cruzi, and 1,647 extracts and 609 pure and partially purified fractions for antileishmanial activity. In addition, the assays have been used to screen purified compounds from the laboratories of Dr. Abimael Rodriguez (University of Puerto Rico) and Dr. David Kingston (Suriname~Madagascar ICBG program). Following submission of a see AP3 Section C.1.1.1.; Cubilla- Rios et al. 2002), a program was initiated in Panama to evaluate both toxier and efficacy of our lead compounds in mouse model systems. (iii) A new natural products laboratory was established at the University of Panama. Although it has existed for only 2.5 years, Dr. Cubilla's lab has purified 24 compounds with activity against the parasitic diseases listed in the preceding section, producing results for one patent application and three publications. The laboratory has trained 8 B.S. and M.S.-level scientists, two of whom are pursuing graduate degrees abroad. (iv) A total of 1,248 plant species have been collected for drug discovery from national parks throughout Panama. From most species, young leaves were collected since ecological theory predicts they will have higher levels of secondary metabolites than mature leaves. For each plant collection, GPS and ecological data have been recorded, resulting in an enhanced knowledge ofthe Panamanian flora.

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(v) We established a productive collaboration with the Novartis Institute for Biomedical Research with whom we will continue to work. A total of 33 plant species were detannified and prefractionated and tested for anticancer activity in Novartis bioassays, from which 3 species have been identified as active. In total, 147 pure compounds and partially purified fractions were tested for activity, from which a potent Sirt2 inhibitor was identified (Sirt-2 is an NAD-dependent histone deacetylase involved in cell cycle regulation and is a current target in cancer therapy). (vi) A panel of 3 cancer cell lines was established in Panama that has been used to screen 2,968 extracts from 1,152 species and 723 compounds or partially purified fractions. The assays were used for the bioassay-guided fractionation of extracts from I2 plant species, resulting in the purification and structure elucidation of 18 cytotoxic compounds. (vii) A non-infectious HIV assay was established in the Republic of Panama and was used to screen 1,269 extracts and fractions. The assays were used to guide the bioassay guided fractionation of 4 plant species, resulting in the purification of 4 compounds. (viii) Whitefly and aphid bioassays were developed in Panama and 221 plant protein extracts were tested for activity. (ix) The Panama ICBG purchased and has maintained the only operational NMR spectrometer in the Republic of Panama. The Bruker 300 instrument was crucial for all of the structural elucidation carried out over the past two years. (x) The Panama ICBG has helped establish intemational networks of scientists whose expertise and facilities have played important roles in training, structure elucidation and technology transfer. Examples include: the collaboration of Drs. Bill Gerwick and Kerry McPhail (Oregon State University) with Drs. Luis Cubilla and Pablo Solis (University of Panama) in structural elucidation; the Ph.D. studies of former ICBG participant, Marcelino Gutiérrez in the laboratory of Dr. Ricardo Riguera from the University of Santiago de Compostela in Spain; and the M.S. studies of former ICBG participant, Lilia Chérigo, in the laboratory of Dr. Rogelio Pereda in the Universidad Autonoma de México. (xi) As a result of the investments described above, namely, the training of students and the investments in infrastructure and equipment, Panamanian scientists are active partners in a viable natural products research program that is isolating and characterizing novel compounds with promising activity in our bioassays, publishing in international joumals, and applying for US patents. (xii) Due primarily to the efforts of the Panama ICBG, there exists a realistic and cost-effective strategy for the protection of Panama's Coiba National Park that incorporates the Panamanian Maritime Authority, the National of the Conservation International Panamanian the Woods Authority Environment, , non-govennnental organizations, Hole Oceanographic Institution, STRI, private landowners and residents from adjacent communities. (xiii) Due to a collaboration between the Panama ICBG and the Panama's National Authority of the Environment, the Coiba National Park has been nominated as a candidate for United Nations Educational, Scientific and Cultural Organization's (UNESCO) list of World Heritage Sites. (xiv) The Panama ICBG has developed innovative benefit sharing agreements in which the majority of benefits go to conservation and to Panamanian institutions. Thus, Fundacion Natura receives 30%, Vida Silvestre (the ANAM trust Hind for Protected Areas) receives 20% and all participating institutions share the remaining 50% of any benefits gained.

C.1.2. List of Publications Kursar TA, Capson TL, Coley PD, Corley DG, Gupta MP, Harrison LA, Ortega-Barria E, DA Windsor. 1999. Ecologically guided bioprospecting in Panama. Pharmaceutical Biochemistry. 37: l 14-126. McManus MG, TL Capson. Bioprospecting and Conservation. 2001. BIOTECH. The Magazine ofthe Biotechnology

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-. .., |"|" `|| 401| C.1.3.1. Workshops Organized by Panama ICBG 1. In collaboration with the Spanish scientific organization, Ciencia y Tecnologia para el Desarrollo (CYTED), the ICBG supported a workshop on colorimetric bioassays used for testing natural products for antiparasitic activity (May 22-26 1999), in which Dr. Ortega-Barria (AP 2) hosted scientists from Panama, Guatemala, Bolivia, Brazil, Chile, Spain, Paraguay, Colombia, the Walter Reed Army Institute for Research and Washington University. 2. Two visiting scientists from Malagasy facility, Centre National Applique a la Recherche Pharrnaceutique (CNARP), affiliated with the Suriname/Madagascar ICBG directed by David Kingston, visited the Ortega-Barria laboratories (AP 2) to learn how to cultivate Plasmodiumfalczparum and to use a tluorimetric assay for detecting antiplasmodial activity. 3. The Naso indigenous group of Panama received instruction in plant collection and in making botanical vouchers, and progress made towards recording ofNaso ethnobotanical knowledge was reviewed, in two workshops held in February 2000 and March 2001. 4. A workshop was held with representatives of the Naso indigenous group to review the progress made towards recording of ethnobotanical knowledge and to show the program to a visiting delegation of two indigenous groups from Suriname (affiliated with the Kingston ICBG) on October 20-21, 2000. 5. A workshop entitled "Conservation and Sustainable Development in Panama: lessons learned and visions for the future" was held at the STRI facilities (November 29, 2002), the participants including Panama-based non- governmental organizations, foreign aid institutions, Panama ICBG representatives as well as representatives from Panama's National Authority of the Environment (ANAM).

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6. A workshop and course on linking our ethnobotany activities with the Naso indigenous group with ecotourism enterprises was organized in collaboration with Conservation International consultants (November 26, 2001 through January 25, 2002). 7. Representatives from STRI, ANCON (a Panama-based non-governmental organization), The Nature Conservancy-Panama, and private landowners near Coiba National Park attended a workshop to coordinate activities among the conservation organizations working in the Coiba National Park (March 7, 2002). 8. Representatives from STRI, ANCON (a Panama~based non-governmental organization), the Panamanian Maritime Authority, and the National Authority of the Environment (ANAM) attended a workshop to coordinate activities among the conservation organizations working in the Coiba National Park (September 23, 2002), C.l.3.2. Community Outreach During the past 4.5 years, ICBG members engaged in a total of 109 outreach activities in Panama, to the following audiences in Panama and in the following forums: lectures at elementary and high schools, presentations to governmental officials, lectures to non-governmental organizations and community groups, lectures to scientific organizations and at imiversities, radio and television appearances, newspaper articles. An additional 9 lectures have been presented by the co~P.I.'s in the US, Australia and Colombia. C.1.4. Accomplishments in Conservation Objectives Conservation activities can be summarized in three categories: (i) outreach activities, (ii) collaboration with Panama's National Authority of the Enviromnent and, (iii) design and implementation of conservation strategies in the Coiba National Park. (i) Outreach activities. The combined impact ofthe outreach efforts listed in Section C. 1 .3.2. is not readily measurable. However, they have clearly contributed to a positive perception of the ICBG program in Panama, both to the public and among the government, and have raised awareness of the importance of biodiversity to human health. Direct examples of this increased awareness are described in AP4 (Section C. l .). (ii) Collaboration with Panama's National Authority of the Environment ("ANAM"). The Panama ICBG has worked closely with ANAM on many levels, both in the tield and with their administrative headquarters in Panama City, to provide information and resources that has resulted in substantial improvements in their operations. A major contribution consisted of a database system for the management of ANAM's permit system. The Panama ICBG developed a database that provides a digital interface for preparing research, extractive (e.g., logging) and export permits. Created at the request of ANAM, the system has fundamentally changed every transaction mediated by permits, from monitoring timber concessions to scientific research. The lack of an electronic system for evaluating permits made it difficult to monitor compliance, e.g., to see if the species approved for harvest in a timber concession were the same as the species that were eventually harvested. The new system also allows ANAM to determine whether a given species is listed on the CITES list of endangered species. The database was created at the request of ANAM's National Director for Natural Patrirnony and was designed by the Panama ICBG systems analyst. The ICBG also provided a computer that serves as an internal server, allowing the use ofthe system by ANAM personnel from anywhere in the administrative center. The system allows the user to determine the status of a given species, for example, whether it is listed as endangered by the CITES treaty. A second database was also developed by the ICBG personnel for ANAM's Division ofNatural Patrimony for organizing their library and documentation on natural resources, such as environmental impact statements and management plans for National Parks. Other contributions to ANAM include data on the flora of Panamanian national parks, which ANAM can access through an internet based database provided by the ICBG. (iii) Conservation strategies in the Coiba National Park (see AP4). Panama ICBG personnel have played a leading role in Panama to design and implement strategies to protect the Coiba National Park, a 2,700 kmz national park that is the home of extraordinary, unique marine and terrestrial environments. ICBG-sponsored research led to the first systematic study ofthreats to the park entailing extensive interviews of fishermen from the nearby mainland as well as commercial ports that fish within the park boundaries. From this study and other data, the ICBG program has developed and begun to implement a strategy for the protection of the Coiba National Park that involves the participation of ANAM, the Panamanian Maritime Authority, Conservation Intemational, the Woods Hole Oceanographic Institution, the Smithsonian Tropical Research Institute, private landowners, and two Panama-based non governmental organizations. The Panama ICBG is working with ANAM in order to have the Coiba National Park placed on UNESCO's list of World Heritage Sites. The application for the inscription of the park to the World Heritage List was submitted by ANAM on January 21, 2003.

PHS 398/2590 (Rev. U5/01) Page |00 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERW|CK, William H€l"|[y C.1.5. Other Contributions C.1.5.1. Culture of Endophytes and Diversity Inventory As part of a collaboration with Monsanto, we isolated endophytes from young, mature and senescent leaves of over 200 plant species (see API, Section C.4.). From the 1,250 pure isolates cultured, 367 species were classified based on morphological traits. An extraordinary diversity was observed in these tropical samples compared to temperate systems. information on each isolate was entered into a database to determine morphospecies. Classification based on morphology showed high congruence with molecular classifications based on DNA sequence data of ITS-1, ITS-2 and the 5.85 gene (Arnold 2002). For long-term storage of fungal strains, we transferred agar blocks containing mycelia from pure cultures to sterile plastic cryovials with distilled water (Qiangqiang et al. 1998). C.1.5.2. Conservation of Ethnobotanical Knowledge of Panamanian Indigenous Groups A program with the Naso indigenous group from northwestern Panama was conducted in order to preserve traditional ethnobotanical knowledge pertaining to medicinal plants. The program involved three groups of Naso students and teachers, one teacher per group and a total of 18 students. Over 3 years, students and teachers met once a week to learn about the plants employed in traditional medicine. Students were also trained to make botanical vouchers and over 200 vouchers have been mounted and preserved. The program was a model for the Kuna indigenous group from Panama and two indigenous groups fiom Suriname (October of 2001; coordinated with the Kingston ICBG). This project resulted in the inclusion of a medicinal plant component in the Naso's developing ecotourism endeavors. C.l.5.3. Biodiversity Inventories and Studies of Beetle-Host Plant Associations In addition to the plant component of the biodiversity inventory program, Smithsonian entomologists collected insects from three distinct locations in Panama (premontane, moist forest; evergreen, moist forest; Pacific dry forest). In total, 124,716 insects were collected and sorted into 7 broad categories (Orders or Families). Of the 1,486 leaf- feeding beetle specimens (Chrysomelidae), 108 have been identified to species. The relationship between selected aposematic insects (i. e. with warning coloration) and their host plants was also studied. From the plant Vismia baccrfera, the compound Vismione B was found in selected instars of the skipper butterfly, Pyrrhopyge pseudophidias, and in larval instars of a satumiid moth, Permhoba arcaei. Vismione B showed potent cytotoxicity in the 3-cell cancer screens (see AP3, Section C. 1 .2. 1 .) showing that the insects can sequester the highly cytotoxic compounds and that warning coloration can be an ecological indicator for sequestration of the compounds. C.1.5.4. Bioassays with Whitetly and Aphids Insect pests, such as whitefly, aphid and the pathogens they transmit, result in excessive pesticide use but still cause high crop losses. Agricultural biotechnology may address these problems. Hence Drs. Dora Quiros, D. Emmen (Biology, U of Panama) and M Heller (STRI) developed rearing techniques, bioassay methods (96-well format for aphid and 25-well format for whitefly), and identified protein extracts, 5 out of 221 tested, that are active against whitefly. C.2. Preliminary Results from the Marine Program C.2.1. Introduction Following initial interactions between members of the existing ICBG and the OSU group to assess our respective interests and goals (beginning in July 2001), it became clear that there was great synchrony in philosophy as it concerns ICBG tenets, and we rapidly initiated efforts to 1) demonstrate the biological and chemical richness of Panama's marine flora, 2) to show the effectiveness of bi-directional transmission ofplant and algal samples for structural chemistry studies as well as for bioassay, 3) to streamline bi-directional information transfer between Oregon and Panama, and 4) to establish a cohesive drug discovery team involving scientists from all of the applicant organizations. Over the last 14 months of active effort to develop a marine component, we have made tangible and productive progress in all 4 of these areas, and this has yielded the isolation of several new compounds from marine algae, some ofwhich are currently being tested in the Panama-based tropical disease bioassays. A relatively large number of compounds from Panama laboratories have been analyzed by spectral analysis in the Oregon laboratories, helping to complete their structure elucidation. In a few cases, the structure elucidation of these terrestrial plant natural products has been a collaborative effort, and these research accomplishments will be under joint authorship between Oregon and Panama scientists. These highly positive interactions are thither described below.

__l PHS 398/2590 (Rev. 05/01) Page lOl Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GER)/VlCK, William Hefty C.2.2. Summary of Collaborative Interactions and Communications between Oregon and Panama Scientists

There have been excellent communications between the three nodes of this ICBG: Panama ~ Oregon - Utah. Communication has been most frequent by email; this has been facilitated by a "list-serve" concept such that information is copied to all participants in an automatic fashion. Phone calls between these nodes have also been highly successful. For example, several conference calls were conducted in preparation and review of this application document. Most valuable has been in-person interactions. Given that the Oregon program is not yet supported in a formal way from this ICBG, the level of interaction has been spectacular. The P.I. traveled twice in 2002 to Panama and met with all Panama participants. Coincident with a scientific conference, Gerwick, Coley, Kursar and Capson had a 2-day intensive work and planning session on this ICBG. A Research Assistant Professor from the Oregon laboratories, Dr. Kerry McPhail, visited Panama for 1 week in summer 2002 during which in depth discussions took place on NMR spectroscopy and NMR operating techniques, including hands-on training on the Panama-based Bruker 300 NMR spectrometer, and involved members of both the Cubilla and Gupta laboratories. In summary, the combined use of telephone, email, the intemet database system (see Section D.8.) and rapid mail services, along with periodic visits at the different applicant institutions, has already established a close working interaction and team spirit between the collaborating scientists of this ICBG. C.2.3. Preliminary Collection, Extraction and Inventory of Marine Algae During the two visits to Panama by the P.I. and one by Dr. McPhail, brief diving expeditions were made to different sections of Panama to assess marine floral diversity and standing biomass, and to make preliminary collections where possible. The diving sites were chosen so as to sample distinct environments in both the Pacific and the Caribbean, as well as to select habitats within National Parks where collection activities will be covered by the permits negotiated with ANAM (see map of Panama, Figure 7, API). The Pacific island of Coiba, a focus ofthe Panama ICBG conservation efforts (see AP4), was visited in January 2002, where a rich subtropical macroalgal and cyanobacterial flora was observed as described in AP3 (Section C.2. l). On the Caribbean side, a variety of habitats were sampled near Portobelo and a total of 16 different algal samples for culture and chemical extraction were collected. Mangrove-bordered coastline in the north-west region of Bocas del Toro was remarkably rich with cyanobacteria, particularly Lyngbya majuscula. As permits became available for collections from this area, four algal samples were obtained and encouraging preliminary results developed as described below. C.2.4. Preliminary Chemical Results with Panama algae Of seven crude extracts of Panamanian cyanobacteria, 5 were toxic (10 ppm) in a standard brine shrimp toxicity assay used to guide extract fractionation. Organic extracts of the largest cyanobacterial sample from Portobelo and from Bocas del Toro (a brown and a red L. majuscula, respectively) were selected for further chromatography. To date, the red L. majuscula from Bocas PANAMA del Toro has a series _ _ yielded complex L"b°'°*°"i°S of intriguing compounds (described in gl'lfffl';'fa'}§o§";I?>f"'°"°s""'§ I ;;'°S§"Y3113 ' Gupta laboratory reishmaniasis ------.- - _ AP3)- C11as=1S` disease C.2.5. Sample Exchanges for - ' Bioassay and/or Spectroscopic Analysis

_ = 4 an overview of Mass S Un" 5 Figure provides pectmscopy - S Gerwick Laboratories ; Low resolution data = 28 the transfer of chemical for Pm compound Hbmyz 7 <_,; samples f°S°1"*i°" dm =13 High spectroscopic analysis or bioassay, and Pam . 5 algae 5 the subsequent exchange of d ta Polpmmemy clude "mm :S (__, a

rgtahgng = 10 between the Panama laboratories and Optical pm compounds = 5 fractions = 1 State These _ _ semipure Oregon University. _ 3 interactions began in August 2002, and T1g§g;';'hagn1isition= 1 lim analysis = 3 i" the ease and efficiency with which samples and data have exchanged 0REq)N STATE UNIVERSTY been portends well for the effectiveness of the Figure 4: Schematic ofSample and Data Exchange between Panama and Oregon Researchers. Panama-Oregon logistic. Numbers indicate number of samples transferred; -P' transfer Ofsamples;----> transfer of data

l__ Pl-is 398/2590 (Rev. 05/01) Page O2» Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERWICK, William HSl'l[y D. RESEARCH DESIGN AND METHODS D.1. Introduction, Goals and Overview of the Associate Programs The Research Plan and organization of Associate Programs have been designed to accentuate and build on existing strengths and talents of this Panama-based ICBG. Ecologically- and taxonomically-directed terrestrial and marine plant collections will enhance our recovery of .novel bioactive natural products. A relational database well integrated into program objectives, operational features of the ICBG, conservation and biodiversity inventory efforts, and the excellent relationship with the host country institution responsible for granting collecting pennits (ANAM) combine to facilitate excellent information tracking and transfer. Innovative bioassays which target tropical diseases are of particular relevance to the host country as well as of global importance, and are appropriately complemented with strong mechanism-based (Novartis) as well cell-based programs in cancer drug discovery. Additional value of these unique ICBG plant collections will be captured through a broad-based agrochemical screen (Dow AgroSciences), and this will bring additional financial resources to Panama-based elements of the program (commitments of $25,0005,000 yearly from DAS, see letter of support, Appendix 3). Two strong chemical isolation and structure elucidation programs, one in Panama and one in Oregon, will work in synergistic fashion to rapidly dereplicate uninteresting known and nuisance compounds detected in the bioassays, thus allowing focus on truly useful materials. Exceptionally strong structure elucidation skills in Oregon will provide further opportunities for training and capacity building in the University of Panama-based chemistry efforts. Conservation efforts involving a combination of Panama governmental support, intemational NGO support, as well as private citizen support, are yielding tangible results in the Pacific Island park of Coiba; a proposal to designate Coiba as a World Heritage Site has been submitted to UNESCO (January 2003, see AP4 Section C.3.l.). D.2. Description of the Associate Programs The following presents a summary of the architecture of the proposed Panama ICBG program. A brief description of the function of each appears earlier in this proposal in section B.2., and a detailed description is provided in each of the respective Associate Program proposals. The interrelationships among Associate Programs are summarized in the following section (D.3.). While Associate Program 4 is especially focused on outreach, all Associate Programs will be involved in outreach and training consistent with their other research activities.

Group Leader = William Gerwick Natural Products Chemistry Ore on Stale U. & STRI

Central Operations Office in Panama ` Todd Capson, STRI

= AP3 Leader = William Gerwick AP4 Leader = Todd AP1 Leader = Phyms Cmey Ap; Leader Eduardo Ortega Capson p|ang Ecomgy Parasitologist/Physician Natural Products Chemist Natura|Products/Conservation STRI U Ulah 3, 3TR| INDICASAT Oregon State U. & STRI

Figure 5: Organizational chart showing the Group Leader and Associate Program Leaders, their disciplines and institutional affiliations.

D.2.1. Associate Program 1 - Panama Plant Collection and Extraction and Database Management Associate Program Leader: Dr. Phyllis D. Coley Smithsonian Tropical Research Institute and the University of Utah Collection of terrestrial plants Drs. Phyllis Coley and Thomas Kursar (Smithsonian Tropical Research Institute and the University of Utah) Extraction of terrestrial plants and data management Dr. Maria Heller (Smithsonian Tropical Research Institute) Collection of marine algae and cyanobacteria Dr. Kerry McPhail (Oregon State University)

_ PHS 398/2590 (Rev. 05/01) Page |O QQ Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERWICK, William Hen!! Associate Program 1, based at the STRI, is in charge of marine and terrestrial collections, extractions and data management. To help with the inventory and protection of Panamanian biodiversity, the Panamanian government and conservation organizations will have full use of our database. D.2.2. Associate Program 2 - Assessment of Bioactivity Against Parasites, Cancer and Agricultural Pests Associate Program Leader: Dr. Eduardo Ortega-Barrio Institute of Advance Scientific Investigations and High Technology Services Secretariat for Science and Technology (INDICASAT) Screening ofnatural products with anti-Tgpanosoma cruzi and anti-Plasmodium falciparum activity. Dr. Eduardo Ortega-Barrio (INDICASAT) Screening of natural products with anti-Leishmania activity, and in Panama-based 3-cell cancer screens. Dr. Luz Romero (INDICASAT) Associate program 2 focuses on the isolation and development of new remedies for the treatment of neoplastic and tropical parasitic diseases, and the discovery of compounds for the control of agricultural pests, Novel colorimetric and tluorimetric assays developed in the AP2 laboratories will be used to test samples for activity against parasites that cause American trypanosomiasis, leishrnaniasis and malaria. Efforts have been initiated to assess in vivo potential of compounds to cure both cutaneous and visceral leishmaniasis, using mouse model systems, with funding obtained from the Smithsonian (see AP2 and AP3). Cell-based assays [H-460 (lung), SF-268 (central nervous system) and MCF7 (breast)] will be run in the AP2 laboratory and mechanism-based assays will be run at Novartis Institute for Biomedical Research (NIBR). Dow AgroSciences (DAS) will evaluate potential agrochemical utility of plant and marine samples from Panama. D.2.3. Associate Program 3 - Isolation and Structure Elucidation of Panama Plant Bioactives Associate Program Leader: Dr. William H Gerwick Smithsonian Tropical Research Institute and Oregon State University Isolation and structure elucidation of terrestrial plant natural products Dr. Luis Cubilla (University of Panama) Isolation and structure elucidation ofmarine algal natural products Drs. Kerry McPhail and William Gerwick (Smithsonian Tropical Research Institute and Oregon State University) Associate Program 3 will focus on the isolation of active components from prefractions and extracts generated by API which show activity in the tropical disease, agrochemical and anticancer bioassays of AP2, and will structurally characterize the bioactive natural products from these sources. Investigations of terrestrial plants will be mainly carried out at the University of Panama in the Cubilla laboratories, While purification of marine algal natural products will be largely accomplished in the Gerwick laboratories at Oregon State University D.2.4. Associate Program 4 - Conservation, Outreach and Biodiversity Inventory in Panama Associate Program Leader: Dr. Todd L. Capson Smithsonian Tropical Research Institute (STRI) Conservation and Outreach Initiatives Dr. Todd Capson (STRI) Coiba Terrestrial Plant Biodiversig; Inventory. Dr. Alicia Ibdfiez (STRI) Coiba Marine Coral Biodiversity Inventory Dr. Hector Guzmdn (STRI) The role of Associate Program 4 is to link the activities of the APs l, 2 and 3 to biodiversity conservation by in the international with Way of public outreach and educational activities in Panama and community. By working the Panamanian govemment and various other stakeholders, we will implement programs to protect Panama's Coiba National Park, including having it designated in UNESCO's list of World Heritage Sites. Additionally, this AP will selected terrestrial and corals from Coiba carry out plant biodiversity inventories on Coiba Island, and provide plants Island for the drug discovery activities in AP2 and AP3, and in the laboratory of our Spanish collaborator Dr. Ricardo Riguera (see letter of support, Appendix 2).

PHS 39812590 (Rev. O5/01) Page O£-L Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERW|CK, William Hefty D.3. Interrelationships of Associate Programs which Reinforce the Program Goals D.3.l. Interrelationships The AP's of this Panama ICBG have been purposefully constructed so as to result in a logical and efficient drug discovery program while simultaneously integrating biodiversity conservation, in-country scientific capacity building, and infrastructure development (see Figure 6). The Program Leader, Dr. Gewvick, will provide overall leadership and administrative responsibility for this ICBG. A unique feature of this ICBG is that a large proportion of the scientific work actually takes place in Panama and is conducted by Panamanian scientists, students and technicians. As a result, it has been and continues to be imperative to have day-to-day administrative oversight and coordination in Panama. Dr. Capson is extremely experienced in this role, is fluent in Spanish, is located in Panama City, and will continue to serve as Manager ofthe Central Operations. Plant collections and extractions and prefiactionations (API) will be overseen by Drs. Coley and Kursar, the terrestrial component of which has been under their combined direction for the past 4.5 years. Dr. McPhail from Oregon will head marine plant collections and extractions/prefractionations under Dr. Coley's administration. A relational database of collection information, collection permits, bioassay results, bioassay-guided isolations, and natural products obtained represents a central repository of data from this ICBG. While under the direction of API, all AP's within this ICBG project will contribute data to this central resource. Its web-based nature allows all participants in this Program to remain up to date with progress on individual projects. Samples from API will be provided to AP2 for bioassay under Dr. Ortega-Barria's administrative responsibility at INDICASAT in Panama. Dr. Ortega-Bairia will supervise the tropical disease screens and 3-cell cancer cell line assays, while Dr. Capson will manage the Novartis collaboration on mechanism-based anticancer screening and Dr. Gerwick will manage the agricultural chemical screening with Dow AgroSciences. In AP3, active prefractions will be chromatographed to pure compounds, re-assayed, and structures determined using spectrochemical approaches under Dr. Gerwick's administration. The Oregon laboratory will focus primarily on leads from marine cyanobacteria and some macroalgae while the Cubilla laboratory will focus on leads from terrestrial plants and some macroalgae. The additional financial resources that will be obtained from Dow AgroSciences

l Pl - William Gerwick will used for postdoctoral the Y g ,__,Samp,eS be supportin P@"a"'@ and Slate STRL U"fQ°f' U""'°'S'W l *infiiimaiion Cubilla laboratory in Panama, and this n o - ~ n 1 | n individual will help inthe chemical isolation

AP1 - Plant corrections and extractions AP1 - Data management and Stnlclure elucidation of active fractions L@@<'5@f» PD C<>'cv.STR'. Panama 4* "* from the agrochemical assays (Dow as well as other bioactive , '5.__ AgroSciences) V compounds. The strong natural products - 3 AP2 screens . isolation and structure elucidation Biological - expertise AP4 c r _ _ 5 , , - inthe Leader s _ Program laboratory provides - cancer anama an ova s ouueacgfarigvfaow - - - - - (Pgrgmazu ) ; , rroplcaltrgseases new training and mentorlng opportunities to _ agriculture (Dow Agmsdences) gggpeéaigggson' the Panama-based natural Leadef E Ortega' |ND|CA5AT_ panama parallel products 5 f efforts (Cubilla laboratoW). Conservation, _ , , ' _ i 5 biodiversity inventory, outreach and APs - cnnmrear rsnrarrnn and structure elucidation ,F economic enhancement will be the focus of - F Dr. Capson in AP4, and will both provide - - - ~ ieffesffla:marine a gaePlanfé( regon(Ut1i/cgi?a e lgrgnatitialers' y) Leader: W Gerwick, STRI and Oregon State University fI1(€;1?;t;(inl;(;,;l;i1§i;u§nhance Fi3ure 6: Overview of the Associate Program interactions and Plant Collection 0PPOrtunities While _ . _ . . interrelationships in this ICBG proposal, including sample and data Simultaneously pi-Omoiiiig biodiversity transmissions. conservation As is clear from this straight-forward program structure, sample and information flow between AP's and participants is a necessity. As detailed in the Progress Report and Preliminary Results section above, We have already accomplished the smooth and timely bi-directional flow of materials between participants within Panama and between Panama, Oregon, Novartis and Dow AgroSciences. The web~based relational database used in this ICBG is our major mechanism for archiving information and ensuring its transmission to all participants. Additionally, all compound and sample transfers between groups are accompanied by electronic spreadsheets that identify the materials, and assay data from the various groups are also received electronically. Email with __,*_ PHS 398/2590 (Rev. 05/01) Page |Q§ Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERWICK, William l'l€l'l[y

attachments between the Gerwick and Cubilla laboratories has allowed for efficient and productive interactions on chemical structure eiucidations. Annual meetings, plant collection trips in Panama that will necessarily have opportunities for face-to-face meetings, and telephone and email communication will ensure the effectiveness and productivity of the above described AP and personnel interrelationships (see also Section D. l 1.4.). D.3.2. Adequate Personnel to Conduct Proposed Research A logical and streamlined AP structure which emphasizes Panama-based scientific contributions and capacity building is the hallmark of our proposed ICBG renewal. In this regard, we have plamied appropriately for adequate personnel to conduct the proposed work, although budgetary constraints have necessitated a less broad-based bioassay approach compared to the previous period of support (see description at end of Section B. 1. of this Group Plan). A self-review of accomplishments from the past 4 years of this ICBG program identified both strengths and weaknesses. The current ICBG formulation has built on program strengths while simultaneously providing solutions to perceived weaknesses. One such perceived weakness was in the area oforganic chemistry and spectroscopy as applied to natural products; this has been strengthened by the addition ofthe Gerwick Research Program at Oregon State University. At the same time, inclusion of the OSU program has added a marine dimension to the overall ICBG, which constitutes a parallel track to the ecologically-guided terrestrial plant program. - AP1: Panama Plant Collection and Extraction and Database Management. This AP has continuing strong leadership by Drs. Coley and Kursar, a team of three full-time field botanists, and the taxonomic expertise of Professor Mireya Correa, director of the STRI and National herbaria. Dr. Maria Heller will continue as laboratory head, supervising the botanists and 2 technicians who extract, fractionate and distribute fractions to collaborators. The experienced internet database manager, Lorna Sanchez, will continue with the project. Marine collections will occur under the direction of a Research Assistant Professor, Dr. Kerry McPhail, and will make use of graduate assistants from Panama and Oregon to provide the necessary work force. Species identification will be made by Dr. Gerwick and Dr. Valerie Paul, both ofwhom have decades of experience in Working with and identifying marine algal species. In Oregon, Dr. McPhail will direct the efforts of a Ph.D. student in the production of extracts and prefractions from marine algal extracts. - AP2: Assessment of Bioactivity Against Parasites, Cancer and Agricultural Pests. This AP will have continuing strong leadership by Dr. Eduardo Ortega-Barria and Dr. Luz Romero. They will direct the efforts of 5 technicians who will perform the assay of ICBG extracts, fractions and pure compounds in the tropical disease area. Dr. Capson will oversee the collaborative aspects with Novartis in mechanism-based cancer screening, and Dr. Gerwick will similarly oversee the collaboration with Dow AgroSciences. - AP3: Isolation and Structure Elucidation of Panama Plant Bioactives. The chemistry AP will be under the leadership of Dr. Gerwick who also serves as Group Leader of the ICBG. For pursuit of most algal and cyanobacteria] active materials in Oregon, he will be assisted by Dr. McPhail and one graduate student. Dr. Paul will also contribute fractionated algal extracts to the AP2 bioassays; these will result from her separately funded chemical ecological efforts. Pursuit of terrestrial plant active materials and some algae will be under the direction of Dr. Cubilla. His team includes 1 postdoctoral researcher, 3 students, and 1 technician. A postdoctoral researcher focusing on isolation and structure elucidation will be added to Dr. Cubilla's Panama-based program through ICBG- leveraged funding from and will focus on both agrochemical as well as human health-oriented projects. - AP4: Conservation, Outreach and Biodiversity Inventory in Panama. Conservation, biodiversity inventory, and outreach will be under the continuing experienced leadership of Dr. Capson. He will be assisted in the terrestrial plant biodiversity inventory by Dr. Ibanez, a botanist who has spent 4 years studying the flora of Coiba and who will be working with two student intems. Dr. Hector Guzman, a marine biologist and STRI staff scientist, will be responsible for coral biodiversity inventories. Biodiversity inventory will occur through the database management efforts of Lorna Sanchez with data derived from the collection and species identification efforts of API. - Central Operations. The Central Operations will ultimately be overseen by the Group Leader, Dr. Gerwick. Day-to-day operation will be the responsibility ofDr. Capson, and he will be aided by a continuing secretarial assistant, Erika Garibaldo. Dr. Capson will also co-ordinate legal agreements with ANAM and administer resources provided by STRI as described in Section D.7. D.4. Group Leader and Group Leader's Institutional Characteristics in Support of Application The Group Leader of this ICBG, Bill Gerwick, a faculty member at Oregon State University for 19 years, is internationally recognized for his contributions in marine natural products chemistry and bioorganic chemistry. His

PHS 398/2590 (Rev. 05/01) Page |06 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERWICK, William H6|'l[y

record of achievements includes more than 150 published research papers, more than 30 graduate and postdoctoral students that have trained in his laboratory, and the discovery of several compounds of broad importance and significance to various branches ofbiomedical science, including curacin A (Gervvick et al. 1994), antillatoxin (Li ez al. 2001), kalkitoxin GX/u et al. 2000), and scytonemin (Proteau et al. 1993). Because he has participated for 13 years as a member of a National Cooperative Drug Discovery Team and for 4 years on a Program Project Grant, and serves as Assistant Director of an NIEI-lS~Sponsored Marine Freshwater Biomedical Sciences Center, he is well aware of the administrative issues and other requirements that are imposed by grants to research teams such as in the ICBG program. In team-oriented efforts he has special abilities to build consensus among members through mutual respect, professionalism, and his obvious joy in scientific research. In Corvallis, he leads a 20-person team of diverse individuals in wide-ranging studies of algal collection and culture, bioassays, assay-guided isolations, structure elucidation by innovative methods, biosynthesis of secondary metabolites, cloning of secondary metabolite biosynthetic pathways from marine cyanobacteria, and biochemical characterization of cloned and over-expressed proteins with unusual reactivities. Successful coordination and management of this team has helped to develop his administrative skills and philosophy. He has participated in international research for many years through his sabbatical in 1990-1991 with Mats Hamberg at the Karolinska Institute, Sweden, his NCDDG program with principle interactions in Curacao, Papua New Guinea and Madagascar, and his recent support and participation in a US-Egypt Grant. His efforts in the field of natural products chemistry have been recognized by his peers through his elected Chair of the 1996 Gordon Research Conference in Marine Natural Products Chemistry, his appointment in 2000 to a National Academy of Sciences Committee on Marine Biotechnology: Biomedical Applications of Marine Natural Products, his appointment as Associate Editor of the Journal ofNatural Products in 2001, and his election as President of the American Society of Pharmacognosy for the temi 2002-2003. D.4.l. The Smithsonian Tropical Research Institute (STRI) Facilities STRI has an 80-year tradition of conducting terrestrial and marine ecological research in Panama, employs a staff of over 25 world-renowned scientists, and every year hosts hundreds ofvisiting researchers from dozens of countries. The STRI and visiting scientists include both marine and terrestrial experts. This ICBG project, based mostly in Panama and having a multitude of logistical requirements, would be impossible without the comprehensive and sophisticated support provided by STRI. In addition, our scientific research has benefited immeasurably from the opportunity to interact with this large group of scientists working on such a diversity of ecological questions. The proposed project also has the strong support of Dr. Ira Rubinoff (see letter of support, Appendix 1) who, since taking the post of Director of STRI in 1973, has promoted a major expansion in the scope of STRI's research, training and facilities. D.4.l.1. Scientific Facilities STRI maintains scientific facilities comparable to those available at a large university biology department. lt also houses the Panama ICBG's Bruker Avance 300 NMR spectrometer. STRI has a history of successfully implementing complex scientific projects. For example, STRI manages a forest dynamics project in which up to 360,000 stems in a 50-hectare plot on Barro Colorado Island are mapped and documented every 5 years, and has managed a multi-million dollar, 5-year project to investigate the consequences of an oil spill near Colon, Panama. STRI also manages the Barro Colorado Island field station which accommodates over 40 scientists, a facility in Gamboa (both with direct access to forest and less than 90 minutes from Panama City), and Marine Laboratory's at Galeta, Naos and Boca del Toro, including boats and scuba facilities. STRI has established and manages two construction cranes, 40-55 m in height with 50 m booms that provide research access to the canopies of dry and wet forests. STRI also maintains the R.V. Urraca, a 30 m vessel with room for 10 scientists and range of 3,000 miles. The Urraca is fully equipped for marine research, with easy access via the Panama Canal to both the Caribbean and Pacific. STRI provides assistance with access to additional marine sites, including Coiba and Coibita Islands and Bahia Honda. Managing projects of this dimension is feasible due to STRI's skilled procurement and accounting staff, state-of-the-art computer and communications facilities (satellite intemet), ease of shipping supplies from the US, permit facilitations, a fully equipped library, lawyers, and personnel managers. D.4.1.2. Interactions of STRI with Institutions in Panama Because many participants in our ICBG are based in Panamanian institutions, we have benefited from STRI's close contacts with Panama's scientific institutions. Many of the STRI staff have joint appointments at the University of Panama, including Professor Mireya Correa, head of the STRI and National herbaria. STRI works closely with Panama's Department of the Interior, ANAM, to arrange research and export permits for hundreds of __l,,1i__ PHS 398/2590 (Rev. 05/01) Page i0 I Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERWICK, William H6rl[¥

visiting scientists annually. This is a key service and one that is not available to visiting scientists in any other country in the tropics. ANAM's Ricardo Rivera, Director of Protected Areas, has worked very closely with Dr. Capson (see AP4, Section C.2.2.l.). STRI scientists serve on boards, technical or advisory committees for many Panamanian institutions including a conservation foundation, Fundacidn Natura, a new NMR and MS facility (INDICASAT), the national scientific foundation (SE . | i ii . | others. In fact, with STRI's institutional P _ t S support, Drs. Coley and Kursar received $69,800 from for bioprospecting research in Panama (prior to receiving ICBG support). For over 20 years, STRI's educational department has published in the popular media, staged workshops for the public, provided visiting scientist fellowships, organized educational programs for the public (e.g. the very popular Culebra Marine Exhibit in Panama City). STRI's education department and administration also educate businessmen, politicians, academics from non~biological disciplines who visit STRI. D.4.2. Oregon State University Facilities The Gerwick research group facilities comprise a total of 5 laboratories fully-equipped for marine natural products isolations. Their complement of analytical instruments includes a polarimeter and IR and UV-Vis spectrometers in addition to Photodiode Array (PDA), UV and refractive index (RI) detectors for HPLC. Structure elucidations are facilitated by ready access to three NMR spectrometers (300, 400 and 600 MHZ) housed in the Department of Chemistry and in the Agricultural Life Sciences Department, as well as the support of the Mass Spectrometry Facility at OSU which houses 7 mass spectrometers including a MALDI-TOF instrument. D.4.3. INDICASAT Facilities INDICASAT was unveiled in October of 2002 by the National Secretariat for Science and Technology in Panama and is based in Panama City. INDICASAT will be the site of the Panama-based bioassay efforts in AP2 and will also provide facilities for the purification and structural elucidation carried out by Luis Cubilla's group. INDICSAT consists of a large, modem complex ofoffices, laboratories, and library facilities. There are seven research laboratories, six for chemistry (850 sq. meters total), and one for molecular and cell biology (308 sq. meters). The laboratory dedicated to the AP2 bioassays is currently operational and includes all ofthe facilities for modem cell and molecular biology research. Dr. Ortega-Barria is the Institute's Coordinator for Research and Development and Dr. Romero is the coordinator of the Center for Biomedical Studies. Equipment for purification and structure elucidation includes a .leol 400 NMR spectrometer, an IR spectrometer, a Jeol HPLC Mass spectrometer, an Agilent Preparative HPLC, and a GC-MS (Quasar, AM-D-INTECTRA). The equipment will be operational by August of 2003. D.4.4. University of Panama, Department of Chemistry Facilities The Laboratory of Biologically Active Natural Products, the site of Dr. Cubilla's research, consists of two laboratories for chemistry (710 sq. ft) and one dedicated to HPLC analysis (163 sq. ft.) with a modern Waters HPLC with preparative capabilities (600E quaternary pump, radial compression preparative columns, diode-array detector, fraction collector and Millenium 32 software). Dr. Cubilla's laboratory facilities include fume hoods, 5 rotary evaporators a UV-Vis spectrophotometer. Office facilities include 4 modern IBM computers, all with email and internet capabilities and with the necessary software (MS Office, Chem Draw, etc.). Each computer has its own printer and one has a scanner. In addition to providing the mentioned above, the University of Panama has also excused Dr. Cubilla from teaching responsibilities (see letter of support from Eduardo Flores, University of Panama, Appendix I). D.4.5. Smithsonian Marine Laboratory at Fort Pierce The Smithsonian Marine Station (SMS) is a research center specializing in marine biodiversity and ecosystems in Florida. The facility serves as a field station which draws up to 100 top scientists and students each year from the Smithsonian and collaborating institutions around the world. D.5. Description of the Associate Program Leaders - API: Dr. Phyllis Coley »~ Panama Plant Collection and Extraction and Database Management Dr. Coley will continue to lead the collection and extraction efforts ofAPI, which will include the collection of both terrestrial plants and marine macroalgae and cyanobacteria, and subsequent extraction and prefractionation of samples. She is an internationally recognized leader in the field of terrestrial plant ecology, whose research focuses on the evolution and mechanisms of defense by plants against herbivores and pathogens. Her published theory on plant defenses (Coley et al. 1985) revolutionized the field and is still the dominant paradigm for understanding plant investment in defenses. She has received a Career Advancement Award from NSF (1995) and was recently listed as a highly cited researcher in the field of ecology/environment (ISI, 2002). Dr. Coley has worked together with Dr. Kursar for over 20 years on the mechanisms by which rainforest plants are defended against attack by herbivores and i_, PHS 398/2590 (Rev. 05/01) Page \O 3 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERVWCK, William HS|'1[y pathogens. The insights obtained from these investigations have been incorporated into the sampling and extraction protocols of this ICBG. The ICBG informational database was developed under Dr Coley's leadership, and the administration of this database, as well as the distribution of samples to the various components of AP2 for testing will continue to fall under Dr. Coley's capable supervision in API. As a faculty member at the University of Utah for the past 20 years, Dr. Coley has trained 14 graduate students, including 9 Ph.D. students, all of whom have taken university positions. - AP2: Dr. Eduardo Ortega-Barria - Assessment of Bioactivity Against Parasites, Cancer and Agricultural Pests Dr. Eduardo Ortega-Barria will work as leader of AP2. He is the head of Research and Development at the newly funded Institute for Advanced Scientific Investigations and High Technology Services (INDICASAT). This Institute was unveiled in October 2002 by the Secretariat for Science and Technology and consists of a large complex ofoffices and laboratories for chemistry, and modern cell and molecular biology research. Dr. Ortega-Barria brings over seventeen years of parasitology experience, including two years in Mexico, six years at Tufts University and five years at Stanford University and has published on the cellular and molecular biology of Giardia lamblia, Trfypanosoma cruzi, Acanthamoeba castellanii, Pneumocystis carinii, and Toxoplasma gondii. During the previous funding period, Dr. Ortega-Barria directed the program responsible for tropical disease research, leading to the development of three novel techniques for screening materials against the parasites responsible for leishmaniasis (both extracellular and intracellular forms, in collaboration with Dr. Romero) and malaria. Those assays resulted in the discovery ofthe compounds discussed in AP2 and AP3 (Sections C). His laboratory is only four years old but is recognized nationally and internationally, having offered its screening services to Dr. Abimael Rodriguez (University of Puerto Rico, Rio Piedras), Dr. David Kingston (Suriname Madagascar-ICBG), as well scientists from African and Latin American countries.

- AP3: Dr. William Gerwick - Isolation and Stucture Elucidation from Panama Plant Bioactives: section D.4.

- AP4: Dr. Todd Capson - Conservation, Outreach and Biodiversity Inventory in Panama (and Central Operations) Dr. Capson will work in two capacities in the ICBG program; (i) coordination of the Panama-based ICBG activities through the office of Central Operations and, (ii) as the leader of AP4. For the Central Operations component, his full-time presence will help ensure the coordination ofthe Panama-based components ofthe ICBG, a role he has fulfilled since the inception of the currently ongoing Panama ICBG headed by Dr. Coley. For the past six years, Dr. Capson has worked productively with two different ANAM administrations, designing and implementing complex and novel initiatives such as benefit-sharing agreements for drug discovery and implementing infrastructure improvements for ANAM. The productive relationship with ANAM has resulted in the timely approval of 40 permits for collecting and exporting materials. Dr. Capson was primarily responsible for building relationships between the Panama ICBG and the Novartis Institute for Biomedical Research, negotiating the legal agreement and implementing prefractionation strategies [in collaboration with Dr. Heller (APl)] and for arranging the purchase, installation and maintenance of the Bruker 300 NMR spectrometer, the first such instrument in Panama. Capson routinely provides an interface between Panamanian ICBG participants and US-based institutions and vendors. His role as leader of AP4 is a logical extension of the conservation initiatives he spearheaded over the past 6 years in Panama. He is primarily responsible for the development of the ongoing conservation strategies for the Coiba National Park, bringing together local and international NGOs, intemational research institutions and private individuals into a coordinated initiative to help protect the park (see AP4). D.6. Prior Collaborative Efforts of Group Members The composition of the group has been carefully selected for individuals that share a common vision for this ICBG andthe ICBG philosophy and have a proven ability to work in multidisciplinary teams. Evidence of effective collaboration is detailed in the Section C.2 of this Group Plan. All members of the program except for the P.I. (Gerwick), the marine natural products chemists (McPhail and student), and collaborating algal ecologist (Paul) have been working on the existing ICBG, and their record of success in plant collections, bioassays, compound isolations, conservation efforts, and outreach strongly supports a continued effective interaction. The P.I. has been developing preliminary results with Panamanian algae, as well as preparing for this competitive renewal application, over the past year, and these interactions have been extremely positive and effective (see section C.2. above, as well as AP3 Section C.2). The construction of this application and research plan has required extensive communication and effort on the part of all associated personnel.

PHS 39812590 (Rev. 05/01) Page ] QS Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GER)/V|CK, William Henry D.7. Functions of the Central Operations Office Central Operations will be located in the main office facility at the Smithsonian Tropical Research Institute in Panama City and will serve the following purposes. (i) organization of meetings, conference calls and report writing among Panama-based ICBG participants and interfacing those activities with the P.I. Gerwick and API leader Coley; (ii) drafting of legal agreements for the ICBG, (iii) coordination with the Panamanian government, in particular, the National Authority of the Environment (ANAM) for all ICBG-related issues, including the drafting of reports, application for collecting, transfer and export permits (see Appendix 6) ; (iv) ensuring a consistent flow of samples and data between all ICBG participants in Panama, US (Universities of Utah and Oregon State, Dow Agrochemical and the Novartis Institute for Biomedical Research) and Europe (Universidad de Santiago de Compostela, Spain), (v) coordination with STRI accounting and vendors for all ordering of supplies and equipment, negotiating with vendors, and follow-up on orders for all Panama-based ICBG participants, (vi) coordination with STRI administration for management of personnel issues including the drafting of contracts and, (vii) maintenance of the Bruker NMR spectrometer. D.8. Description of the Group's Relational Database The current ICBG project has developed an information system specifically tailored to our needs for maintaining records of plant collections, transfers of samples and bioassay and chemical results. The goal of our information system is to maximize accuracy and ease of use, and to facilitate rapid access to results by all members ofthe Panama ICBG. To accomplish this, the infonnation system has a database located in the API laboratory at STRI, and an internet-accessible, password-protected database that can be accessed from the other participating institutions in Oregon and Panama. The database includes information on collections of marine and terrestrial plants (e.g. taxonomic identifications, collection locales, collectors, dates and GPS coordinates, ecological information). All collections by API are given a unique barcode identification, and bar code labels are placed on all samples leaving the laboratory, as well as the herbarium voucher specimens. In addition, the database contains information on extracts, distribution of samples to different laboratories, results from our bioassays, results of bioassay-guided fractionation, and structures of active compounds. Each laboratory has its own barcode reader and software. Results from the bioassays are recorded directly from the 96-well plate readers into an Excel file where all identifying information has been obtained from the barcode. The Excel format is the same for all AP's, so the information can easily be imported directly into the centralized database via the Intemet. The database is described in more detail in AP l (Section D.l 1, also see Appendix 7). D.9. Overview of the Training Programs The training of young Panamanian scientists has been a hallmark of this ICBG since its inception and will be emphasized in each of the four APs. Because the majority of this program's activities actually take place in the host country, training of students occurs as an integral and essential element of the project. In addition to the specific roles described below, participants in each laboratory will be involved in outreach activities in which they will organize and present their results in public (described in greater detail in AP4, Section D.l.). Participants will also learn the importance of working as part ofa large, well-coordinated, results-oriented team andthe importance of each of the individual components. Participants will learn to organize and present their results in frequent and objective research meetings. Participants will also learn and refine the skills of writing reports and drafting manuscripts for peer-reviewed journals. API will employ three full-time botanists and two Panamanian interns who will gain experience, both in the field and in the herbaria at STRI and at the University of Panama. ICBG botanists will continue to work and train with Professor Mireya Correa (a foremost authority of Panamanian flora and Director of the STRI and National Herbaria), with Drs. Coley and Kursar (each with 25 years experience of working with the Panamanian flora), and with AP4 participant Dr. Alicia Ibanez (an expert in Neotropical flora with four years of experience working on the flora of the Island of Coiba). In addition, two chemists will gain experience by making extracts, pre-fractionating samples for Novartis and analyzing samples by TLC and HPLC. In AP2 a total of 5 BS- and MS-level Panamanian scientists will be working under the supervision ofDrs. Eduardo Ortega-Barria and Luz Romero and will continue learning the techniques required to culture cancer cell data lines as well as malarial, leishrnanial and trypanosomal parasites and perform in vitro assays and management. In AP3, the expertise of Drs. Bill Gerwick and Kerry McPhail and a Ph.D. student in Oregon will be an extraordinary resource for Dr. Luis Cubilla and his group of researchers in the areas ofpurification and structural PHS 398/2590 (Rev. O5/01) Page ILO Continuation Format Page Principal lnvestigatorlProgram Director (Last, First, Middle): GERVWCK, William HGH!!

characterization of natural products. Through the Oregon facilities, Panamanian scientists will have access to a wide array of modern equipment for structural analysis. In Dr. Cubilla's laboratory there will be 5 Panamanian scientists who will receive training in natural products chemistry (1 M.S.-level chemist, 2 B.S.-level chemists, l technician, and 1 postdoctoral scientist). In AP4, Dr. Alicia Ibanez will continue to train under Professor Mireya Correa and the API botanists. Dr. Ibanez will provide training to two Panamanian botany student interns. The ICBG program will continue to provide exceptional opportunities for Panama-based NGOs to be involved in large-scale and multi-institutional programs directed towards biodiversity conservation. D.10. Strategic Plan Outlining Schedule of Activities, Expected Products, Benchmarks for Years 1, 3, 5, and 10 and Long Term Sustainability Beyond the ICBG Program Year 1 ~ We expect to evaluate crude extracts of 150-200 species of plants and 50-75 species of marine algae and cyanobacteria in the first year in the tropical disease and cancer cell assays. Prefractionations of a subset of these will generate approximately 1,500-2,000 materials for testing with our collaborators (Novartis and DowAgroSciences). We expect pursuit of approximately 20 active materials (extracts or prefractions) during the year. If the Workload exceeds this, Dow AgroSciences has offered to perform fractionations of agrochemical leads in Indiana, and AP1 can provide some follow-up fractionation of materials as well. We expect the rate of publication to increase to 5-8 research papers per year, and we hope for one patentable discovery to be made. Training of2-4 Panamanian students in botany and an additional 2-4 students in natural product isolation and structure determination is expected. The Coiba conservation project should be well underway with efforts to obtain additional funding to support delineation ofthe Park and a floristic survey. Year 3 - The level of productivity identified above will continue resulting in a three year screening total of 4500 - 6000 materials, each of which will be evaluated in the various bioassays. This should result in 15-20 research publications, 2-3 patents, and 12-20 Panamanian students being trained. The antileishmanial aporphine alkaloids recently discovered in this ICBG program will be characterized (during year 1-2) for in vivo toxicity and therapeutic activity using funds from STRI ($65,000) which are supplemental to this application. We expect that at least one of our promising lead compotmds, such as the aporphine alkaloids described above, will enter advanced pre-clinical testing with a collaborating pharmaceutical company during year 3. The Coiba park will be well advanced as a national showcase for conservation efforts and the ICBG program, with a well defined flora, a buoy- defined park boundary, and a strengthened and knowledgeable corps ofpark guards. The Panamanian people will know of the Coiba-ICBG project and be aware of the economic value of conserving biodiversity through our outreach activities.

Year 5 - A vigorous and well-established natural products drug discovery community will exist in Panama, including chemistry expertise at the University of Panama and a superb bioassay facility at INDICASAT. Strong collaborative connections will exist between these organizations and STRI as well as with a number of US-based universities and pharmaceutical companies. A tive-year total of 5,000-8,000 materials will have been screened, with efforts in the latter years ofthe grant increasingly focusing on developing lead compounds discovered earlier. This may be through analog synthesis or isolation, mechanism of action studies, in vivo evaluations, scale-up culture and harvest of biomaterials, and/or technology transfer issues. Publications (25-35), patents (3-5), and student training (20-30) will be widely appreciated in Panama through our outreach activities, and this will additionally enhance Panamanian support of biodiversity conservation. The Coiba project will be at a mature state with a published and a widely accessible web-based flora, a well established Park Botmdary, and synergistic interactions with adjacent stakeholders insuring appropriate resource utilization and an enriched economy. Year 10 - This Panama-based ICBG has provided critical support for programs in Panama-based organizations (University of Panama, INDICASAT, STRI), thereby developing the people and the facilities in long-lasting and significant ways. It is not possible to know if the ICBG program will be providing support to this program in 10 years; however, the infrastructure and personnel support will continue to reap benefits for Panama for many years. It can be anticipated that investigators currently supported by the ICBG grant will obtain funding from other sources for their natural product drug discovery efforts, and will continue these efforts and training long after ICBG support is completed. It is conceivable that some ofthe agents discovered as a part of this ICBG will be advanced as clinically-useful drugs or pharmacological tools, and a revenue stream will be directed to Panama. Conservation efforts underway at present and proposed under this application will result in a strengthened agency for conservation in Panama, a greater appreciation of the economic value of biodiversity, and a well-defined conservation focus (e.g_

PHS 398/2590 (Rev. 05/01) Page 11] Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERWlCK, William H€f1[y

Coiba National Park); at the 10-year benchmark we expect Coiba to be a World Heritage Site with a well-defined park boundary (buoys), a defined and accessible flora, a knowledgeable Park personnel, and a balanced policy for meeting the needs of conservation, resource utilization (fishing) and tourism. D.11. Assurances to be Considered Responsive to this RFA D.11.1. Statement of Compliance with ICBG Program for Access, Intellectual Property and Benefit Sharing The team members ofthe Panama ICBG assure compliance with the ICBG Program Principlesfor Access, Intellectual Property, and Benefit Sharing as detailed in the RFA. Our compliance with Intellectual Property and Benefit Sharing is addressed in detail in section D.l2 of this application. D.11.2. Outline of Steps to Obtain Prior Informed Consent to Carry Out Proposed Research All of the necessary legal arrangements for the ICBG were addressed in section D.l2. We do not intend to use traditional knowledge or work with indigenous or campesino communities for any drug discovery work associated with this ICBG program. D.11.3. Statement of Acceptance of "Terms and Conditions of Award" " The team members ofthe Panama ICBG accept the "Terms and Conditions ofAward as described in the RFA. We understand these to include l) Awardee Rights and Responsibilities, which involve a program lead by a Group Leader (William Gerwick) which focuses on Drug Discovery and attendant rights to proprietary data, intellectual property, and publication; Biodiversity Conservation with a focus on species inventories, enhanced host country capabilities and value of biodiversity, meeting national laws and regulations, voucher specimens, publications, and development of biodiversity databases; Scientific and Economic Development in Panama, including identification of natural products of value, enhancement of the scientific infrastructure, strategic plan, involvement of host country governmental and non-governmental organizations and policy's, sustainability and communication of results through a variety of mechanisms, and 2) the Nature of the US Government Assistance, which is recognized to include advice, suggestions and assistance from the Coordinator, access to the NCI's 60-cell line screen, use of NIH contract-based resources to facilitate development of lead compounds, access to reference compounds, laboratory testing capacity, searches of computer databases, and experimental biological materials, and 3) Data Access and Standards, including minimum data quality and format standards, and integrated relational database of inventory and drug discovery activities which are provided to the Coordinating Center on a regular basis, and 4) Collaborative Responsibilities, including regular meetings between team members and participation in ICBG-wide conferences at the NIH campus, and 5) Arbitration, as specified in the RFA. D.11.4. Plan to Maintain Close Collaboration and Effective Communication Among Members ofthe Group - Team Building This ICBG program in Panama has been functioning for the past 4.5 years, and most of the lines of communication and relationships among investigators have been established and are now functioning smoothly. The inclusion of the Oregon Program into this ICBG creates a new long distance interaction; however, the Oregon program has 1) been working closely with the Panama participants over the past year in sample acquisition, testing and analysis, as well as in the planning and writing of this grant application, and 2) the Oregon program is highly experienced in working effectively with collaborators at distance, having participated in the following funded programs: Human Frontiers in Science projects (US-Japan-Italy), US-Egpyt Program, NCDDG program (Oregon- California-Oklahoma-Florida-New Jersey), and an on-going P01 grant (Oregon-California-Mirmesota-Florida-New Jersey). Specific plans for maintaining close interaction of all members of this ICBG team include regular monthly conference calls involving all team members to review progress, plan experiments, and establish priorities. We will integrate the Panama ICBG website into these discussions so that data can be looked at in real time by all participants during these conference calls. Twice annual meetings of all participants will occur, mainly in Panama; however, during the course of the 5-year grant, we will have one meeting in Oregon of all AP leaders and several we will key personnel, probably in year 2. If funds are available (possibly from our collaborating industrial partners) also seek to have a meeting of all AP Leaders, in addition to the annual ICBG meeting in Panama, at the Novartis in Indiana. One of these campus in East Hanover, New Jersey and/or at the Dow AgroSciences Campus Carmel, twice annual meetings will occur during research activities in Panama by the Oregon and Utah groups, and will thus will occur at make synergistic use of travel funds. Additional meetings between the Panama ICBG team members the prescribed two meetings at the NIH Campus, as detailed in the ICBG RFA. By rotating the location of these

I PHS 398/2590 (Rev. 05/01) Page HL Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERWICK, William Hen!! meetings, enrichment in the interactions between team members and a knowledge of each others institutional strengths will occur. All Panama ICBG meetings will have a chair and a secretary; these leadership responsibilities will also rotate so as to encourage team and consensus building. The chair will be responsible for drafting a.n agenda before the meeting and running the assembly. The secretary will be charged with noting key developments and progress inthe ICBG program as well as Action Items deriving from the meeting. The secretary, working with the website administrator, Ms. Lorna Sanchez, will post this report and action item list in a timely fashion on the group's website. These documents, constituting a 'Newsletter', will ensure a timely follow-up on research findings while at the same time providing a mechanism for dissemination of research results and directions to students and other laboratory workers that may not have been able to attend the meeting. The password protected nature of this website will ensure that data and research priorities are shared openly and in a timely fashion. As noted in the proposals for Associate Programs 1 to 4, a substantial number of training and workshops are planned. Some of these will provide important avenues for training and team building. For example, as a part of Associate Program 3, personnel from the Cubilla laboratory at the University of Panama will visit and receive additional training and experience in 2-dimensional NMR spectroscopy as applied to structure elucidation. The close hands-on interaction between these laboratories will substantially aid in building a strong and cohesive team effort. D.12. Plan for Intellectual Property and Benefit Sharing In the previous funding cycle, participants in the Panama ICBG negotiated a novel suite of legal agreements forthe ICBG program, working in collaboration with experts in intellectual property for drug discovery such as Mr. Michael Gollin, a specialist in intellectual property law at Venable & Associates (Washington DC). For the sake of expediency and flexibility, a series of two-party agreements were established between STRI and each of the institutions collaborating in the ICBG. The first agreement was negotiated with ANAM and signed on the April 8, 1999 and defined (among other issues) procedures for collecting and exporting biological materials, the distribution the of access payments and revenues that may result from royalties and milestone payments from drug discovery, establishment of an environmental trust fund, ownership of intellectual property, and the terms of STRI's collaborations with academic and industrial collaborators for their ICBG program. ANAM has indicated their willingness to re-negotiate the agreement between STRI and ANAM for the next cycle of the ICBG program (see letter of support from Ricardo Rivera, Appendix l). Two-party agreements were also signed between STRI and the following institutions: the University of Panama, the Panamanian Ministry of Health, the University ofUtah, and Novartis Pharmaceuticals Corporation. Memorandums of Understandings were also drafted and signed between STRI and Oregon State University; and between STRI and the Universidad de Santiago de Compostela in Spain. Agreements that have been drafted and whose signature is expected in near future include (i) an agreement between STRI and Fundacion NATURA for the establishment of an enviromnental trust iiind and (ii) between STRI, Conservation Intemational and ANAM for the installation of a series of buoys around the boundaries of the Coiba National Park (included as Attachment 1 to AP4). Upon renewal of the ICBG program it will be incumbent upon STRI to renew or draft the two party agreements with (i) ANAM; (ii) the University of Panama, (iii) INDICASAT, (iv) Novartis Institute for Biomedical Research, (v) Oregon State University, (vi) the Universidad de Santiago de Compostela in Spain. We anticipate establishing a similar sharing agreement to the current one, which stipulates that Fundacion Natura receives 30%, Vida Silvestre (the ANAM trust ftmd for Protected Areas) receives 20% and all participating institutions share the remaining 50% of any benefits gained.

PHS 398/2590 (Rev. 05/01) Page jj Q Continuation Format Page Principal Investigator/Program Director (Last, First. Middle): GERVWCK, William l'|Qfl[y E. HUMAN SUBJECTS None

F. VERTEBRATE ANIMALS None

G. LITERATURE CITED

Andraka S. 2001. World Wild Life online article. http://www_worldwildlife.org/wildworld/profiles/terrestrial/nt/nt0224 full.html Ballou TG, Dodge R, Hess S and A Knap. 1989. ASTM Special Technical Publication, 1018 (Oil Dispersants: New Ecol. Approaches): 229-256. Barthlott W, Lauer W and A Placke. 1996. Global distribution of species diversity in vascular plants: Towards a world map of phytodiversity. Erdkunde 50:317-327. Barthlott W, Biedinger N, Braun G, Feig F, Kier G and J Mutke. 1999: Terrninological and methodological aspects of the mapping and analysis of the global biodiversity Acta Bot. Fennica 162: 103-110. Burke L. Reefs at Risk in the Caribbean. In: Prioritiesfor Caribbean Coral ReefResearch: Resultsjrom an International Workshop ofthe National Centerfor Caribbean Coral Rez#Research (NCORE). October 3-5 2001. Capson, TL, Coley PD and TA Kursar. 1996. A new paradigm for drug discovery in tropical rainforests. Nature Biotechnology: 14: 1200-1202. Cervino J, Goreau TJ, Nagelkerken I, Smith GW and R Hayes. 2001. Yellow band and dark spot syndromes in Caribbean corals: distribution, rate of spread, cytology, and effects on abundance and division rate of zooxanthellae. Hydrobiologia 460: 53-63. Chicarelli-Robinson MI, Gibbons S, Mcnicholas C, Robinson N, Moore M, Fauth U and SK Wrigley. 1997. Plants and microbes as complementary sources of chemical diversity for drug discovery. Special Publication - Royal Society ofChemistry 200: 30-40. Coates AG and JA Obando. 1996. The geologic evolution of the Central American isthrnus. In Evolution and Environments in Tropical America. Eds. Jackson BC, Budd AF and AG Coates, Univeristy of California Press, CA. p 21-56. Coley PD and TA Kursar. 1996. Anti-herbivore defenses ofyoung tropical leaves: physiological constraints and ecological tradeoffs. In. Tropical Forest Plant Ecophysiology. Eds. Smith AP, Mulkey SS and RL Chazdon. ha man and Hall N.Y. » 305-336.

7

' ' ' ' Condit R, SP Hubbell, JV LaFrankie, R Sukumar, N Manokaran, RB Foster P an s ton _ _ pecres- area and species-individual relationships for tropical trees: a comparison of three 50-ha plots. J. Ecology 84:549-562. Condit R, Pitman N, Leigh Jr EG, Chave J, Terborgh J, Foster RB, Nunez VP, Aguilar S, Valencia R, Villa G, Muller-Landau HC, Losos E and SP Hubbell. 2002. Beta-diversity in tropical forest trees. Science 295: 666- 669. Cragg GM and DJ Newman. 2000. Antineoplastic agents trom natural sources: achievements and future directions. Expert Opinion on Investigational Drugs 9: 2783-2797. Cragg GM, Boyd MR, Hallock YF, Newman DJ, Sausville EA and MK Wolpert, 2000. Natural products drug discovery at the national cancer institute. Past achievements and new directions for the new millennium. Special Publication - Royal Society ofChemistry 257: 22-44. Cragg GM and DJ Newman. 2002. Chemical diversity: a function of biodiversity. Trends in Pharmacological

- ' 1 1.1 1. PATENT PENDING

D'Arcy WC. 1987. Flora ofPanama Checklist and Index, Missouri Botanical Garden, St. Louis, MO.

PHS 398/2590 (Rev. 05/01) Page'] [L-1: Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): GERWICK, Wi|lia[!1Hen[y D'Croz L and DR Robertson. 1997. Coastal oceanographic conditions affecting coral reefs on both sides ofthe isthmus of Panama. Proceedings ofthe International Coral Req'Symposium, 8th, Panama, June 24-29, 1996 Ed(s): Lessios, Harilaos A.; Macintyre, Ian G. 2: 2053-2058. Publisher: Smithsonian Tropical Research Institute, Balboa, Panama. Document of the World Bank. Project appraisal document on a proposed grant in the amount of USUS$25.345.34 million equivalent from the global enviromnent facility trust fund to Panama for the Panama Atlantic Biological Corridor Project, March 16, 1998. Earle SA. 1972. A review of the marine plants of Panama. Bull. Biol. Soc. Wash. 2:69-87. Food and Agricultural Organization (FAO). 2001. State ofthe World 's Forests. Food and Agricultural Organization of the United Nations, Rome, Italy. Frormann S and G Jas. 2002. Natural Products and Combinatorial Chemistry - The Comeback ofNature in Drug Discovery. Business Briejing: Future Drug Discovery 84-90. Gerwick WH, Proteau PJ, Nagle DG, Hamel E, Blokhin A and DL Slate. 1994. Structure of Curacin A, a Novel Antimitotic, Antiproliferative and Brine Shrimp Toxic Natural Product from the Marine Cyanobacterium Lyngbya majuscula. .I Org. Chem. 59: 1243-1245. Glyrm PW and .IL Mate. 1997. Field guide to the Pacific coral reefs of Panama. 8" International Coral Req' Symposium, pp. 145-166. Smithsonian Tropical Research Institute, Balboa, Republic of Panama. Goreau TJ, Hayes RL and T McClanahan. 2000. Conservation of coral reefs after the 1998 global bleaching event. Conservation Biology 14(1): 1-18. Gross EM. 1999. Allelopathy in benthic and littoral areas: case studies on allelochemicals from benthic cyanobacteria and submersed macrophytes. Ed(s): Inderjit, Dakshini KMM, Foy CL. Princioles and Practices in Plant Ecology 179-199. Publisher: CRC, Boca Raton, Fla. Haber WA. 2000. Plants and vegetation. In N. M. Nadkarni, and N. T. Wheelwright, editors, Monteverde: Ecology and conservation ofa tropical cloudforest. New York: Oxford University Press. Harborne JB. 1988. Introduction to Ecological Biochemistry, 3'd Edn, Academic Press, London. I-Iaug GH and R Tiedemann. 1998. Effect of the formation of the Isthmus of Panama on the Atlantic Ocean thermohaline circulation. Nature 393: 673-676. Haug GH, Tiedemann R, Zahn R and AC Ravelo. 2001. Role of Panama uplift on oceanic freshwater balance. Geology 29: 207-210. Hay ME and SD Gaines. 1984. Geographic differences in herbivore impact: Do Pacific herbivores prevent Caribbean seaweeds from colonizing via the Panama Canal? Biotropica 16: 24-30. Hay ME and JN Norris. 1984. Seasonal reproduction and abundance of six sympatric species of Gracilaria Grev. (Gracilariaceae; Rhodophyta) on a Caribbean subtidal sand plain. Hydrobiologia. 116/117: 63-94. Hay ME. 1996. Marine chemical ecology: what's known and what's next? .L Exp. Mar. Biol. Ecol. 200: 103-134. Hay ME. 1997. Calcified seaweeds on coral reefs: complex defenses, trophic relationships, and value as habitats. Proceedings ofthe International Coral ReefSymposium, 8th, Panama, June 24-29, 1996 Ed(s): Lessios, Harilaos A.; Macintyre, Ian G. 1: 713-718. Publisher: Smithsonian Tropical Research Institute, Balboa, Panama. Henkel T, Brunne RM, Miiller H and F Reichel. 1999. Statistical Investigation into the Structural Complementarity ofNatural Products and Synthetic Compounds. Angew. Chem. Int. Ed. 38: 643-647. Hubbuch, C and P Craft. 1995. Searching for Palms in Eastern Panama. Journal ofthe International Palm Society 39(3). Ibanez R, Condit R, Angehr G, Aguilar S, Garcia T, Martinez R, Sanjur A, Stallard R, Wright SJ, Rand AS and S Heckadon. 2002. An ecosystem report on the Panama Canal: monitoring the status of the forest communities and the watershed. Environmental Monitoring and Assessment 80: 65-95. ISI Web of Science, www,siI-1ighlyCited.com drift on a Kilar, J. A., and J _ N. Norris. 1988. Composition, export, and import of vegetation tropical, plant- -reef Panama Coral Re¢ 7:93-103. dominated| frinl ini i atform iCaribbean

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Li WI, Berman FW, Okino T, Yokokawa F, Shioiri T, Gerwick WH and TF Murray. 2001. Antillatoxin is a marine cyanobacterial toxin that potently activates voltage-gated sodium channels. Proc Natl Acad. Sci. USA 98: 7599-7604. Myers N, Mittermeier RA, Mittermeier CG, Fonseca GAB and J Kent. 2000. Biodiversity hotspots for conservation priorities. Nature 403: 853-858. Navarro JC. 1998. Panama, National Parks. Ediciones Balboa S.A. Panama City, Panama. Newman DJ, Cragg GM and KM Snader. 2000. The influence ofnatural products upon drug discovery (Antiquity to late 1999). Nat. Prod. Rep. 17: 215-234. Newman DJ, Cragg GM, Holbeck S and EA Sausville. 2002. Natural products and derivatives as leads to cell cycle pathway targets in cancer chemotherapy. Current Cancer Drug Targets 2: 279-308. Panama ReefMonitor Update RMU Portobelds Coral Reefs: Healthy and Holding - October 2001 http://wwwreetkegper.org/CRM/DownloadSite/PANAMA/Panamahtml Paton S. Smithsonian Tropical Research Institute's Terrestrial-Environmental Sciences Program (T-ESP) Meteorological and Hydrological Monitoring Program on BCI. http://www.stri.org/tesp/Data.htm. Proteau PJ, Gerwick WH, Garcia-Pichel F and R Castenholz. 1993. Indolic structure of scytonemin, an ultraviolet sunscreen pigment from the sheaths of cyanobacteria. Experientia 49: 825-829. Qiangqiang Z, Jiajun W and L Li. 1998. Storage of fungi using sterile distilled water or lyophilization: Comparison after 12 years. Mycoses 41: 255-257. Reigosa MJ, Sanchez-Moreiras A and L Gonzalez. 1999. Ecophysiological approach in allelopathy. Critical Reviews in Plant Sciences 18: 577-608. Rich PV and TH Rich.1983. The Central American dispersal route: biotic history and paleogeography. In D. H. Janzen, Ed, Costa Rican natural history. Chicago: University of Chicago Press. Robbins CS, Sauer JR, Greenberg RS and S Droege. 1989. Population declines in North American birds that migrate to the Neotropics. Proc. Natl. Acad. Sci. 86:7658-7662. Stevenson CS, Capper EA, Roshak AK, Marquez B, Eichman C, Jackson JR, Mattern M, Gerwick WH, Jacobs RS and LA Marshall. 2002. The identitication and characterization of the marine natural product scytonemin as a novel antiproliferative phaimacophore. J Pharmacol. Expt. Therapeu. 303: 858-66 Tosi J. 1971. Zonas de vida. Republica de Panama FO:SF/PAN 6, Injbrme Tecnico 2. FAO, Roma. Pp. 123. Tulp M and L Bohlin. 2002. Functional versus chemical diversity: is biodiversity important for drug discovery? Trends in Pharmacological Sciences 23: 225-231. Waterman P. 1998. Natural Products for Drug Discovery: an Overview. In Harvey AL (ed), Advances in Drug Discovery Techniques. Wiley, Chichester, UK, p. 13-23. Webb SD. 1985. Late Cretaceous mammal dispersals between the Americas. In Stehli FG and Webb SD (eds), The Great American Interchange. Plenum Press, New York, p. 357-386. Wellington GM. 1997. A field guide to the corals and coral reefs of the Galapagos Islands, Ecuador. 8"' International Coral Req" Symposium, pp. 145-166. Smithsonian Tropical Research Institute, Balboa, Republic of Panama. WHO Infectious Diseases Report, 2000. http://Www.who_int/infectious-disease-report/2000/index.html Wu M, Okino T, Nogle LM, Marquez BL, Williamson RT, Sitachitta N, Berman FW, Murray TF, McGough K, Jacobs R, Colsen K, Asano T, Yokokawa F, Shioiri T and WH Gerwick. 2000. Structure, Synthesis, and Biological Properties of Kalkitoxin, a Novel Neurotoxin from the Marine Cyanobacterium Lyngbya majuscula. .L Amer. Chem. Soc. 122: 12041-12042. Wysor B, Kooistra WHCF and S Fredericq. 2000. Marine Macroalgal Diversity of the Republic of Panama. Poster presentation at the Annual Meeting of the Phycological Society of America, San Diego, CA, 15-19 July 2000 http1//morayeel.louisiana.edu/SeaweedsLab/Wysor/PSA 2000/poster.html#anchor2837646

H. CONSORTIUM/CONTRACTUAL ARRANGEMENTS Subcontract to Oregon State University in Associate Program 3

I. LETTERS OF SUPPORT See Appendices 1 through 4

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~ Leiter §r<:m Augei L1;iS .Huesu I\f1"€>1§wH_, \-'ice Rectm <26 {3€s§z§rfu21§é¢;aoic;n 3 3>r<>x_¢:cL:=ic»az Ext¢afif;11' Elrmivfarsiiiaéls €1¢:.§fé11ztiiz§<`:= de Qcrnpsstcia - mtiiar from Qnfique Lupez '=f<:i<>sc>, Ciabifzeie dc Imacisma 'EEmcr§<>r:e§, €§<:>rr11nursicac§.<>s'= ez P§'€}'?§,f,1~iL£}i{fii'2 Ex'1@,§'ioz" Lia 'U;;§=férsiriaéeS2mt'iag¢:>fic:€€§I§`1§§f3$¢i€';§t ée S2mt'iag¢:> fic: €€§I§`1§§f3$¢i€';§t

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}3y1his iaiter I agree: so the féfoup Piaz; as <>ut`iine(i in £1z<:¥{ZiE`»€l¥ we §I'TiF§OiZ`lff}/ ~pr@p=ari_ng. Ihavf: read. tha §?,E%"'A ,for tizis grsmt ,.zpp1icazion, as wail as me -Cifaup 263 E'izaumz¢;'t`21;EIL!i Hg Fiexu and mise? ,éxswc-iatc d.owznr>rx£;s ass»acia§f:1.i with tixis (Zan-a¥¥3s. {><'e;;i2§x Progiwtu app§i:;at,i-;m, 3. am is $733 §»f$§i}§' maxi smihusiaaio partécipata in ihis pragaaizz as P.rizxci;>£c»z invwiigatcr sf Msocsiam ?rogram 3 as we!! as Gmap Leader tizr the averaii apgii¢a£iQn¢ 'fffxe mcfrgéng and irztazg-§,fz\iio'i`1*<:swrc§\aifisriaincanwrandxi1:<:=pé¢_'>:1§diseasedwg o'i`1*<:swrc§\ aifisria in canwr andx i1:<:=pé¢_'>:1§ disease dwg éiscovéfy' Wiilx ?;1`§fITE'¥$§F£1i°l`ii.§Ti3 ani? racofriczalfaif; iizzvzlrainrzzcsxi ;u:;c¥. tfairzing in Panama, as wfrii gas c-mzsewation ané biadiversity invcuiary efforis, is an cx.<:a&a¥sg f>f1';m r§nr?=r§;y is Eaave gmsitivc impafris an I1umazahandf§§'J¢3{£}[}!I1£}!Tz¥,' and f§§'J¢3{£}[}!I1£}!Tz¥,' issues in Pzmazna, iam £1121 y in aga,'c=¢¢~fwn§ wi££z the ICEQE Fzograrn §'rin<>ipif=s fb: Access, I1§te¥¥¢<:tli:;¥ Propzérty anfé l;en_¢i'§`i-s.Exaa'ing sw éaiaiifbfi in Sfzciian 4 af

' tim ""i'f:m1s; and ilosrdiiions ef f§wai'd" inf" Q'i§ i{.i"A '3`Wf€33-66%.

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?r@i"e§s<§: William Gatwick ¥C§3-G iwgram Laacier Caiiegc of Fiuarmacy Gfegon Siaicz l,5n§' Curvezliis, Gregmn "9'?33I

Qaar B§§¥:

/as me teazier oz? Associate, ivogram 3 3124i the 1% o;r1'ihe pwvi-omg gxanz, E elm akiigixteci im par.ti¢§p»a£e in the ICBG projeci for Effmama.1@;c¢wihe<3roupE'¥ar;as <>u'1'fined éza ibn ICBG we arejointly preparing. Z have raw time RPA for ihis grant appiécaiion, mv weii ws lbs: Group Fiim awe? x>1§zez' Associaie Yrogfam documenis wsasiaawé wi£i=a this fzpplicaaiion, The merging @s;1;§if;tr:§;'a£ir>i\ ef :esesa:~c§>_ effbns in can#/er imc? impieai c¥£§ca$f: drug d§s~so=.f¢ry witia igiifasirilcvxae ami eeonmnic nievmE»;>;>x§;<2n£ ami if&'§§1ing £3 Panaxrm, as w&E§ as C(3i"iS&{'V&{§_fZ![`£ ami §;ig>§iversity inxfn;1£<3zy'c§f0r£s, is an ~ excéii ag; oppwiunéiy to have pos£§iv¢e ixxzpacis ofa hurnasi }ma¥tiQ ami i§i€?\f*Z'Ji'€§§?i'i"i§k'if issues -in ?:ma1na@ E arf; fuiiy in agfe¢m¢111 wiih l§€1¢iC§3eG f*rog1'an1 §}riz1ci;'1i=zcs for Access, iniclisetxsai §?'sap=°:rty semi benf:i`ii~sbau~ing as r;i¢i::.iieri' in the llf§BG' WA.

With ima wishes ,fer szmzess!

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Q; £hks¥£9shcQmupPimaasowimdéntheNEHGwea:-ejfrimiypr::pmfi_ng,¥mfs: £9 shc Qmup Pima as owimd én the NEHG we a:-ejfrimiy pr::pmfi_ng, ¥ mfs: rsmci the R¥=`f%, fer ih¥s gwmi appiication, as Wd? as the Group P3a]1_zmd miner Assmiata Proyam éwammss assafnimczé wEt§1ih§S ¢7=;>§.lEc:»miQr1, and fam emieusiasiic £9 parii<;ipatf:§ni¥1i$ program, The _mgrgjng and iniegfaiizm of researcia a~§f<>:£s in www and ampécai ciése»as»a» drug vriéh iZi§6S§¥l}¢fLi¥'£3 and scffmcmic c_lm»*eio;7mef;t mi? 'training in Pmaizm, as w¢Ei as ¢i>;§m*f§i£on and hiodiversiiy i|'1'V<:¥2ts;:fibm,_is3.¥'!_@KQ§1;.l§§<>p§:z§>f°£;mi£yiohaveposiiiveimpsasisonhuman s;:fibm,_ is 3.¥'!_@KQ§1;.l§§ <>p§:z§>f°£;mi£y io have posiiive impsasis on human Emkh and éssuwiniwzanza,Earaf:;i%§finaj;,re<:¥I=<~>f¥iwithtize1€¥%GPmgram éssuw in iwzanza, E ara f:;i%§f in aj;,re<:¥I=<~>f¥i with tize1€¥%G Pmgram Primiplrrs fsf AKMSSS, 1f12e£i<:=<:.1zmE Propnmy ami ?:en<>i2t¢s.21ariz1g as cistaiiect én the ICRC? REQL

will bmi wishw for Summa!

Sineeraai >f , , ix =" _ ~i f-'ii _` Eiéuardo ri »» fr§a,?=é.I`>, iloorédmtoz, 'Rei I-;>i1a,nci ¥}w¢iopz'1mz§_ Insxituta of Acbfansreé. Saixmtific §fnvessti_ga*.:£arxzs éz; High Tecixxz-rziegif fiecvicfzs3* 11\E?ZJ3€IA5A'%"_

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HEAT) `\~~4' Sm§_ths<>§¢§an opizzal l2.a$eamh §ns¥:itzm v. v - 5- . Ekzsiixtuio Srzxzthsorxzan de, l{T»'@S{Eg£l€3i€}§`§€$S Trapicaiiizs

Iasmargg 30, 2C¢

Professor Wikliam %~er'wir>é< PCBG i'mgram Leads; Ceiiagfa oi' i*harmAa¢y <}reg>;:»r1 State Univszs§1y Cr:-wfsiiis, Gatgon 9'f33i

Ifhzar Biiiz

By ihis iettm 1 agrfse £9 time Gtcup Pixu as intheICBGweare§oint15fprepaxing. in the ICBG we are§oint15f prepaxing. I have read tin: Rlffég fm* this gram application, as weii as fha (imap Pizm and other Associate ?rogram éocments asseeéaizd with this &§1}§§§¢&fi¢31i,§i1}€i § am eniimuséamk in parzinipata in this pmgram, 'Fha mefgizzg a;>£1intn_Qfres@arf:kx e;#£s in mmf smé tfopimai éiserase ciiscovesywithinirast-mammaand¢CCfZIOH`1i£3+;i<"va1spf¢1_an1arré ciiscovesy with inirast-mamma and ¢CCfZIOH`1i£3 +;i<"va1spf¢1_an1 arré irairiifzg 5:1 Panmm, as wel! as conservation and iwiudiverséry imfsnimry efforts, is an exciting Qpgwxiwxity io iiasfez pesétive imgagxis an Ezumam ixcaith an-ri dev<~;.l<;»p1z1en§ issuesg in ?am11na, fam §ui§y £3 afgreauteai wiik tha {Ci%{i ?rogra1°11`¥?risaf;¥_§»Ies for Access, §n=`.e§isa¢§=;;;»§§ Pmperty ami bcne;=§it'~shaifing as f;if:2£a&i§§<§ in the ICBQ RPA.

'ii`i€:1 hes! wisivss tb: szxmess!

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Dr, Wi11i2m Ei-L €3i°r~&~;f2< » _{>m§es:;m* ofivicéicilaal amé Natura? Precfums €§IIze;r'e§§=;1°y ` CQ1iz%ge of §?'§1:?¢z1:'z9Jc;f Qregon Stax: Urzivezaaity C0,l°'\¥aE§iS, Qregmi §??3§§ 43507

QM Dr, Gerwiciaz

This E<:t€fer<§2*s1§ppcsrt fznsiozses the irfterzxaiifmal Coeagmvative Biodiversity Groups {ZC%G§ pfnpesw cmiil-ed "I%iand§`>1>:zigyDiwaiexiI13f;§g;1">§;~;@§<>1f<':¥';f*if;F2m&zrxa" and §`>1>:zigy Diwaiexi I13f;§g;1">§;~;@§<>1f<':¥';f* if; F2m&zrxa" which yan will be sainxsiming up iim i't"€Jg,ar1y ixxtamafrional iflfzsamr Qfiiae !\Ia§iQ_m{ Knstitmes af Health.

The Smithsonian "f.`ropi§>a1 Rwcarzix E:ezs£§is,§ic is cfkznrnéiwzii to cazaiisming tha goak of Q36 Fémziina §€§3{`i p19<>g;i'&z13 as w¢i¥ as time speciiizzs qi? ysxuf p1'1;::§€><;i_ We feel that thi; progimxm comriianies is tim basic mseamiz programs of13"§`R¥ and c>omg;¥_cm¢:nis wr <.x;ng»ervatioz;, aducaiisn ami cuLr<2a»c%wf'12>rts. As we §'1§£`~if3 agrzzede, ST&?'\1¢>misez°x'~¢ as Zine siie £3fYQ§E£ Qli.1"IZlZ`Z£§ 0§l$i`@.§.i{}¥`¥3, '§l£`<)¥'i.£$G iaboraxtory apzxm, as Wei! £13 ¥§x§s_;'zeg:<°zs"$£1£;f IogiSii<:é3,¥, admini§=1_ra;!_iva and wsomzniing s_;zp;>c>r¢,` We will aku assist with wfablishing garuacfsilip with Pau1;1;'rz:;z1ia1z fxgmiwiians cQ1iai">0ra2izzg with thég pmjwst.

We wisix you ilu: i'f-fssé of Zack. with your exmeiient pwposzai,

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Bsiimaéo Dr. Capsenz

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Dinar Mr, Capsmz:

We I"mm¥a;,* wésh to thank yan for the fmiifui mopmmien \#i1§¢i1 we £225/a had ww: me :mama af ihe past ya-51? 2052. it has hmm a pleasure be Weffk§<}i:1-z1y,in several Emma ixswar-52; cmzservaI.i<>n K3 ?&n2J§12s,

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As; a Rzatcsr of tha £Iniv»:z~si_i"y Qi Qanama, i am very pieaseci because Dr. Cu bilm £s par; of £32 Efacuity of Naimal, iifcarxis ané Tacixnniogy Seimas Qi this instimiicn ami :lisa pewficipani in mis ;,>m§e<;4;, '¥'§zc ]}i'»i)_fifAL3$, zéaovs mswon, Em :méc pessibia tha pzazciaaszz of mq:ai';m;<:ni and ma§r:1§a¥S éhm imve fa¢:5§§'£=5zt¢é tim §raim§n§; nf <:.he_m.i§£ry s€1§de§°»§:s sud oihars 1f'»€'.Ez,si=~1=:f;i §f:§és of siuéy, fmatthe:sametimeithas;c<>11trii>uz¢dinmeprc¢§'wc~r¢onnitm: at the :same time it has; c<>11trii>uz¢d in me prc¢§'wc~r¢on ni tm: Univefsiiy of}?§:§§1m,a ai rxaii¢;ma§ and inzemarienai Eevei .as walk in the same way as xv-s, have sag;-pthe¢>oi_iabafDr.(Zubiliainthezesasarchpfeicct"_}5`e;a>!agica3£ygwifiezfE2£a;Jrf2apfer:z'i1;g-in_Pafwm:¢*'.§wma?foIe-EyoukngawthatIWD11Ec}.faaiiiiaicihélfwiipemiciiixaticwxlQ25Ui.Cfuiaiiiain£2335fH»se§z2z'a?131projeilt.Formatpr,zrp£>s;1;hewiiis:zz;,§aszzfemmzéx;>ro£es§<§rwiifixsmteachingcfu£i¢:sasiozzgaswepoggiiziycan,Wearewiflingtoxvriwa:wwsgrwxneni;iz;zhis,razgaréifneeded, the ¢>oi_iabafDr.(Zubiliainthezesasarch af Dr. (Zubilia in the zesasarch pfeicct "_}5`e;a>!agica3£y gwifiezf E2£a;Jrf2apfer:z'i1;g- in _Pafwm:¢*'. § wma? fo Ie-E you kngaw that I WD11Ec} .faaiiiiaic ihél fwii pemiciiixaticwxl Q25 Ui. Cfuiaiiia in £2335 fH»se§z2z'a?131 projeilt. For mat pr,zrp£>s;1; he wiii s:zz;,§ as zz femmzéx ;>ro£es§<§r wiifix sm teaching cfu£i¢:s as iozzg as we poggiiziy can, We are wifling to xvriw a :ww sgrwxneni; iz; zhis, razgaré if needed,

5. xugpon mis-s iniiiaiivc zifzé wifi provisié 2131 necassexry aéminislrativc supgaori and other ¥<<1ai`iities so that Er. C¥2¥>i¥}a Can 5a1fcf:@a¢.5f;1i§y mari? fmt 1-his proffeil;

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Dt. {}:m.wi¢i;_ fihaak yen fer giw me passibiiky than Dr. Cubiiia Lzaiws part of aim you; for me msasamla gmpesai *thai you and mlm' ef your wiieague me swnziziing to tim Natinnak inszissuws af Hcalih ¢:ri`1¥xe¢ L§ni§e& Stains xviih iixzz §iE~:z: "Biez-may ané Emiegf Hireeteé Bmg Discavezgf ` in Panama".

Z an very piuaad that Qs, Qxziailia as par; af the Qoiéege of Ewlzurai, Emote and Tcmcxlsggf Scimzcez is paxtiazipatin in tizizs prc;§eci. in éhe wma way as we i33¥¢ suppcrieé tha partiaipaiéefn of Er. Cubilia in 'Jae msssamh '*§miog&<:4e11y ga§d»;»é bimpwsmeiwg in I*'ana;~n&?', Time proéeet has made p<,>ssih%e the puzcimse of cquipxneni anci mateziais thai has facrliitatsri the: ftnailzézzg nf aheniishy sfzxécwfis and mixer fEfz1z'?»s='»'Jf smégf rcizxtcd fzz;§ it has cxmizihxrirsd at the same time iss the ;;»ro§er;'f§§m of the Univzfzxsiw af P`3,¥1i'3Ii1§§-i§12'3A miiionai -as we1I ess hztexzzzazioxaai i»2:v¢::E.

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f\.ft£ir.1»f;1e: ma lrmmi. _ 6G»E,9Q<3n1a§3f,:~vm A I'_recip:itaii0zx he£;we=r;.=n 2,'2Q{}~4,f}l`3'€I mm pear year. Bcoayfstrsna §}f§e;az Tviaaist and Wet "§'a~<:»pi1:a§ Fosest, Pxemimtzanfe Wet Fo-mst mad ?fenz<'>z1Lmiw Ra_iizfgfe5i4_

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Gmar '1`o.;;_§';@§ AH, Na£iQzxz»1! Pgzrk 25,2395 ¥'1c'x~I1.Eiz"~:'\':Si1"i (Koala §=1'0Vi2'i<;f?>, ii? fini ci3L1;a,try*ss ..._ <:;:ntralnmnntain,1'a;1gr1__ ,M.____M-__ ..,_, ,__._.-,,,_,__,,,, ,W _-,_____,._,_,_,*_,_,,_,`,__. ..:AHti1§§5E,§§.§§~I;3.€¥&§§§§§é_§éé*E'?§1_; ?recipi'§:atin§1: 2,890 mm of; tim Pacific aiop-ea and 4,506 mm on ihae Caribbuan siups. iioosyst-:'ax2'1 iyfgzesz Pfcn1<>'§1!;ame Rain I?€>1"4'3,Sf, 'Wei ?re1no»1'§'€fanWet'£`wpi»ca§`§4`o;'fzsi. Wet '£`wpi»ca§ `§4`o;'fzsi.

]*»i1m§%ner GF E1m3'¥ifss: 35 Nxmxber Qfgexaefii; 62 (gms £6 mm iQIes§i£§<: Numbszr Qfspecies; 50 (pins 39 nor; id

in Qfsgégerag §ati=m1a¥ Psxrg 4 EQQGQ iaestarcs on téxz maxi si&¢ ¢f§?;f:. E;>¢;:r<§¢=z*s Qfihsf; Panaina Ca;;ai,, in lime pfovi-aces of }"'zzm1;°z1a ami Co¥ Aiiifmdsa; 2€§~?.€3{% rf; n§>m>vf: sm iw-fe! ?rec§piiaciQn: l5¢§¥}€¥ :um para' year. §G(3$§f8f£}l"i'1 iypei mafia: i'm;,a§<:aE fomsi,

Numb;/rr of ihmiiica; 3.5- Nw';%bc:° cpfgrcnera: I 113 (piws S H-on =irien£ii§¢n£} ?=P*.1mbe.r Qf`SjI§&§CiG$! 123 (plvs 6 u-on idiiféiiiieci)

'éalcan iéam Nziianai Fark £4,322 hacimezs in Cixériqui preaxfincc. .f5x1£i¥udzr.; iA,3§{> 'iii 3,4'?4'§;E &f3€3`&f€t sea lfswl Precipifatio nz 4,(}Q{}»5,¢3{}f} rm; pez* year, §3<:oay:¢£ems £_~,=~;:>§=a; low ¥'I`§f)§S£ m<>=a¥a1;e fewest, low §m:>az§rafxf; ami mgiamfao razixaliaaxsem, wan imv n1<;>n'1zm<> ibrest araci pr<°:f_n£1nlan'f§ raii§;fQ§"f;3Sl

WWWWV P'¥'4$ 3§T!J`;§;`;>0 iiféav. i35»"f3TF§ Qage ______C~rzntin ;\Ti*¢nnat '§`*a§§; r>rzw;;;=fa' |f=weszig¢=z¢>1~zr»f<_=Qfam uramfggasr, F§fs'I, Midri¥e}t €_-3E3RWiff;§, $?'~*E¥€iar15;x Hgmgy;

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Fariuna Hgrh'ograQh Rwerve i9,§€i'3 lwciafifs in Chiriqui province, AEt§!;xzde: i,2®~ 2.,Gf}lf} ITL fi{3=f)5}*'S€¢fIi Type: ?¥emomane rainfowst, *wi prezaawztazm forest and iw; mzarzwmz raimfarcst,

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Aims: ée €f§a:a'a;1aaa'I\?a£iona§ ?afk @3155 éwxitgws QQ the wasizerra s§<>p¢ :sf tha §'anasr;a Cami Ai$it=sd;¢:; 4€?8»8§€} HE above sea ievei. I>'¥<:¢>§}Ji¥ⅈ§<>£§: éxzmficis 2¢,'5(}Q mm pcs yfmr. §3cmsys§cm_ iypfsx moisi arid, wei trcpicai forfzsi, wxrl §3i`5LI£IEO¥§lB¥l<'5, garernonezme mimafomst.

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?~%11z'nbez'o££&mi§i»ss; 31 Nn4m_b<;r oi" gamma; 4iI¥ (plus L non i Numbzr of speaies: 35 (pix £6 non i&mniE<":ci}

Qtirexrs gfuws §_zz;is;:eiia§1#w-11s ealleutimlsg P€{u1n?:>sr of famiiéesz 3? Numbsr of gefmraz 5? (plus 12 mm idez"1ti1?ie&} Nuxnbaf of S;'§f=¢ic;s: 45 (pins 25 fum ié::nzif§§:ci}

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'iiewo iiogm ¥'~§§1i§i>f§aI Fark ` 325399 iii-'?Cf¥1I"f3S iii iflfi' p£"<>§fiz2G<:5 *I3f'XI€?1'ilg`£££§S and L05 Sémtfila. ,$4,S59m-aiscvaseaIcvei. $4 ,S59m- aiscva sea Icvei. mmm in Fmcipifatian; 2,G€}£} a,nua§Ey the ivwiands near tiw was! Q-Q waxirnaszn <;f'4~,£`}OG mm on me laighesét fr\fs1.mtain_ pe:a£<;s_, Eow mantafa-Q mira m<>ir;£ Eiswsystcm types: fmrcsi, very éow xnontaim fmmfst, premonwnc rain Eoresi, very moist ami prmncanimzs f`Qm2t_ moist irropical fmcsi. ,

>Cai¥m Natiwzai _Park 2.'?Q,0€3iZ¢ §ef.;£ams= <2-1* ismnda, féwsts, Emazcrires, £"l7££l[£g¥'C¥'v'€»S mi c<>ra~E rwfs. Lacam* in the Famanzanwn Facific in '¢'§r§ggaze-vim/iz, gaze-vim/iz, ,:5§.~l€ifZ¥.¥€1@Z G~ 416111 abfévc wa ievaif Pmcipim-tifxni Qafimatfed if; iw; 3,§€]€} inn! pei" yew. `E%ca>S5:;»a£¢|.rz tygvfesez waist iropicai Foraisi, vgfy zz";<:»§i»:'i preemcfxrlierxe iizzmsi.

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ifgmta ?at_§§;> ?*~ia!§1»,1'e gmcervsf 3€`§,€)€}{I1 §1<:<:£az<:.§ Q? iocaiezi in Qarieia pfwvflzwrz. .éiiitudaz Q»i€3£`3 m abcwc aaa icvsi Pre<:i;pim!i§3£fG~§5€3i3mmpwyear §3£fG~§5€3i3 mm pw year fiwsysmm types: mais# pazmoniane f<#£¢s;£.

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Se1*mu§a_ Qia Bavgfe §ig}f;g§cfa§ CQJVQQ 36,908 heatafes in Darian Fmvince, Ymcipiizftionz a'§f:>v©?.,5€*Q mm pe1'y<:&i' Ecosystem iygesz mr>is£ tmpical Earesi, very mais; impiaal. fm1~,st&f2¢;i v'~:»;iy mc>§s£ _pr<:11s<>1amr1c frwesi.

A £'§Zx1zg1éz1_ I?oIi&sE R1¢$<2r¥é 3 1 55% hfzcmws of highiy diszurbed lefwiand Forest ixz tix: Darien Province.

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` 13.6. Marine ifkéififziiorn 3§£L:s €s;mei_i'i1é aim Qi.) - 2% 93. ?I'ax9;;=;>my' af A!g;x¥ Cij§}{£i3fi€%EiS {s;f;airixn#3) airixn #3) 2% f QS. Escxiatiea z¢n<¥`C\,;{f;1xrf> of Marine -iiyasmbact-en-'ia fvsgseciéic aim-fiigi V 2% $3.52. Ex£z'acti<>1s and iwfefracfrionaiiolx E*r<>eQforMarianaQeliectinns for Mariana Qeliectinns ispawzifin 3§¥I-1 #23 Ziff? 3.39, 1'itrmi$$ fm" {;`6¥§e£¥i.0n 3:16 ,$§IB1f}§¢'¥1`3¥¥?,€f£§!` {§pr¢4:§i'Ec aim #3) 2i'lfZ, 3,1 3, Baia i\"¥ar_\ag;e§=m::;;¥_ {$}3c§s;§i'i¢ aim #Q 283 9.12, ()xf§rea;h and ikissemim-ltinn Qi' l`nf0r|n§1t}Qn(s;;e£i¥§c a_in1?§S) 234

` £3*.i3., 'i"z*2z3§xiX1g and '§*fschfw¥fJg§f 'I`r~ansfer fspecific aim ?f'é»} 265 lil. i;¥U£\fiA€*3 SUB.§EfI"¢§YS 2% Ei. V§iR'§*%$E3 R_A,'§`I§ _A§'€iP=f¥A 206 Ci, L-I'F`i?l¥ifi"¥S¥5¥l}£ {L'I'E'¥§I} Z0-6 ff. €ff0I'3S0i'§'§`¥ U M/{f{}I`2'1T`Ré (I"i`§,?A L A R§¥,A.N GEMEMS ZH i. L¥?3"§"i`¥§R$ QF SUPP'€}R'I`{Cf;msu1f;arzisfifulmboramrs) 213

m»*Www»w~ A M ' £f'H-3 i3£§fii2§»Q£'> (§@v_{?§31`£E1) Page; CQ#'e§!nz.4a€ii&|'z ff-£2?[¥li§£ Paga f=m»¢¢;:@=: zwwiiwfwwgfafn mmm g;¢1f»i,¢1f==§, mmda@1¢,§L€§»€ifff£€3K, Wgigggggqslq A. SYECHHC A`{E'¥iS

'Ffhe izvex-nil Qi"/§saociate goaia ?r<>gram I (fam), amish mirwr those; £`>{'IQZBG,amioprmneze IQZBG, am io prmneze cwncmic isisciiversiiy conservation, <;a.pa<:f§i.y buiiaiing, ami effective éiscaxfery ef €h<:rapeu€i;: ageffm fm* hurnan heaith. te inzzrfzase ihe We ;z3a1z, prebabiiiiy nf éiscovaring aatiw ccrzzgnounés througi; the: use =::fe¢;oiogi¢a§ irsight te- gnidc want oolieciisns as Wei! as the prociuction of high quaiify extfacis made fmm fresh -tissue. 'Pa ;;r<>;r;o.§;e c,apac§iy iauilding amd txainirag far Panamzmians, we are coeaduciing tim majorisjv Qfiifa §escs=arzi:, in Panama. To with heign iise i{¥\~'€€I¥i0¥`§f and gwteaxliofa of?a;§a;1°;_arfian b§,od§vwewiliworkciwsiywiththe we wili work ciwsiy with the f£'arfamf1:1izm arxi frsrsserrvation gnvemnaerxt organizaiions such tha: they szaa :make riaaximum use -of sur awk-abase csntairzing <:itzfafmaticmcmther§¥s£z'i¥:>u¥:ic>11,aialmfinncfaandééanti§i<.;at£Qnofgxiaseis,Md§inaiiy,_tm itzfafmaticm cm the r§¥s£z'i¥:>u¥:ic>11, aialmfinncfa and ééanti§i<.;at£Qn ofgxiaseis, Md §inaiiy,_ tm enhance gmbiéc awareness of the value: ami iiawats is 'b§c>:iiw,rs§zy, we wi§§ §'!H§i€}i}}&fS in f%,P4»<:<><>:c&irmz»:d acfiviiiws $0 rcgai.arIy gs; gnfassiataéivns ia puisiic and private $<$§1*(}{3lS, ia park gsxzzsds, to the ganefai }'li,1b']§0, and tc scziecixiifk a§;&§¢~:ac>@s_

'Jfhfs speciiie aims of the ¢<%.P1 r@>s¢fn'prograxnareasfoiiowsf prograxn are as foiiowsf

Ti.. TQ use eeuhgical iz:»s,ig¥1t is guide c¢x¥¥e;:£Em\s 0i"f|'1sSi1 tissue fiom £ferresi`riai and au-arirae pkanis. ir; the €}u1'a;>pAf~ir;the£>urm§1tPa11an1aIQZBQEhaslaw;tvasc=.*2=<:oi<§gica3insighi€@ezokiecttwesizialplants,andto £>urm§1tPa11an1a IQZBQE has law; tv asc =.*2=<:oi<§gica3 insighi €@ ezokiect twesizial plants, and to exiract ffzsb raifxcr than cirieai fm? iissnc, Tizis approach has pz'ovi<3ed rf:pr<;<3;1c>i2>¥§.>,"QuaIiiy mxiracis thai have shown high :sctiwiy in hi-Qassays, ?uI§d£)§)`¥`i§'¥§C§ fzmgi uziii be izwiamd ffom fresh ieavesf 'Eze a.ridi££<>u of maxim-Q aigal cQEk:ciifa-as imiiris fm tha sllcsass UED1 {3e>iabomimzyw¥'t§1Qém§sc;»Ea£i<>rxofIEGVCE,compounds'wiih iabomimzy w¥'t§1 Qém §sc;»Ea£i<>rx of IEGVCE, compounds 'wiih ziemfapazutic pr¢>§c1"Ei¢s` Tim iTnpl»ém¢raia£ion Q¥`,'1'»,Pi 53 émixrxdcfd to iake iidi advanriagzz af tim fast ihai ijaglaana is Q; izimiivfzrséiy E§<:»zs»1pu£' wiih am erzormmas diversity <:'I°@a§i£;f ac¢e5siE>iandrfzarineixaizzizats. and rfzarine ixaizzizats.

""""""'21éE'r.fpre;rarwr1;zse"ix:f"maticancer"surfi1'u";1'irrsi"';§i§ea'se"hirmssa§1si1:"¥*anarrm';"z¢az'¥~¥#:a":frf<':r* 1;zse"ix:f"maticancer"surfi1'u";1'irrsi"';§i§ea'se"hirmssa§1si1:"¥*anarrm';"z¢az'¥~¥#:a":frf<':r* away; at Névartis md agr§ei11£m*ai§n:r©ensak Imw Agm$cien4:cs.: Term$1§1'ia} piazxi Sampiezs; Wifi' be ezxtrafiwi at Ein: f§xui£13s§>'n%an "{`r~<;pi<;:.1I R~,":2¥f¢arQ:E'f Iagtiww {S"£`i€,{} for tesiing, in AW izioasmg/-3 in Ewfzazna (impicai d§s§::xS§:5 arid 3 ounce! wil lines). in acidiéécm, 2; sales; s§1Z>s§£ot`~p§am ezxtxacia wiii be €£eta;m§fEeand;;;°¢~§`1~:§<:t£urszz£efiibrbiuassaysin_i?af1,ar1w;3\€cavar£isamiQWAgmS¢i¢[email protected]@l§atf2sof and ;;;°¢~§`1~:§<:t£urszz£efi ibr biuassays in _i?af1,ar1w; 3\€cavar£is ami QW AgmS¢i¢za@es. E3@l§atf2s of e1apkyl'ic fuagi WEB be Sen! £9 BOW far frigiturc aafié h¥¢;[email protected], Pviarine cilgafs ami syaxxzzilaafztcria WH? be fgfeswrvad ami re§§srfwcI in (3;<@;_;on State ¥JnE\fersit;~' for dirazct chansicai mczraeiioxl, Qr tb; ¢a3§;us<: and e¢x_§fac§io_n as; ai>;§f0;>i*ia§'c.

3. Tc: f:f;iixesii;s§r§¥ruii1>¥iofSampiesfm*hisassaysbyAmhfiiatéPwgramZ,in§.§§;~sia'iaiam! iixe sii;s§r§¥ruii1>¥i of Sampies fm* his assays by Amhfiiaté Pwgram Z, in§.§§;~sia'iai am! miivfersity cukkaimratarsk Ai!! wiI1<:;>0;*C¥_ézmt¢z the d_is§rimstioz1ofsasnpics if: aéi Eahomiaries Qondzwfing bioassays, ha acifiiiiwl, large recokiccliorls £3fé1€$£i vc tezmzzzsiriak planks; WB? be gzmccszmi and é§.s=u"i¥3§stm;I tm fir, ifixibiih {AF'f§ ~ ¥L_i`n~ive.rs;iiy fat" Panama) fix ésoiaticm anzé simcmre f:'lz1<:Ef¥a's%mz of aciive ¢;ompounds_ Marina: zsaznpies will iw sesrzii to Da; Ge:1:*>~fiC:l{§5?3~QregouSéatfsU11_§vezf:~zity}. {§5?3 ~ Qregou Séatfs U11_§vezf:~zity}.

4. 'En :naisniain ai frcntrai database af eoiicefians and bioassay -and eiwmistry rfrszlhs. Sata naanagcxxzwi is key £0 <10-5>rcEim1E,i21g such an iafgfa priizjcci, SQ was iwxfe ckzvcioped az rcciariursai néaéahase is trzzck samgée aiistlébuiifm and reszzits. 'iiae <,:e:f1€1"a.iE2<:r2 d:mzbs\;;e ir; t(a:i¥<;>red ta cm: needs and acaessibie =;>n_i§1f> i'zztem=:=t. "%`h§s grezztiy lmiiitates sms-ring of fesmitx arfiorzg zzii of the ICBG ;s:frti<:ipa=zrs. The sysmmz is ffmiifxfzigf ugrdazeai in acczm1r:wria_tc naw ZCSG acfixfitm such as Eiae marina camgzoneati.

5. To wxié uct mxireach :fz<:ti¥E¥ies io s}is~seminfate inffzfmatimz zaimnt Eaiia-nxassAi,an ¥>¥o¢,iiifer§a§iiy, ~ We Blake Qin: iiofi-ivcrsiry inw=:n,€ori<:s avzziiabiéa flu: geexerssi uae, amd wi£lf;1§n£imu¢a: £0 wok with. the P`€%f}2Ii?}2i¥"i§2i¥`i gavemrswnt, we ¥;}`f'fiuf¢;s§i§s ef PEi¥¥£L!Ti&1, ami mr_1~;>r1s§"i£ <>a"g;\:1§_zai%€ffss to iae§;m iiwrz; mzaximize téze ¥:»21:r:£i£f»; <'i?§i&.§ri»=<.%<¥ i?<:f_m .i`§;£s iz3fu;"rz1a£i0za` WQ wiki a¥sQ GUI? higizijy sxzccsssfizl geragmm amd WMM* NMWWWMWMW cezzgfixxuc» A"' `A" <;>i ;z§ \..»M»~.¢.~...... ,...... ,...... _,. was a§a.f2s»aiJ UQ?"I`1'Z:§!~.'ii 3 Aéiaga _ggféw c;ffargnaiéage ffargnaiéage Ffincipaé m~fes§eg;ato:IPmg;fw= Sweats: Qamak. ¥§f$'?. !'~éid€$1'§F§W|Ci{,Wii¥§£imH@§'2¥',>j €$1'§F§W|Ci{, Wii¥§£im H@§'2¥',>j to demfxnstraricns schamich-itzciren, the §.<¢n.<>1pnztniicauégxzwemfncniofiiciais,-GutreachzrctiviticsforourICBG pnztniic aué gxzwemfncni ofiiciais, -Gutreach zrctivitics for our ICBG Mil be cfacffziirzawci by AP4.

ii* 'fn pruvicle training mai t;ec_imfrlE°=ransf`€:x'toE'azxz:_nxaaians. E°=ransf`€:x' to E'azxz:_nxaaians. A is as ma_§¢f gm? pmvilie im.xme¢;iiaif: and §aszing benefits Qu imnama, even ifreyailiies are naewf aizaizaeé. '1`ize xnoxt efliwiive means o€ thés is io enhanc <3-Qing f>3I!Bi"¥\&$S eagzaeity fm' drug ¢ii¥§§:»Qvery ami io engage ¥*arxars1anian§ in the zcseafxziz pzoccss. Ahnosi all af AM activitiw will occur in ¥'aaama aw wiii pmsfiée cmpi»;>);1xz@at, tra.in§ng ami raswch csxpcfixzncza fer Pamm-azzians_ Cuwesztzly, all APE er:r|p1<§yf:=©f¢:aa1'eLaiigz Ansafifmzxs and we mmain csomznittcaci ics tizés §l`¥iil%.iI`!g emiwavor.

K BA{f¥'lGR(}§§?~=¥¥} f§?'¥D ?:1i'GI*~l1F1CA1'\¥CE

3.1. E3`}§1*i1§£'icl)EYer§i1yin'I'errQ$£ri§'¢¥§1r§6 Mix rinw- _¥E`1r¢vir<>nm§m£~S Pananaa £9 in a1z_cxr:eii§:1ziai§¢z wixiclx to u§;de§%.a3;~e an dwg rtiscovefy guregmna besauge Qf im; unsufjgxzsseé fi<:aris§¢ I;>io<§ivefsii§/~ In Wifi", £i'1is is because ?aam§ iifaks mfr: Qnnrixsents ami two oceaxzs ané was large ;§;*ac1?em§, 21; faififail :mai a¥iiE23f3¢ Gauwé by 3 rnsusxiaiaoua §»;:cI<;b$ri§. }?°`§3§1h¢Hra@r¢, this t@:'f'¢2santinzzsfine anti nzzsfine aiiversity occurs wiihi-:1 £1 naiativeiy sruaii and acoassibic area, xnakfag c{>!E_<,=:<>tiamirecwtleciimnsfeasible. ami recwtleciimns feasible. Panama is at £%1¢ <><¢1"fte:r of the region with me greafest =;xm¢;en£ra£i_Qn ef ieffefmiai giant apsaics in its Wiiffii (>fE§~€3{} s§;»c~x:iew'§Q £3{}T§km2, ¥<'ig,m=e 1) and is ~=;o11_siéf§rzz"bivd_iwrs§xyixoispof'f;§3i'¥f`1}0{=l6;af.I§€?5, zz "bivd_iwrs§xy ixoispof' f;§3i'¥f`1}0{=l 6; af. I§€?5, Conga-wgtican In1.=2fi1ae§0_:;z1i ZGQBQ Myers :ff af, 2£3€}£3}. Px§i§i£|>f§§1°}.3.§ val°'iati€>1°x an-si pwt refzionimz isrxiivily als.; may so cormibaitxe high €fi,`V¢i`§§i§#' fiélathuréa arxi Ganeshaiala 2992). §i is zzsiimaifzé that there are ow: £3 §it`¢ zaziezs cenmirfing wswszfen 35% ané 966% s;s~z>r:i¢of§T3Qw'erixagp_%§z1is,,wiihover$4£¥i3aircadyicientiiiicni1uy"t.:s;-aozzomic of §T3Qw'erixag p_%§z1is,, wiih over $4£¥i3 aircady icientiiiicni 1uy"t.:s;-aozzomic expcris {"i`osiQ lS%?i,, D'f§:'<:y E9$'?, M, C=>If¢21 mm G0m.}, Qnckmzic speeies zxmuzxz for ¥.4% of ihc flora. In aciéitinn, P§¥1'i31"§3&'$ tmirguf: geszrgmgnlzi 1: ;§f>§il:ior§ mexam; §£ ix borne in spmies fmni bolts ilemrai ami $'OI_ii§1

s:1waAL9ai¥w&k:a:w_ saws swam; as mamm Pima 3A;'Ti¢3'3G33m¥°m"€X3mp1¢#

_ __.,- _ _ 9§*"*3'113"*3'f¥1`@A`i1'£@@£" », __,~_,,,,_,_ ,

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