ABSTRACT

The UIC-based ICBG is a multidisciplinary, interna-tional research program, comprised of one academicinstitution (PCRPS/UIC, the base institution), tworesearch institutions (NCST, Vietnam; RIMP, Laos),one national park (CPNP, Vietnam), and one indus-trial partner (GW). The goals of this ICBG are (a) toperform inventory and to promote the conservation ofbiodiversity of Vietnam and Laos; (b) to search forbiologically active compounds from plants of Viet-

nam and Laos as potential candidates for drugdevelopment; and (c) to promote economic develop-ment in host countries (development of humanresources, including strengthening of institutionalinfrastructure, and improvement of standard of livingof communities participating in the project). The pro-ject’s efforts are targeted to terrestrial organisms,specifically, the seed plants (angiosperms and gym-nosperms) in Vietnam and Laos, while the therapeu-tic focus includes antimalarial, anticancer,antiviral/anti-AIDS therapies, and therapy againstdiseases of the central nervous system, including painand Alzheimer’s disease. For the implementation ofthe project, the 5-member Group is bound by a 5-wayMemorandum of Agreement that defines the obliga-tions and responsibilities of each member, and thejoint obligations and responsibilities of all memberstogether. Implementation of the project is effectedthrough individual bilateral subcontractual agree-ments between the UIC and other member institu-tions. Members agree that more than 51% of royaltystream that may accrue will return to the countriesproviding genetic material that led to the discoveryand commercialization of a compound.

Keywords: ICBG; University of Illinois at Chicago; Viet-nam; Laos; Glaxo Wellcome Research and Development;biodiversity inventory; drug discovery; economic develop-ment; plants; antimalarial; anticancer; antiviral; CNS-relateddiseases.

Address correspondence to: Djaja Doel Soejarto, PCRPS,College of Pharmacy, University of Illinois at Chicago (UIC),833 S. Wood St., Chicago, IL 60612, U.S.A.

Pharmaceutical Biology 1388-0209/99/370S-0100$15.001999, Vol. 37, Supplement, pp. 100–113 © Swets & Zeitlinger

STUDIES ON BIODIVERSITY OF VIETNAM AND LAOS:

THE UIC-BASED ICBG PROGRAM

Djaja Doel Soejarto1,2, Charlotte Gyllenhaal1, Jacinto C. Regalado1,2, John M. Pezzuto1,Harry H.S. Fong1, Ghee Teng Tan1, Nguyen Tien Hiep3, Le Thi Xuan4, Do Quang Binh4,Nguyen Van Hung5, Truong Quang Bich6, Nguyen Nghia Thin7, Phan Ke Loc7, Bui Minh

Vu8, Boun Hoong Southavong9, Kongmany Sydara9, Somsanith Bouamanivong9, Melanie J.O’Neill10, Jane Lewis10, Xinmin Xie10, and Gregg Dietzman11

1Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), College of Pharmacy, Universityof Illinois at Chicago (UIC), Chicago, IL 60612, USA

2Botany Department, Field Museum, Chicago, IL 60605, USA3Institute of Ecology and Biological Resources (IEBR), Hanoi, Vietnam

4Institute of Biotechnology (IBT), Hanoi, Vietnam5Institute of Chemistry, National Center for Science and Technology (NCST), Hanoi, Vietnam

6Cuc Phuong National Park, Ninh Binh Province, Vietnam7Department of Botany, Hanoi University, Hanoi, Vietnam

8Forest Research Institute, Hanoi, Vietnam9Research Institute of Medicinal Plants, Ministry of Health, Vientiane, Lao PDR

10Compound Diversity Unit, Medicines Research Centre, Glaxo Wellcome Research and Development (GW),U.K.

11White Point Systems Inc., Friday Harbor, WA 98250, USA

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INTRODUCTION AND HISTORICAL BACK-GROUND

Initiating InstitutionIn response to RFA TWA-98-001 (NIH Guide vol. 26,no. 27, August 15, 1997), the Principal Investigator ofthis ICBG consulted faculty members of the Programfor Collaborative Research in the Pharmaceutical Sci-ences (PCRPS) at the College of Pharmacy, Universityof Illinois at Chicago (UIC), to discuss the possibilityof submitting a proposal to the Fogarty InternationalCenter (FIC).

Central to the issue of proposal submission was aseries of questions, such as “Who will be our institu-tional counterparts?”; “Are there qualified scientists ina prospective collaborating institution to direct and staffan Associate Program?”; “What specific projects willthe ICBG be focused on?”; “Do we need an industrialpartner, and if so, which firm will that be?”. Severalprospective partner institutions and pharmaceuticalcompanies were contacted.

Selection of Partner InstitutionsThe research mission of the PCRPS at UIC has been thediscovery of new/novel molecules from tropical plants,which potentially may serve as candidates for drugdevelopment, primarily in the treatment of cancer andinfectious diseases (particularly malaria) and in cancerchemoprevention (Soejarto et al., 1997b). It is a strongconviction of members of the PCRPS that the high bio-diversity of the tropical rain forests reflects a high bio-diversity of chemical compounds, which may serve asthe basis for the discovery of novel molecules as possi-ble drug candidates. In conjunction with this mission,the PCRPS has been involved in the promotion of con-servation of natural resources in tropical countries inthat their forest resources harbor species with pharma-ceutical and potential pharmaceutical value, whichshould be protected for the future generations.

As a result of its active natural products researchprogram in the search for bioactive compounds fromplants (Cordell et al., 1993; Pezzuto, 1995, 1996;Farnsworth, 1996; Kinghorn, 1996; Soejarto, 1993,1996), the PCRPS has developed a network of institu-tional collaborators worldwide, in particular with bio-diversity-rich countries.

In selecting institutions from among its institutionalcollaborators as partners in the proposed ICBG, the fol-lowing criteria were considered: (a) partner institutionsmust be in real need of assistance; (b) partner institu-tions must be located in countries with high biological

diversity; (c) partner institutions must have a good trackrecord of good working relationships with thePCRPS/UIC; (d) for reasons of logistics and commu-nication, partner institutions must be in close proxim-ity to each other geographically; and (e) partnerinstitutions must be located in countries having diplo-matic relations with the U.S. After reviewing the stand-ing of its numerous institutional collaborators, based onthese criteria (Tables 1 and 2), a decision was made towork with institutions in Vietnam and Laos.

In Vietnam, collaborative studies were initiatedbetween the PCRPS and the Institute of Natural ProductsChemistry/INPC in 1993, with the Institute of Ecologyand Biological Resources/IEBR in 1994, and with theInstitute of Biotechnology/IBT in 1995, under sponsor-ship of the John D. and Catherine T. MacArthur Foun-dation (1994–1997, 1997–1999) (Anonymous, 1997a,1998). These institutions are daughter institutions of theNational Center for Science and Technology/NCST,located in Hanoi. Collaborative work has involved,among other things, plot-based tree inventory inside theCuc Phuong National Park and collection of plants forbiological evaluation in various bioassay systems, fol-lowed by chemical isolation of active compounds fromplants showing interesting activity. In Laos, collabora-tion with the Research Institute of MedicinalPlants/RIMP started in 1994, mainly involving ethnob-otanical and ethnopharmacological surveys of anti-inflammatory plants as part of collaborative researchwith Glaxo Wellcome Research and Development. Thus,a PCRPS/UIC-based ICBG that would include NCST(IEBR, IBT, ICH) and RIMP would assure a good under-standing between members of the Group.

As to the industrial partner, Glaxo WellcomeResearch and Development, Ltd. (GW), has had a closecooperation with the PCRPS/UIC since 1990. First,GW was a partner in an extramural project under thefunding of the NCI, referred to as a NCNPDDG(National Cooperative Natural Products Drug Discov-ery Group, 1990–1995). Second, PCRPS/UIC has beencollaborating with Glaxo in the acquisition of plantsamples of worldwide origin for biological evaluationat GW (1993–1996), followed by a second plant acqui-sition program for plants with a history to treat inflam-matory diseases, 1996–1999.

ICBG Concept PaperBased on a number of ensuing discussions, a conceptpaper was developed and circulated among interestedfaculty for criticism and continuing discussion. A finalconcept paper was sent together with a Letter of Intent

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to the Fogarty International Center on October 3, 1997.In this concept paper, the goals of the ICBG weredefined and the proposed institutional members of theGroup (University of Illinois at Chicago/UIC, NationalCenter for Science and Technology/NCST and CucPhuong National Park/CPNP in Vietnam, andResearch Institute of Medicinal Plants/RIMP in Laos)were presented.

Immediately following the submission of the Letterof Intent, discussions were held with the UIC’s IPO(Intellectual Property Office) Director to draft a bene-fit-sharing plan that would be responsive to the require-ments of the RFA. A preliminary skeleton of abenefit-sharing plan was produced and follow-up com-munications with scientists at counterpart institutionswere instituted. This was followed by travel of the PI of

102 D.D. SOEJARTO ET AL.

Table 1. Countries where the PCRPS/UIC has active institutional collaborators in natural products research and biodiversity conservationa.

Country GDP per capitab GDP rankc HDI rankd Biodiversity(US dollars) per capita (1–230) (1–175) richnesse

Laos 850 205 136 2Vietnam 1,140 183 121 1Nicaragua 1,570 165 127 ?Philippines 2,310 148 98 1Dominican Republic 3,070 130 87 3Guatemala 3,080 129 117 2Indonesia 3,090 128 99 1Peru 3,110 127 89 1Ecuador 3,840 115 72 1Panama 4,670 106 45 2Colombia 4,850 103 51 1Costa Rica 5,050 97 33 1

aData on GDP, HDI and Biodiversity richness are based on Table “Economic Development and Biodiversity” from the Internet(http://www.nih.gov/fic/res/countries.htm), September 27, 1997.bGDP � Gross Domestic Products. Based on data from: United States Intelligence Agency, Office of Public and Agency Information. 1995.The World Factbook 1995.cData from same source as b above. The higher the ranking number, the poorer the country.dHDI � Human Development Index; the larger the number, the less developed that country is, based on a combination of GDP figure, lifeexpectancy, and education attainment (a measure of social and economic progress). Based on data from: M. Shea. 1997. The United NationsHuman Development Index: A User’s Guide. ESDS Technical Report, July, 1997.eGroup 1 comprises the 25 most biodiverse countries. Group 2 comprises the 25 next most biodiverse countries.Based on: Anonymous. 1997. New map of “Biodiversity Hotspots” aids targeting of conservation efforts.Based on data from: Diversity 13(1): 27–29.

Table 2. Status of plant diversity in countries where PCRPS/UIC has active institutional collaborators in natural products research and bio-diversity conservationa.

Country Estimated number of Estimated Broadleaf forest Estimated deforestationspecies of vascular plants endemism cover (hectares) rate (hectares/year)

Laos No estimate No estimate 2,700,000 100,000 (3.7%)Vietnam 8,000–12,000 ca. 10% 7,816,900 60,000 (0.8%)Nicaragua 5,000 ca. 1% 4,170,000 105,000 (2.5%)Philippines 8,000 ca. 5% 9,320,000 90,000 (1%)Dominican Republic 5,000 (for Hispaniola) ca. 36% 444,000 2,500 (0.6%)(Hispaniola)Guatemala 8,000 ca. 15% 4,902,000 90,000 (1.8%)

(70% in highmountain flora)

Indonesia ca. 10,000b High 101,800,000 600,000 (0.6%)(no estimate)

Peru 14,000 No estimate 69,300,000 260,000 (0.4%)Ecuador 10,000–20,000 No estimate 14,230,000 340,000 (2.4%)Panama 8,000–9,000 ca. 15% 4,165,000 36,000 (0.9%)Colombia 45,000 ca. 33% 46,400,000 820,000 (1.77%)Costa Rica 8,000–10,000 14–17% 1,638,000 65,000 (4%)

aData from Davis et al., 1986.bTree species alone.

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this ICBG to these institutions in Vietnam and Laos inOctober, 1997 to discuss and draft out the details of theproposal.

Following discussions with counterpart scientists atvarious pharmaceutical companies, GW was recruitedas the ICBG industrial partner.

Once the first draft of the 5-way Memorandum ofAgreement (MOA) was completed, proposal writing atrespective organizations was initiated during the monthof November, 1997. When the draft of the proposal wascompleted, a second trip to Vietnam and Laos, this timeby the ICBG Co-Investigator (Charlotte Gyllenhaal),was made at the beginning of January, 1998. Later, fol-lowing further refinements, the ICBG Proposal wassubmitted to the Fogarty International Center/FIC onJanuary 20, 1998.

PROJECT DESCRIPTION

Nature and ScopeThe UIC-based ICBG is a multidisciplinary, interna-tional research program, comprised of one academicinstitution, two research institutions, one national park,and an industrial partner (a pharmaceutical company).

The long-term goals of this ICBG are to performinventory and to promote the conservation of biodiver-sity in Vietnam and Laos, to search for biologically

active compounds from plants of Vietnam and Laos aspotential candidates for drug development, and todevelop the human resources, to strengthen the institu-tional infrastructure, and to promote the improvementof the standard of living of the communities in hostcountries participating in the project.

The project’s efforts are targeted primarily to terres-trial organisms, specifically, the seed plants(angiosperms and gymnosperms). In Vietnam, the geo-graphic focus of the project is the Cuc Phuong NationalPark (Fig. 1), a 20,000-hectare primary forest on lime-stone formation, and the indigenous communities whoinhabit the areas surrounding the Park, namely, theMuong communities. In Laos, the geographic focus isthe entire country, but primarily in ten sites (Fig. 2), allof which are communities located near forested areas,where Traditional Medicine Stations are found.

In view of the seriousness of certain diseases whichaffect human populations today, and in consideration ofthe scientific and institutional expertise of member-institutions, the drug discovery effort of the UIC-basedICBG is focused on malaria, cancer, AIDS, and dis-eases related to the central nervous system (CNS).

Specific Aims and ObjectivesThe specific aims of the Chicago-based ICBG are:a. To produce a documented inventory of tropical for-

est plant diversity in Vietnam and Laos, specifi-

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Fig. 1. Diagrammatic map of the Cuc Phuong National Park.

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cally, the seed plants of the tropical rain forest ofthe Cuc Phuong National Park in Vietnam, thatincludes botanical inventory and ethnobotanicalsurveys on one hand, and on the other, ethnob-otanical/ethnopharmacological surveys amongselected tribal communities throughout Laos, par-ticularly in areas where Traditional Medicine Sta-tions are located.

b. To discover novel biologically active moleculesfrom plants of Vietnam and Laos as possible can-didates for drug development in the treatment ofmalaria, cancer, viral (including AIDS), and CNS-related diseases, including pain and Alzheimer’sdisease.

c. To improve the standard of living of the membersof the tribal communities participating in theICBG studies, and of the countries in general,through community education and biomass pro-duction of plants that have been identified as hav-ing promising medicinal and economic potential.

d. To develop the human resources and to strengthenthe institutional infrastructure of member-institu-tions of the ICBG in Vietnam and Laos throughvarious forms of training activities on-site, in-country and outside of the country, particularly, in

the United States (PCRPS/UIC in Chicago) and inthe UK (GW in Stevenage), and through variousforms of support to the institutions.

Member Institutions, Responsibilities and Inter-ests of Participating ScientistsIn order to achieve the goals and the specific aimsstated, five Associate Programs (AP) have been cre-ated. Each AP is led by an “Associate Program Leader”(AP Leader), supported by one or more Co-Investiga-tors (Co-I) and research assistants. The work and activ-ities of the five Associate Programs is coordinated by aPrincipal Investigator (PI or Group Leader).

The Chicago-based ICBG is structured as follows:(a) ICBG or Group Program: Studies on Biodiversity

of Vietnam and Laos. This is the Central Opera-tions Office (COO) of the ICBG and is based at thePCRPS/UIC (Chicago, U.S.A.).

• Principal Investigator/Group Leader (PI): D. DoelSoejarto, Ph.D. (taxonomic and economic botany;overall ICBG management and coordination).

• Co-Investigator: Charlotte Gyllenhaal, Ph.D.(ethnobotany; data and reporting management,financial administration and ethnobotany-relatedproblem-solving).

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Fig. 2. Provincial Traditional Medicine Stations (TMS) in Lao PDR.

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• Co-Investigator: Jacinto Regalado, Ph.D. (taxo-nomic botany; problem-solving in taxonomy andnomenclature; database management).

(b) Associate Program 1 (AP-1): Inventory and Con-servation of Plants of Cuc Phuong National Park.Physically and administratively, the operation ofAP-1 is based at the CPNP in Vietnam, as the pri-mary site, and at the IEBR in Hanoi, Vietnam, asthe secondary site.

• AP-Leader: D.D. Soejarto, Ph.D. (taxonomic andeconomic botany; project’s overall management;inventory).

• Co-Investigator: Truong Quang Bich, Forest Engi-neer (ecology and bioconservation; project man-agement at CPNP).

• Co-Investigator: Nguyen Tien Hiep, Ph.D. (Co-APleader; taxonomic botany; inventory).

• Co-Investigator: Nguyen Nghia Thin, D. Sc. (plantecology; inventory; conservation).

• Co-Investigator: Phan Ke Loc, Ph.D. (taxonomicbotany; inventory).

• Consultant: Gregg Dietzman (GIS specialist; GISplanning, development and maintenance).

(c) Associate Program 2 (AP-2): Lao MedicinalPlants as Potential Source of New Medicines. AP-2 is based at RIMP in Vientiane, Lao PDR (Laos).

• AP-2 Leader: Boun Hoong Southavong, Ph.D.(pharmacognosy; overall management and projectcoordinator; ethnobotany interviews; natural prod-ucts chemistry).

• Co-Investigator: Kongmany Sydara, Ph.D. (naturalproducts chemistry; reporting and financial admin-istration).

• Co-Investigator: Somsanith Bouamanivong,Botanical Engineer (pharmacognosy, ethnobotany;ethnobotanical interviews, plant collection andidentification).

(d) Associate Program 3 (AP-3): Drug Discovery fromPlants of Vietnam and Laos for AIDS, Malaria andCancer Therapies. The primary site of AP-3 isPCRPS/UIC; the secondary site is Institute ofChemistry (ICH), a daughter institute of NCST(Hanoi, Vietnam).

• AP-3 Leader: John M. Pezzuto, Ph.D. (biochem-istry; pharmacognosy; overall AP-3 project man-agement and coordination) (UIC/PCRPS).

• Co-Investigator: Harry H.S. Fong, Ph.D. (naturalproducts chemistry; pharmacognosy; overall AP-3chemistry coordination) (UIC/PCRPS).

• Co-Investigator: Ghee Teng Tan, Ph.D. (pharma-cognosy; bioassays) (UIC/PCRPS).

• Co-Investigator: Nguyen van Hung, Ph.D. (naturalproducts chemistry) (NCST/ICH).

• Consultant: Heléne Guinadeau, Ph.D. (naturalproducts chemistry) (Faculty of Pharmacy, Uni-versity of Angers, France).

(e) Associate Program 4 (AP-4): Biomass Productionand Economic Development.AP-4 is based at Institute of Biotechnology/NCST(Hanoi, Vietnam).

• AP-4 Leader: Le Thi Xuan, Ph.D. (tissue culture;plant physiology; ethnobotany; overall projectcoordination).

• Co-Investigator: Bu Minh Vu, Ph.D. (forestry; for-est economics; sociology; economic develop-ment).

• Co-Investigator: Do Quang Binh, Ph.D. (sociol-ogy; economic development).

(f) Associate Program 5 (AP-5): Drug Discovery andDevelopment. AP-5 is based at Glaxo WellcomeResearch and Development, Ltd. (Hertsfordshire,U.K.).

• AP-5 Leader: Melanie O’Neill, Ph.D. (naturalproducts chemistry; overall project coordination).

• Co-Investigator: Jane Lewis, Ph.D. (natural prod-ucts chemistry; isolation and structure elucida-tion).

• Co-Investigator: Xinmin Xie, Ph.D., M.D. (neuro-science; bioassays).

Each AP-Leader will act as the liaison personbetween the ICBG PI/Group Leader and his/her insti-tution and will be responsible for the overall coordina-tion, implementation and maintenance of the programunder his/her direction. The scientific personnel of anAP may be changed, subject to approval of the APLeader, following consultation with the ICBG ProjectLeader and the Fogarty International Center/FIC Bio-diversity Program Director. The organizational struc-ture that includes lines of communication of theUIC-ICBG is presented in Figure 3.

RESEARCH PLANS

Inventory of Plant DiversityIn Vietnam, members of AP-1 will undertake year-round plant collection at the Cuc Phuong NationalPark. The Park, established in 1960, has an area of22,000 hectares, 90% of which is made up of primarytropical rain forests on limestone substrate. Accordingto existing inventories, nearly 2,000 plant species occurin the park, 1,700 of which belong to the flowering

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plants (angiosperms). This high plant diversity can pro-vide an adequate array of chemical diversity as a basisof our drug discovery program.

For the first three years, between 1,000 and 1,500collection numbers of herbarium specimens (5 dupli-cates per collection) are projected for collection annu-ally for biodiversity inventory from the park. Collectionintensity will be decreased by year four. The primarysite for taxonomic identification of herbarium speci-mens collected will be the IEBR Herbarium in Hanoi.Other identification sites are the CPNP Herbarium andthe Field Museum Herbarium in Chicago, as well as theNatural History Museum Herbarium in Paris and theKunming Herbarium in southern China. A major goalof the project is to produce an annotated and scientifi-cally documented catalogue of plants of the park, bothin printed and electronic (Internet) forms. Herbariumfield data and taxonomic determination will be enteredinto a database maintained at IEBR. Collaboration oftaxonomic specialists working in Southeast Asian florawill be solicited. Plant conservation status will also berecorded.

All botanical data (field collection, taxonomic iden-tification, conservation) will be entered into a softwarepackage program called NAPIS (Natural ProductsInformation System) which has GIS capabilities, aswell as full capacity to handle taxonomic, ethnomed-ical, chemical and bioassay data. The initial imple-mentation of NAPIS and preliminary GIS work wereperformed in consultation with Gregg Dietzman, a con-sultant to AP1 (White Point Systems, Inc., Friday Har-bor, Washington, U.S.A). Versions of NAPIS have nowbeen installed at UIC, IEBR and RIMP, and initial stafftraining has been completed. Databases at IEBR andRIMP will be linked with the central database at UICas the project progresses.

At the outset of the project, a large-scale map of theCuc Phuong National Park was divided into quadrats ofapproximately 3.6 � 3.5 km. Since the grid layout isbased on units of map minutes, the location of eachquadrat is easily interpreted in the field, directly from aGPS (Global Positioning System) receiver display.Handheld GPS-reading will be performed for everycollection site in the park. GIS data analysis of satellite

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Fig. 3. Organizational structure and lines of communication between program components.

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images, combined with analysis of Cuc Phuong vege-tation diversity will pinpoint locations of plants col-lected (including data of biomedical collections; seebelow), of different biodiversity hotspots and of differ-ent plant associations within the park, in a three dimen-sional GIS-based DEM (digital elevation model). Sucha model will guide the park personnel in their continu-ing conservation efforts of the park’s biodiversity. GISdata analyses will be performed at the GIS facilities ofthe White Point Systems, Inc.

Ethnomedically Based CollectionsIn addition to the biodiversity-based collections, eth-nomedical interviews and plant collections based onthose interviews will be performed by members of AP-4 team among the indigenous communities livingaround Cuc Phuong National Park who previouslyinhabited the park and who have developed knowledgeon the medicinal uses of plants within the park. Insecuring field ethnomedical information, members ofAP-4 team will work in collaboration with and underthe guidance of representatives of the Local People’sCommittee for Cuc Phuong Communes, as well as ofthe National Committee of Ethnic Communities head-quartered in Hanoi. Methods of plant collecting willfollow those described by Soejarto (1993), while eth-nobotanical interviews will follow methods describedin the ethnobotany manual by Alexiades (1996). Eth-nomedical leads for interviews and sample collectionfor bioassays will also be obtained from existing data inthe literature of Southeast Asian medicinal plants.

In Laos, members of AP-2 based at RIMP will con-duct ethnomedical interviews among healers and mem-bers of the local communities located in areasassociated with Traditional Medicine Stations. Tradi-tional Medicine Stations were established by the Laot-ian government and staffed by personnel of theMinistry of Health, which has the responsibility to tapethnomedical knowledge of these healers to be used forthe wellbeing of the nation. Ministry personnel workwith local traditional healers in the areas of the Sta-tions. RIMP is the national agency that has the respon-sibility to adapt such local ethnomedical knowledgeinto products for country-wide use.

All interview-based data are also entered in theNAPIS database separately in Vietnam and in Laos.

Drug Discovery StrategyIn Vietnam, approximately 500 samples for biomedicaltesting will be collected from the park (approximately150 species per year), without regard for their history

of medicinal use. Samples are extracted at ICH inHanoi, and a fraction of the extract of each sample(equivalent to 100 g dry weight) is dispatched to UICfor bioassays (antimalarial, antiviral, anticancer) by theChicago-based AP-3 team. Sample showing promisingactivity will be recollected from the park in amounts of1–3 kg dry weight for isolation and structural elucida-tion of the active compounds.

Additionally, based on ethnomedical interviews (seeabove), documented medicinal plant samples will becollected and the samples extracted by ICH. Extracts ofsamples with a history of medicinal use to treat malaria,cancer and viral diseases will be sent to UIC-based AP-3 for bioassays, while those with a history of medicinaluse to treat CNS-related diseases will be sent to AP-5team at GW in the UK for bioassays againstAlzheimer’s disease and pain. Active samples will berecollected for isolation studies.

Documented medicinal plant samples will also becollected in Laos, based on field interviews (see above),and either raw samples or their extracts will be sent toUIC (antimalarial, anticancer and antiviral history ofmedicinal use) or to GW (CNS-related use) for bioas-says. Samples showing promising activity will be rec-ollected for isolation studies at UIC on the one hand,and at GW on the other.

Following consensual endorsement by all membersof the UIC-based ICBG, and by members of the USGovernment Advisory Committee, a characterizedactive compound, discovered at UIC or at GW, will bedeveloped as a pharmaceutical product by GW, withoutcost to the ICBG grant. GW’s participation in the ICBGconsortium, in fact, does not involve any cost to theICBG grant.

Bioassay ProtocolsBioassays conducted at the University of Illinois atChicago include the evaluation of the anti-HIV, anti-malarial and cytotoxic potential of extracts of plantsprocured by AP-1, AP-2 and AP-4 using proven in vitroscreening assays with the aim of discovering new/novelbiologically active candidates for pharmaceuticaldevelopment as viable therapies for AIDS, malaria andcancer. Anti-HIV screening of plant extracts and purecompounds is performed with the whole virus in theHOG.R5 reporter cell line based on the transactivationof the green fluorescent protein (GFP) gene (Tan et al.,1997) while antimalarial activity is assessed using cul-tured chloroquine-sensitive and chloroquine-resistantPlasmodium falciparum clones (Desjardins et al.,1979). The cytotoxic potential of compounds and plant

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extracts is assessed utilizing cultured mammalian celllines (KB and LNCaP) using the method of Skehan etal. (1990). Cytotoxicity in the HOG.R5 cell line is alsoassessed in conjunction with the evaluation of anti-HIVactivity.

Several more advanced assays are planned forpromising compounds. Anti-HIV compounds will betested against several virus strains including clinicaland drug-resistant isolates in peripheral blood mononu-clear cells (PBMCs) and tissue culture-derivedmacrophages (TCDMs) to explore their clinical poten-tial. Combination drug testing and studies on mecha-nism(s) of action will be useful towards characterizingpossible effects on selected molecular targets in theHIV replication cycle such as the HIV reverse tran-scriptase (RT) and protease, in an attempt to betterunderstand the overall pharmacological properties ofactive isolates. Similar studies may also be performedon new and existing antimalarial agents. Mechanisticstudies that may be conducted include (i) the inhibitionof parasite-mediated host erythrocyte permeability, and(ii) potentiation of intracellular oxidative stress. Toassess the in vivo efficacy of antitumor agents uncov-ered in the in vitro cell-based screens without the sub-stantial expenditure of time, labor, and cost associatedwith conventional animal models, 10 of the most activeplant extracts uncovered in the prescreen will also beevaluated in the hollow fiber assay per year. This invivo assay was developed and introduced by theNational Cancer Institute as an intermediate screenthrough which compounds must pass before full evalu-ation in xenograft tumor models (Hollingshead et al.,1995).

Glaxo-Wellcome will be performing assays onplants collected by AP-2 and AP-4 used for central ner-vous system activities. Several proprietary assays willbe used to evaluate such plants for use in pain andAlzheimer’s Disease.

PhytochemistryThe isolation of biologically active constituents fromextracts demonstrating anti-HIV, antimalarial or cyto-toxic activity is achieved through bioassay-directedchromatographic fractionation, after which the struc-tures of active compounds are elucidated by state-of-the-art physical and spectroscopic methods such asNMR and LC/MS/MS. Molecular assays aimed at elu-cidating the mechanism of action of pure compoundsdemonstrating good “in vitro therapeutic indices” willbe initiated.

Economic DevelopmentIn Vietnam, improvement of the standard of living ofmembers of the communities who participate in thepresent ICBG project will be achieved through a num-ber of projects. In the first place, direct support throughfunds from the ICBG will be provided to the commu-nities that will promote:• education (improvement and strengthening of

local school facilities);• health (clean water sourcing, education on good

hygienic practices, support and strengthening oflocal health stations and dispensaries);

• community consciousness of the importance ofbiodiversity conservation, especially as it relates toCuc Phuong National Park (community meeting,seminars, and promotion of community associa-tions);

• determining the economic potential of one or morespecies of medicinal plants already in use by theMuong communities in Cuc Phuong, or growing inthe Park but not used by the local community, withthe goal of developing a product for market use,locally, nationally, or even for foreign export, thusgenerating income to the local communities in theproject area. These efforts will include determin-ing the extent of the use of the species locally,regionally, and nationally (literature-based, fieldinterviews, and market surveys), and the potentialtoxicity of the plant (literature-based). Biomassproduction of a successfully selected species willbe implemented through traditional methods (seedgermination, cuttings) and through modern meth-ods (tissue culture-based propagation). Theseactivities are expected to lead into the generationof income (through cultivation and harvesting ofraw materials) by members of the communities.

In Laos, much of the economic development plansare to be implemented through the Traditional Medi-cine Stations, in the context of their relationship withRIMP. These plans include:• improvement of the Stations, including equipment

purchase, purchase of conventional essentialdrugs, assistance in organizing local educationalefforts, or locally oriented publications;

• working with communities around the Stations todetermine what needs they have that the ICBGmight address, including areas such as health careand education;

• organizational efforts among the traditional heal-ers working with the station, including thedevelopment of a national traditional healers’ asso-

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ciation, meetings of all the Traditional MedicineStation staff with RIMP in Vientiane, and resum-ing publication of RIMP’s Quarterly Bulletinwhich was previously circulated to the Stations.

For both Vietnam and Laos, economic developmentwill also be promoted through the training and pur-chase of equipment for the collaborating ICBG institu-tions. Equipment purchased for NCST, CPNP andRIMP as part of the project is substantial, and includesboth scientific facilities (e.g., herbarium cases, glass-ware, etc.) and provision of necessary office equipmentand computers. Renovation of rooms used by the ICBGproject is also on-going. The long-term contribution ofthe project to the economic development of the com-munities lies in the potential funds to be derived fromroyalties of a successfully developed compound. Anysuch funds will be disbursed to the communitiesthrough the Trust Fund as outlined below (“ContractualDesign of the MOA”).

Overall Plan for Training and Other Types ofTechnology TransferIn Vietnam, training activities will include on- and off-site training of personnel in research locations. Thesites include the Cuc Phuong National Park, in theInstitute of Ecology and Biological Resources, and inthe Institute of Biotechnology in Vietnam, and at theResearch Institute for Medicinal Plants in Laos. Train-ing outside of the country will be conducted at thePCRPS in Chicago and at GW in Stevenage, U.K.Areas of technology transfer for the project includefield collecting and taxonomic identification, herbar-ium curation and management, taxonomic revision andfloristics, ethnobotanical field methods and analyses,GIS field data collection and recording, biodiversityconservation practices, data management and analyses,traditional and tissue culture propagation, bioassays,chemical isolation and bioassay methods.

The plan for research training activities for the UIC-based ICBG is summarized in Table 3.

INTELLECTUAL PROPERTY RIGHTS ANDBENEFIT-SHARING

BackgroundThe discovery and development of the anti-HIV com-pounds calanolide A and calanolide B from two speciesof Calophyllum, namely, C. lanigerum Miq. var. aus-trocoriaceum (T.C. Whitmore) P.F. Stevens and C.teysmannii Miq. var. teysmannii (King) P.F. Stevens

(Guttiferae), respectively, of the tropical rain forests ofSarawak, Malaysia (Kashman et al., 1992; Fuller et al.,1994), provide a useful model. In that case, we con-ducted collaborative research and successful negotia-tions in the sharing of benefits as a result of thediscovery of candidate drugs between a biodiversity-rich, but biotechnology-poor country and an institutionin a biotechnology-rich country – the United States (tenKate & Wells, 1998; Flavin & Jenta, 1998). CalanolideA is now in Phase II clinical trials, while calanolide Bis in advanced preclinical trials (Jenta, personal com-munication, October 3, 1999).

In that project, the discovery of the calanolides wasa successful result of the plant exploration and anti-HIV plant screening program of the United StatesNational Cancer Institute/NCI, 1986–1996 (Cragg &Boyd, 1996). The collection of the plant that yieldedthe first of the two compounds, calanolide A, was madein 1987, and the active test result was revealed in 1991,leading to a request by the NCI for a larger quantity ofthe raw plant material (Soejarto et al., 1997a). Thepatent on the discovery of these compounds was filedin 1992 (first filing) and in 1993 (second filing; contin-uation in part) by the NCI (Boyd et al., 1997), while thelicensing of this technology required a negotiationbetween a prospective pharmaceutical company,MediChem Research, Inc., and the source country ofthe compound, namely, Sarawak, Malaysia (Mays &Mazan, 1996; Soejarto et al., 1997a). Such a require-ment would assure the return of benefits to be derivedfrom the NCI’s drug discovery effort and from theeventual commercialization of the compound, toSarawak (Malaysia). The negotiation betweenMediChem Research and the Sarawak Governmentresulted in the establishment of a joint venture com-pany, Sarawak MediChem Pharmaceuticals, Inc. (tenKate & Wells, 1998) for the development of calanolideA, which entered Phase I clinical trials in June, 1997(Anonymous, 1997b).

Philosophical ApproachThe discovery and development of the anti-HIVcalanolides provide an indisputable example that nego-tiations can succeed and have succeeded in a mannersatisfactory to the compound discoverers, the pharma-ceutical company, and the host country.

Unfortunately, it has not always been clear to biodi-versity-rich countries that such successful negotiationsare possible or can be implemented. In fact, significantdistrust by developing nations of people and organ-izations wishing to explore genetic resources for poten-

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tially useful drugs has resulted in the virtual shutdownof the permit-granting process in several countriesincluding some in which PCRPS/UIC has recentlyattempted to negotiate agreements for collaborativeprojects.

Therefore, it becomes necessary for any project thatwishes to explore the resources of biodiversity-richcountries to develop in advance specific mechanisms toassure all parties that equitable sharing of potentialbenefits of drug discovery or other potentially valuableeconomic discoveries will take place. Such a mecha-nism assures all parties that their collaboration will pro-ceed in an ethical fashion. In order to enable thisphilosophy, and to be responsive to the requirements ofRFA TWA-98-001, a contractual agreement has beenstructured to be signed by all members of the UIC-based ICBG.

Contractual Design of the MOAThe design of the contractual agreement that binds thecomponents of the UIC-based ICBG consists of a 5-way Memorandum of Agreement between UIC, NCST(legally represented by IBT), CPNP, RIMP, and GW. Inthis MOA, the obligations of each party and their jointobligations are fully defined. These include issues onproperty rights and intellectual property rights for plantgenetic material to be used in the studies, within theproposed ICBG. All members agree that property ofthe plant genetic material (plant species) belongs to the

country where that genetic material originates, and thatany discovery or invention that may arise as a result ofresearch under the framework of the ICBG, and newtechnology that will be developed based on this geneticmaterial should be protected, and that the benefits ofthe discovery be shared in an equitable manner betweenthe participating members. Benefit-sharing alsoincludes the assignment of authorship of publicationsthat may result from the ICBG’s efforts. GW, however,waives its rights to any share of monetary benefits thatmay result from a royalty stream.

Two schemes of benefit-sharing are created. In thefirst, a commercialized compound may have beenderived from a discovery or invention made at UIC. Inthe second, the discovery or invention of a compoundthat results in the commercialization of a product ismade at GW. In both cases, the drug developmentefforts may have been carried out by either GW or byany other pharmaceutical firm.

The benefit-sharing schemes include the establish-ment of a Trust Fund from a portion of the royaltyincome. The fund will be managed under service con-tract to UIC. This Trust Fund is intended to reciprocatewith the country from which the plant that yielded thecommercialized compound has been derived, includingcommunities that participated in the project, to govern-ment agencies and non-governmental organizations, aswell as to educational establishments involved inresearch, education and conservation activities. Over-

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Table 3. Summary of training activities projected for personnel of AP-1, AP-2 and AP-4.

Training Activities

AP-1GIS field data collection and recording; IEBR/CPNP field staff (Assistants and Botanists)Field Methods in Plant Taxonomy; IEBR/CPNP Research AssistantsPrinciples and Methods in Plant Taxonomy; CPNP Assistants and Junior Botanist (Herbarium staff)Research in Plant Taxonomy in Chicago (UIC/Field Museum); Junior Botanist from the CPNP (3 months)(Year 3/4)NAPIS database utilization, IEBR (Research Assistants, Botanists)Computer database utilization and computer-based herbarium specimen tracking of CPNP personnel (Year 2/3)

AP-2Methods on ethnobotany/traditional medicine; Traditional Medicine Station personnel by RIMP staff,starting Year 1Ethnobotany Research Training; RIMP scientist, in Chicago (3 months) (Year 4)Chemistry Training at Glaxo WellcomeBioassay Training at Glaxo Wellcome

AP-4Ethnobotanical Field Methods; field staff of AP-4 (Year 1)Ethnobotany Research Training; Jr. scientist, in Chicago (3 months) (Year 3)Tissue Culture Methods, one CPNP personnel, at Institute of Biotechnology/NCNST (Hanoi) (Year 2)Woody Tissue Culture Methods, Australia, Junior Scientist at IBT (3 months)Chemistry Training at Glaxo WellcomeBioassay Training at Glaxo WellcomeEcotourism training in Cuba; a CPNP personnel, Year 4/5

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all, more than 51% of the total royalty income that maybe derived as a result of the commercialization of aplant-derived compound, either in its native form or asynthetic derivative, will go back to the source coun-tries. Other participating institutions, in countries fromwhich the source materials did not originate, will alsoreceive lower portions of the royalty income.

Under the blanket of the 5-way MOA, bilateral sub-contractual agreements are set-up between the UIC andeach participating institution, namely, NCST, CPNP,and RIMP. These agreements provide the mechanismby which the work to be performed is defined and thetransfer of funds is effected.

Permit-Giving Organization(s) in Host CountryAccess to Vietnam’s genetic resources is provided bythe Ministry of Agriculture and Rural Development,which also issues permits for export of plant (genetic)material. In the case of protected areas, a specific per-mit for the collection of plants within such areas, suchas a national park, is given by the authority controllingthese areas. Thus, a permit to collect plants in the CucPhuong National Park is given by the Director of thePark.

In Laos, access to genetic resources is provided bythe Ministry of Agriculture and Rural Development,which also issues permits for the export of plant(genetic) material.

Informed ConsentInformed Consent (IC) is defined as the consent or per-mission given by a governmental or a non-governmen-tal organization or by a community, includingindigenous communities, or by individuals, followingthe presentation of a request to access physical things,such as plants or genetic material, or knowledge orinformation, such as information on uses of medicinalplants, owned by or under the control of such an orga-nization, community or individuals.

Thus, in the context of the ICBG, a signed collectingpermit signifies that a consent has been given by a gov-ernment agency that regulates the collection and exportof plant (genetic) material of the host country, followingthe presentation of a request for access supported by theICBG proposal document. For the UIC-based ICBG,such a signed permit has been obtained from the Min-istry of Agriculture and Rural Development of bothVietnam and Laos. Similarly, a written permit from theDirector of the Cuc Phuong National Park, for the col-lection of plants from the Park, for use in the researchproposed in the ICBG has also been granted. Permits or

informed consent by specific community or individuals,for the collection of plants within the territory owned byor under the control of such a community or individualswill be obtained, as the need arises in specific circum-stances. In either case, a signed document or letter givenby such a community or individuals will be evidence ofan informed consent given.

Novel Features of the UIC-Based ICBG MOAThe UIC-Based ICBG MOA has two novel features.The first is the fact that the five organization-compo-nents or members of the ICBG are unified in this 5-waydocument that spells out the obligations and responsi-bilities of each member and the joint obligations andresponsibilities of all members together. The secondnovel feature of the UIC-Based ICBG MOA lies in thespecific benefit-sharing schemes. This includes theestablishment of a Trust Fund that guarantees the returnof more than 51% of royalties income to the sourcecountry from which the plant that gives the commer-cialized compound originates, as well as the return of asmall share of royalties to the other plant-source coun-try, which is also a stakeholder in the successful oper-ation of this ICBG project.

ACKNOWLEDGEMENTS

The UIC-based ICBG is funded under grant 1-UO1-TW01015-01 from the Fogarty International Center,Bethesda, MD. To the following institutions and offices, fromwhich support in the writing of the proposal and for theimplementation of the UIC-based ICBG project has beenobtained, the authors wish to express their thanks: the Boardof Trustees of the University of Illinois at Chicago, Chicago,USA; the National Center for Science and Technology,Hanoi, Vietnam; the Cuc Phuong National Park, Ninh BinhProvince, Vietnam; the Ministry of Agriculture and RuralDevelopment, Hanoi, Vietnam; the Embassy of the UnitedStates in Vietnam, Hanoi, Vietnam; the Research Institute ofMedicinal Plants, Vientiane, Lao People’s DemocraticRepublic (Lao PDR); the Ministry of Health, Vientiane, LaoPDR; the Ministry of Agriculture and Rural development,Vientiane, Lao PDR; the Embassy of the United States inLaos, Vientiane, Lao PDR; the World Health OrganizationRepresentative, Vientiane, Lao PDR; The Food and DrugAdministration Office, Vientiane, Lao PDR. Travel and othercosts, including salaries of C. Gyllenhaal and J.C. Regalado,in the structuring, negotiations and finalizations of the ICBGproposal and award, were provided, in part, from funds fromGlaxo Wellcome Plant Acquisition Contract with the Univer-sity of Illinois at Chicago and from a MUCIA InternationalProgram Development Travel Grant awarded on November 7,1997, to D.D. Soejarto.

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Accepted: December 28, 1999

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