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192 Combinatorial Chemistry & High Throughput Screening, 2014, 17, 192-200 Building a Discovery Partnership with Sarawak Centre: A Gateway to Access Natural Products from the Rainforests Tiong Chia Yeo*, Margarita Naming and Rita Manurung

Sarawak Biodiversity Centre, KM20, Jalan Borneo Heights, Semengoh, 93250 Kuching, Sarawak, Malaysia

Abstract: The Sarawak Biodiversity Centre (SBC) is a state government agency which regulates research and promotes the sustainable use of biodiversity. It has a program on documentation of traditional knowledge (TK) and is well-equipped with facilities for natural product research. SBC maintains a Natural Product Library (NPL) consisting of local plant and microbial extracts for bioprospecting. The NPL is a core discovery platform for screening of bioactive compounds by researchers through a formal agreement with clear benefit sharing obligations. SBC aims to develop partnerships with leading institutions and the industries to explore the benefits of biodiversity. Keywords: Benefit sharing, biodiversity, natural product library, Sarawak Biodiversity Centre, Tiong Chia Yeo traditional knowledge.

INTRODUCTION Sarawak’s position and policies on biodiversity are predicated on the strong desire to harness its genetic Biodiversity resources for scientific benefits and to encourage scientific The island of Borneo is dominated by vast tropical research including pharmaceutical development [1]. The rainforests thought to be 130 million years old. One of the State recognizes the value of bioprospecting its rich most diverse tropical habitats on earth thrives on the island. resources. With a clear message and a vision for the future, These habitats, being the source of numerous medicinal the State Government enacted the Sarawak Biodiversity cures and natural drugs, are a promising source of future Centre (SBC) Ordinance and the Sarawak Biodiversity pharmaceuticals that need to be preserved. Environmental (Access, Collection and Research) Regulations [2]. These threats from development have raised concern on loss of laws provide the regulatory mechanism to facilitate and valuable biodiversity invariably linking drug discovery to monitor research on biological resources to secure benefits conservation efforts. sharing obligations. The laws also provide for the formation of a Council to make decision on policy matters and to Sarawak, which is located just above the equator in establish SBC. It is through the SBC that research activities northwest of Borneo, is the largest state in Malaysia and it are implemented with a common vision to attain biodiversity shelters one of the most diverse ecosystems in the region. research excellence, and a mission to discover and harness The rainforest habitat implies a rich biodiversity that covers the benefits of biodiversity. all diversity of life including the plants, animals and microorganisms that co-exist at the genetic, and In the initial stage of its set up, the SBC undertook ecosystem levels (Fig. 1). general inventory and of biodiversity as its main function. However, when general inventory of biodiversity Biodiversity has an intrinsic value to humans and the overlapped with another agency, the law was amended to global community. Its importance was highlighted in the change SBC’s role to focus only on traditional knowledge events leading to the signing of the Convention on (TK) documentation and bioprospecting. Steering clear of Biological Diversity (CBD) in 1992. The CBD has three the conflicting roles to emphasize on a subset of the main objectives: to conserve biological diversity, to promote biodiversity related to TK and bioprospecting are key the sustainable use of its components, and to exercise fair changes that launch a unique program for natural products and equitable sharing of benefits arising from the use of research at the SBC. genetic resources. To configure these objectives into a working model, the Convention recognizes a country’s sovereign rights over its genetic resources, and it puts the GENETIC RESOURCES LINKED TO TRADITIONAL responsibility on the country to devise a legal framework to KNOWLEDGE manage and utilize its own biodiversity. A majority of the indigenous communities in Sarawak maintains a close connection to the biodiversity. SBC is

given a mandate to document and record TK of these *Address correspondence to this author at the Sarawak Biodiversity Centre, communities which are related to the use of plants. This KM20, Jalan Borneo Heights, Semengoh, 93250 Kuching, Sarawak, provision is stipulated in the Sarawak Biodiversity Centre Malaysia; Tel: +60 82 610610; Fax: +60 82 611535; (Amendment) Ordinance 2003, a state law enacted after the E-mail: [email protected] CBD.

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Fig. (1). Biodiversity of Sarawak. The rich biodiversity in Sarawak is abundantly found in various types of forest ecosystem that thrive in Borneo including mixed dipterocarp, kerangas, mangrove, montane, riverine, peat swamps, beach and shrub lands.

TK has been used as a method for selecting particularly extracts for research can be achieved in an ethical way promising plants for drug discovery [3]. Viewing this as a through an agreed framework by signing a research shortcut to screen the rainforests, SBC embarked on agreement. It is a way to evaluate the natural products and documenting TK using the guidelines of the CBD. As it was protects the collaborator from charges of biopiracy. difficult to cover thousands of villages, the best alternative TK is a good tool for pharmaceutical discoveries but the was to cover each indigenous group of which, there are scope could extend beyond the medicinal uses. There are about 30, to obtain a fair representation of TK-linked plants. opportunities to screen for ingredients for flavours and To date about 4,000 plants have been documented with some scents, nutrition, taste modifying agents, cosmetic and food overlapping species between different groups. This approach components which are as valuable as pharmaceuticals. is practical as it employs a rapid survey to record traditional Natural product is a prolific resource for a wide range of claims and collect living specimens for SBC’s ex-situ industries that relies on discovery of novel compounds that conservation program. Plant materials are also collected to lead to product development. supply research materials for extraction and depository of their extracts in the Natural Product Library (NPL). The NPL is SBC’s main research platform for bioactive compound NATURAL PRODUCTS AND DRUG DISCOVERY screening with collaborators. “When you have no idea where to begin in a drug There are many challenges in the TK program: discovery program, Nature is a good starting point”. C&E organizing field trips, interagency coordination, consultative News (2003) Vol. 81, p. 77. meetings, accessibility of areas, multi-lingual communicat- A lot has been said and written about the nobility of ions, taxonomic identification, viability of transplanted wild natural products as a valuable resource for drug discovery. species and repeat collections. Researchers interested in TK Indeed over the last 50 years, a majority of new could bypass all these complications and avoid unforeseen pharmaceuticals were inspired by natural products [4]. risks by collaborating with SBC. The goal to acquire plant Despite this trend, in the 1990s, the pharmaceutical industry 194 Combinatorial Chemistry & High Throughput Screening, 2014, Vol. 17, No. 3 Yeo et al. made a marked policy change which diverted critical However, there are intrinsic disadvantages of its use in resources from natural product discovery programs to drug discovery. Isolation and characterization of bioactive pioneer cutting edge, high-throughput screening (HTS) compounds is labour intensive and substantial quantity of technologies [5]. To understand the basis for this change, the source material is necessary to purify a minimal stock for advent of computation, robotics and HTS, caused a paradigm profiling and preclinical studies. Consistent supply of raw shift away from traditional process of drug discovery and a materials could be susceptible to seasonal and environmental surge in the demand for synthetic compound libraries to feed factors thereby aggravating the pursuit of bioactives. The screening campaigns. This surge in demand outstripped the process must also avoid ‘rediscovering’ common known ability of chemists to provide novel compounds worthy of compounds, requiring a compulsory de-replication step. screening. Subsequently, the combinatorial libraries in the When a good candidate is discovered, more often than not, early years had numerous shortcomings and failed to provide its chemical structure is complex and difficult to synthesize sufficient innovative drugs to keep the R&D momentum [6]. due to, among other elements, many chiral centers [8]. They were so flawed, according to a prominent scientist, Moreover natural products are not easily amenable to the that, “… if you took the libraries across pharma from 1992 to HTS systems that proliferated in the 1980’s and 1990’s. In 1997 and stored them in giant dumpsters you would have short, there are specific costs and steps required to find improved productivity” [7]. In spite of the massive active compounds from natural sources that are not a investment in HTS, the lack of increase in new drugs led limitation in analogous synthetic compound screens. scientists and academics to debate whether natural products should make a comeback. A DYNAMIC NATURAL PRODUCT LIBRARY The notion of a natural product library is to make natural THE ADVANTAGES AND DISADVANTAGES OF chemical diversity accessible for the purpose of screening NATURAL PRODUCTS bioactive compounds. Having a rich diversity of natural The key advantage of natural products is that they offer resources (Fig. 2), SBC implemented a strategy to build up a unmatched chemical diversity and structural complexity that Natural Product Library (NPL) that is adaptable to the multi- convey biological activity. Nature has evolved diverse faceted needs of users. The key selling point of the NPL is chemical scaffolds to bind cellular targets that perform diversity and reliable supply. biological functions [5, 6].

NaturalProductLibrary

fordiscovery

Fig. (2). Natural Product Library. SBC’s core function is to build and maintain a diverse natural product library (NPL) for screening. The NPL is based on a variety of components of the biodiversity that are important for discovery of new compounds for innovative applications. Discovery Partnership: Gateway to Access Rainforests Combinatorial Chemistry & High Throughput Screening, 2014, Vol. 17, No. 3 195

SBC aims to transform access to natural products to make it To access the NPL, a Material Transfer Agreement a desirable resource for searching new bioactive compounds. A (MTA) and a Non-Disclosure Agreement (NDA) or a full concept of a factory line was designed to handle the influx of Research Agreement (RA) is signed with the prospective raw materials from sample processing or fermentation (in case parties. SBC will communicate with the user to craft of microbes) to solvent extraction and, accruing the dried accurate specifications of extracts needed i.e. type, quantity, extracts in an organized manner. Each extract is coded and secondary processing such as fractionation, clean up steps, annotated with information of its origins. In the case of plants and shipping format. The user could specify the type of linked to TK, traditional uses, location, informant and plant extracts from a particular of plant or microbe, or opt to morphology are archived. For microbes, information such as the target leads from TK, or converge on new species and type of samples, the unique environment of collection, untapped resources from metagenomic and marine sources. methodology of isolation, morphology description, and DNA SBC aims to support the researcher on a specific-need basis. identification are recorded. In the microbial library, the It draws on its experience of local knowledge and the components include actinomycetes, fungi, endophytes, algae biodiversity to find solutions to ensure consistency in supply, and myxobacteria isolated from a variety of ecosystems. Further repeat collection of specimens and, to the extent of contract information generated on the extracts in the NPL such as basic farming to scale up raw materials, if necessary. screening e.g. cytotoxicity and antimicrobial assays, including data from collaborators are value-add to the extracts. Currently BIOPROSPECTING OPPORTUNITIES IN THE NPL there are 23,000 plant and 18,000 microbial extracts in the library. Current efforts are devoted to enhancing the quality of Contemporary bioprospecting covers a wide range of the library by improving diversity, pre-fractionation, desired targets with biological properties: drug leads, taste minimizing replicates, identifying the active chemical structures modifiers, scents, flavours, cosmetics, biocontrol agents, and and creating a unique set of sub-libraries such as, UniQAct and reagents for elucidating biological pathways. UniQMyc, which are collections of diverse actinomycetes and With a clear mandate to bioprospect the biodiversity, the fungi respectively (Figs. 3-5). Essentially, the library offers a NPL was developed with a strong link to traditional representation of the chemical diversity of the flora and knowledge, plants and microbes uniquely found in Borneo. microbes from Borneo. The purpose of the NPL is for screen for bioactive

DistributionofActinomycetesStrainsinDifferentGenera(30Genera)

Nocardia(60) Dactylosporangium(52) Microbispora(38) Kitasatospora(33) Streptosporangium(20) Unidentified(16) Planosporangium(16) Streptacidiphilus(15) Actinoallomurus(13) Tsukamurella(11) Microtetraspora(11) Mycobacterium(10) Verrucosispora(9) Nonomuraea(8) Sphaerisporangium(7) Actinomadura(6) Rhodococcus(3) Planotetraspora(3) Pseudonocardia(2) Microbacterium(2) Amycolatopsis(2) Promicromonospora(1) Luteipulveratus(1) Kocuria(1) Kineosporia(1) Geodermatophilus(1) Actinoplanes(1) Actinobacterium(1) 0 102030405060

Fig. (3). A total of 1977 strains of actinomycetes was randomly selected from the NPL and partially sequenced in their 16S rDNA. A majority of the strains were classified under the genera Streptomyces (69%) and Micromonospora (13%). Rare actinomycetes such as genera Luteipulveratus, Verrucosispora, Planosporangium, Tsukamurella and Streptacidiphilus were also found. Efforts are currently dedicated to isolating very rare actinomycetes such as Planomonospora and Catellatospora. 196 Combinatorial Chemistry & High Throughput Screening, 2014, Vol. 17, No. 3 Yeo et al.

Fig. (4). Distinct types of isolated in Sarawak. (a) anisopliae; (b) Chrysoporthe hodgesiana; (c) Pilidiella wangiensis; (d) Penicillium sp.; (e) Phomopsis sp.; (f) Fusarium sp. compounds - via in-house screening assays or by a network The TK building houses a herbarium for taxonomic laboratories established through collaborations on a benefit identification and reference of TK plants. The key role of TK sharing basis. It is a one-stop centre for acquiring natural research group is to communicate and facilitate TK product extracts with all the amenities to assist the users. documentation. Their activities include organizing expeditions for sampling trips to villages, national parks and The scientists could access the chemical space of natural the interiors. Activities are coordinated with the indigenous products from the rainforests without having to set foot in communities for the purposes of documenting the knowledge the jungle through the NPL. SBC maintains good facilities and traditional uses of plants to support the research. The and laboratories to provide a running start for researchers, nursery and the ethnobotanical gardens provide the raw circumventing the necessity of a lengthy field collection event. However, there will be opportunities to participate in materials to obtain sufficient quantity of purified compounds for structure elucidation. Optimizing plant propagation field work to collect samples under the guidance of SBC’s conditions or scale-up planting of rare species are options research team to add-on the experience of a natural product other than repeated collection from the wild which can be discovery process. carried out at these facilities. FACILITIES AT SBC The six laboratories are: Extraction, Molecular Biology, Microbiology, Plant Tissue Culture, Analytical Chemistry SBC is located on a 50-acre plot of Nature Reserve land and Bioinformatics (Fig. 7). The extraction and analytical about 20 km away from the city of Kuching in Sarawak. The laboratories cater to upstream natural product work facilities and laboratories stand out against the background emphasizing on sample processing leading up to isolation of of forests that are inhabited by the endangered Orang Utan bioactive compounds. A natural product scientist would be (Pongo pygmaeus) from a nearby rehabilitation centre -- the able to operate with familiarity using equipment such as Semengoh Wildlife Rehabilitation Centre (Fig. 6). rotary evaporator, driers, separatory funnels, fractionation SBC comprises of facilities with interconnecting functions. column, High-Performance Liquid Chromatography (HPLC) It includes the TK building, an ethnobotanical garden, a nursery and Gas Chromatography-Mass Spectrometry (GC/MS). for plant research, six laboratories, a lecture theatre for public Currently, Liquid Chromatography-Mass Spectrometry talks and chalets for visiting scientists. (LC/MS) and Nuclear Magnetic Resonance (NMR) analyses

Discovery Partnership: Gateway to Access Rainforests Combinatorial Chemistry & High Throughput Screening, 2014, Vol. 17, No. 3 197

DistributionFungusStrainsinDifferentGenera(Excludeunidentified)

Phomopsis (8%,70strains) Colletotrichum (6%,58strains)

Pestalotiopsis (4%,37strains)

Diaporthe (6%,50strains)

Penicillium (13%,121strains) Fusarium (4%,38strains)

Generaandstrains Total:898strains,145genera (6) Ajellomyces(1) Amphilogia(1) Arthrinium(5) Ascotricha(1) Aspergillus(37) Aurantiosacculus(1) Auratiopycnidiella(1) Bambusicola(1) Bionectria(8) Bipolaris(1) Biscogniauxia(3) Botryosphaeria(3) Byssochlamys(3) Calonectria(2) Camarosporium(4) Campylocarpon(1) Capnodium(1) Cercospora(2) Ceriporia(1) Chaetocalathus(1) Chaetomium(18) Chaetosphaeria(10) Chaunopycnis(7) Chloridium(4) Chromocleista(1) Chrysoporthe(1) Cladosporium(12) Clonostachys(1) Cochliobolus(6) Colletotrichum(58) Coniochaeta(1) (7) Corynespora(6) Cosmospora(2) Cryptosporiopsis(3) Curvularia(4) Cylindrobasidium(1) Cylindrocarpon(2) (3) Cytospora(1) Dactylaria(1) Diaporthe(50) Diplogelasinospora(2) Earliella(1) Edenia(3) Elaphocordyceps(2) Emericellopsis(1) Endomelanconiopsis(13) Epacris(6) Eutypella(3) Exophiala(1) Fomitopsis(2) Fusarium(38) Galactomyces(1) Ganoderma(3) Geomyces(5) Gibberella(5) Gliocephalotrichum(1) Gliomastix(3) Glomerella(13) Gongronella(1) Grosmannia(1) Guignardia(23) Gymnopilus(2) Harknessia(3) Heliscus(1) Helminthosporium(1) Holocryphia(6) Hydropisphaera(1) Hymenochaete(1) Hyphodontia(1) Hypoxylon(12) (2) Lecanicillium(1) Lentinus(1) Leptographium(2) Leptosphaeria(8) Lichtheimia(1) Lophiostoma(1) (2) (1) Metarhizium(13) Microdiplodia(1) Microsphaeropsis(1) Mortierella(6) Munkovalsaria(1) Muscodor(1) Mycoleptodiscus(2) Mycosphaerella(8) Myrothecium(9) (1) Nemania(3) Neocosmospora(7) Neofusicoccum(2) Neoscytalidium(1) Neurospora(1) Nigrospora(2) Obolarina(1) Ochroconis(1) Oidiodendron(1) (21) Paraconiothyrium(21) Paraphaeosphaeria(2) Penicillium(121) Penidiella(1) Pestalotiopsis(37) Phaeoacremonium(1) Phialophora(6) Phoma(5) Phomopsis(70) Pilidiella(3) Plectosphaerella(19) (5) Pseudallescheria(9) Pseudocercosporella(1) Pseudofusicoccum(2) Pseudoplagiostoma(1) (3) Resinicium(2) Rhinocladiella(1) Rhizopycnis(1) Rhytidhysteron(1) Rigidoporus(2) Sarocladium(2) Scedosporium(1) Schizophyllum(3) Schizopora(2) Sporothrix(6) Staphylotrichum(1) Stenella(2) Stephanonectria(1) Sydowiella(1) (1) Talaromyces(12) Tolypocladium(3) Trametes(2) Trichosporon(9) Tritirachium(1) Umbelopsis(1) (1) Virgaria(1) (4) Westerdykella(1) Xylaria(4) Fig. (5). Analysis of Fungal Diversity in the Library. From a group of 1071 strains were randomly selected and identified based on their internal transcribed spacer (ITS) region. 869 strains were widely distributed among a total of 65 known families. A significant number of strains, 202 (19%) out of the 1071, did not have a match to any known ITS sequence in the GENBANK suggesting a potential for the discovery of new strains.

Fig. (6). The Facility. SBC is located in a nature reserve about 20 km from the city of Kuching. A frequent comment from visitors about the Centre is the excellent setting of the laboratories in a natural environment that highlights the value of natural products from the biodiversity. are outsourced. In support of the chemistry work, the DNA cloning. The microbiology laboratory isolates and molecular biology section offers sequencing of genetic cultures a variety of microbes including actinomycetes, markers for taxonomic identification, mammalian cell tissue fungi, endophytes, myxobacteria and algae for the NPL. The culture, bioassays, Polymerase Chain Reaction (PCR) and plant tissue culture laboratory propagates rare plant species 198 Combinatorial Chemistry & High Throughput Screening, 2014, Vol. 17, No. 3 Yeo et al.

Fig. (7). Researchers at SBC. The Sarawak Biodiversity Centre is a state government research agency under the Ministry of Resource Planning and Environment. The Centre has 100 employees with a major group of employees being research officers and laboratory support. SBC supports internship exchange with collaborators for capacity building and technology transfer. to generate materials for mass propagation and compound accurate, up-to-date data and relevant historical information. isolation. The key feature is the ability to connect all these The LIMS assists in achieving Good Laboratory Practice research activities through a robust bioinformatic network (GLP) and FDA 21CFR Part 11 compliance to enhance that allows information, samples and data to be compiled, research credibility and increases the capacity for analyzed, tracked and reported. collaborative opportunities. The Laboratory Information System (LIMS) is a software system that manages samples, laboratory users, instruments LEGAL INSTRUMENT FOR BIODIVERSITY RESEARCH and other functions, such as workflow automation (Fig. 8). According to the CBD, the country is responsible for The inherent flexibility of the system allows inclusion of TK formulating the legal framework and the mechanism for documentation and deployment across the different institutions and companies to obtain proper permission to laboratories. Such integration leads to the optimal use of carry out biodiversity research [9]. Sarawak implements this biodiversity data and preserve the trackable features of each provision through the SBC’s Ordinance and Regulations in extract and compound as it develops through the discovery one of the following ways: 1) Research Permit System, 2) process. It enables SBC and collaborators to generate Rapid Screening Collaboration, and 3) Research Colla- knowledge and make decisions, based on a combination of boration Agreement.

Fig. (8). LIMS deployment architecture at SBC. Discovery Partnership: Gateway to Access Rainforests Combinatorial Chemistry & High Throughput Screening, 2014, Vol. 17, No. 3 199

RESEARCH PERMIT SYSTEM and education. Benefit sharing from IPs, patents and revenues will be included, which may extend to licensing Under the Sarawak Biodiversity Regulations 2004, a rights of each party and rewards for reaching milestones in research agreement is signed after a research application is the product development process. Although this approach is submitted, evaluated and approved by the Sarawak time consuming to reach a final agreement, it is meant to Biodiversity Council. The application form and the guideline manage a long-term collaboration and relationship leading are available online [10] and the process takes about 2 up to a commercial agreement, an arrangement that is months to complete. Upon approval, the researcher and the usually preferred by the industry. Council sign a template research agreement that defines the obligations of the applicant in terms of depository of specimens, report, sharing of IP, future revenues and FUTURE PERSPECTIVES publications. This system is meant for an individual The goal of the SBC is to make natural products researcher or a team from a university/teaching institution available for research through various channels that are who wish to carry out collection of biological resources for suitable for collaborators. The existence of a law governing further research. In this scenario, the laws on access of the use of biological resources for research actually promotes biological resources in national parks and forest reserves are collaboration because there is a clear legal framework. While enforced by the Forests Department and therefore, a separate benefit sharing and other obligations might be permit from this agency is necessary. The Sarawak ‘overwhelming’, they are valid and justifiable under the Biodiversity Council under the Regulations is authorized to rights recognized by the CBD to ensure fair play between the issue 4 types of permits: 1) Permit to collect protected technology-rich but biodiversity-poor countries, and resources, 2) Permit for export of biological and protected biodiversity-rich but technology-poor countries. resources, 3) Permit for sale of protected resources, and 4) Permit for ethnobiological research. Sarawak seeks both monetary and non-monetary benefits – research funds, equipment, technology transfer, training, depository of specimens, reports, education, scholarships, RAPID SCREENING COLLABORATION publications and scientific exchange in return for the This collaboration is suitable for researchers from privilege to bioprospect its biological resources. The view is institutions and companies who want a supply of extracts to to exercise flexibility in seeking mutually agreed terms, screen. The researcher has to communicate the intention and without compromising the State’s interest or protection of its provide a research proposal to SBC. The proposal is resources while at the same time building up research evaluated and approval is given by the Council, based on the capacity. A good practice remains - not to overburden the recommendation of a technical appraisal, to sign a Material prospective collaborator and, to aim for collective gains as Transfer Agreement (MTA) and a Non-Disclosure the basis to establishing meaningful partnerships. Agreement (NDA). SBC undertakes the extract selection, SBC has built a unique centralized resource in the NPL preparation and shipment in consultation with the researcher. that is continuously growing for bioprospecting. Methods are When the extracts have been tested or screened, the ‘hits’ are continually improved to diversify the NPL by exploring revealed by the researcher and information on the ‘hit’ unique ecosystems for rare genetic resources. With the extracts is revealed by SBC under the NDA. Thereafter, increasing emphasis on DNA sequencing and the further work to scale up the extracts, fractionation, advancement of highly robust sequencing technology, the compound purification and structure elucidation are opportunity is right to fully leverage on the benefits of discussed and divided between the two parties. It is biodiversity. important at this point that both parties contribute equally to justify the sharing of benefits in intellectual property (IP), patents, and publications, which are stipulated in the MTA. CONFLICT OF INTEREST The advantage of this type of arrangement is that it allows The authors confirm that they do not have any conflicts for a rapid arrangement to be made without a prolonged full of interest. negotiation process that includes monetary and non- monetary benefits in the event if a product is ACKNOWLEDGEMENT commercialized. Having the MTA and NDA in place, it does not prevent both parties from planning to generate products The authors would like to thank Jonathan Rosenblum for from the rapid screening collaboration, which will be dealt comments on a draft version of this paper. with under a commercialization agreement. REFERENCES RESEARCH COLLABORATION AGREEMENT [1] Fong, J.C. Interest and policies of the state of Sarawak, Malaysia This agreement is usually more extensive and defines the regarding intellectual property rights for plant derived drugs. J. 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Received: November 18, 2013 Revised: December 12, 2013 Accepted: December 17, 2013