Bioprospecting (also known asbiodiversity prospecting) is the exploration of natural sources forsmall molecules,macromolecules and biochemical and genetic information that could be developed intocommercially valuable products for theagricultural,[2][3]aquaculture,[4][5]bioremediation,[4][6]cosmetics,[7][8]nanotechnology,[4][9] orpharmaceutical[2][10] industries. In the pharmaceutical industry, for example, almost one third of all small-molecule drugs approved by theU.S. Food and Drug Administration (FDA) between 1981 and 2014 were eithernatural products or compounds derived from natural products.[11]
Terrestrialplants,fungi andactinobacteria have been the focus of many past bioprospecting programs,[12] but interest is growing in less explored ecosystems (e.g.seas andoceans,caves andpolar regions)[7][13][14][15] and organisms (e.g.extremophiles,tropicalcorals andnecrophages)[16][17][18] as a means of identifying new molecules with novelbiological activities.[10] Species may be randomly screened for bioactivity or rationally selected and screened based onecological,ethnobiological,ethnomedical,historical orgenomic information.[10][19][20]
When a region's biological resources orindigenous knowledge are unethically appropriated or commerciallyexploited without providing fair compensation, this is known asbiopiracy.[12][21] Various international treaties have been negotiated to provide countries legal recourse in the event of biopiracy and to offer commercial actors legal certainty for investment. These include theUNConvention on Biological Diversity and theNagoya Protocol.[2][10] TheWIPO is currentlynegotiating more treaties to bridge gaps in this field.[22][23]
Other risks associated with bioprospecting are the overharvesting of individual species and environmental damage, but legislation has been developed to combat these also. Examples include national laws such as the USMarine Mammal Protection Act and USEndangered Species Act, and international treaties such as the UN Convention on Biological Diversity, the UNConvention on the Law of the Sea, theBiodiversity Beyond National Jurisdictions Treaty, and theAntarctic Treaty.[10][24]
Bioprospecting-derived resources and products used in agriculture includebiofertilizers,biopesticides andveterinary antibiotics.Rhizobium is a genus of soil bacteria used as biofertilizers,[26]Bacillus thuringiensis (also called Bt) and theannonins (obtained from seeds of the plantAnnona squamosa) are examples of biopesticides,[27][28][25][29] andvalnemulin andtiamulin (discovered and developed from thebasidiomycete fungiOmphalina mutila andClitopilus passeckerianus) are examples of veterinary antibiotics.[30][31]
Examples of bioprospecting products used in bioremediation includeCoriolopsis gallica- andPhanerochaete chrysosporium-derivedlaccase enzymes, used for treatingbeer factorywastewater and for dechlorinating and decolorizingpaper milleffluent.[9]
Cosmetics and personal care products obtained from bioprospecting includePorphyridium cruentum-derivedoligosaccharide and oligoelement blends used to treaterythema (rosacea,flushing anddark circles),[7]Xanthobacter autotrophicus-derivedzeaxanthin used forskin hydration andUV protection,[8]Clostridium histolyticum-derivedcollagenases used forskin regeneration,[8] andMicrosporum-derivedkeratinases used forhair removal.[8]
Becausemicrobiallaccases have a broadsubstrate range, they can be used inbiosensor technology to detect a wide range oforganic compounds. For example, laccase-containingelectrodes are used to detectpolyphenolic compounds inwine, andlignins andphenols inwastewater.[9]
Many of theantibacterial drugs in current clinical use were discovered through bioprospecting including theaminoglycosides,tetracyclines,amphenicols,polymyxins,cephalosporins and otherβ-lactam antibiotics,macrolides,pleuromutilins,glycopeptides,rifamycins,lincosamides,streptogramins, andphosphonic acid antibiotics.[10][32] The aminoglycoside antibioticstreptomycin, for example, was discovered from the soil bacteriumStreptomyces griseus, the fusidane antibioticfusidic acid was discovered from the soil fungusAcremonium fusidioides, and the pleuromutilin antibiotics (eg.lefamulin) were discovered and developed from the basidiomycete fungiOmphalina mutila andClitopilus passeckerianus.[10][30]
Other examples of bioprospecting-derived anti-infective drugs include theantifungal druggriseofulvin (discovered from the soil fungusPenicillium griseofulvum),[33] the antifungal andantileishmanial drugamphotericin B (discovered from the soil bacteriumStreptomyces nodosus),[34] theantimalarial drugartemisinin (discovered from the plantArtemisia annua),[1][35] and theantihelminthic drugivermectin (developed from the soil bacteriumStreptomyces avermitilis).[36]
Bioprospecting-derived pharmaceuticals have been developed for the treatment ofnon-communicable diseases and conditions too. These include theanticancer drugbleomycin (obtained from the soil bacteriumStreptomyces verticillus),[37] theimmunosuppressant drugciclosporin used to treat autoimmune diseases such asrheumatoid arthritis andpsoriasis (obtained from the soil fungusTolypocladium inflatum),[38] the anti-inflammatory drugcolchicine used to treat and preventgout flares (obtained from the plantColchicum autumnale),[1] theanalgesic drugziconotide (developed from thecone snailConus magus),[14] and theacetylcholinesterase inhibitorgalantamine used to treatAlzheimer's disease (obtained from plants in theGalanthus genus).[39]
Bioprospecting has both strengths and weaknesses as a strategy for discovering new genes, molecules, and organisms suitable for development and commercialization.
Bioprospecting-derivedsmall molecules (also known asnatural products) are more structurally complex than synthetic chemicals, and therefore show greaterspecificity towardsbiological targets. This is a big advantage indrug discovery anddevelopment, especiallypharmacological aspects of drug discovery and development, where off-target effects can causeadverse drug reactions.[10]
Natural products are also more amenable tomembrane transport than synthetic compounds. This is advantageous when developingantibacterial drugs, which may need to traverse both anouter membrane andplasma membrane to reach their target.[10]
For somebiotechnological innovations to work, it is important to haveenzymes that function at unusually high or low temperatures. An example of this is thepolymerase chain reaction (PCR), which is dependent on aDNA polymerase that can operate at 60°C and above.[16] In other situations, for exampledephosphorylation, it can be desirable to run the reaction at low temperature.[14]Extremophile bioprospecting is an important source of such enzymes, yielding thermostable enzymes such asTaq polymerase (fromThermus aquaticus),[16] and cold-adapted enzymes such as shrimpalkaline phosphatase (fromPandalus borealis).[14]
With the Convention on Biological Diversity (CBD) now ratified by most countries, bioprospecting has the potential to bring biodiversity-rich and technologically advanced nations together, and benefit them both educationally and economically (eg. information sharing,technology transfer,new product development,royalty payment).[2][41]
For useful molecules identified throughmicrobial bioprospecting, scale up of production is feasible at reasonable cost because the producing microorganism can becultured in abioreactor.[8][42]
Although some potentially very useful microorganisms are known to exist in nature (eg.lignocellulose-metabolizing microbes), difficulties have been encountered cultivating these in a laboratory setting.[44] This problem may be resolvable bygenetically manipulating easier-to-culture organisms such asEscherichia coli orStreptomyces coelicolor to express thegene cluster responsible for the desired activity.[16][45]
Isolating and identifying thecompound(s) responsible for a biological extract's activity can be difficult.[45] Also, subsequent elucidation of themechanism of action of the isolated compound can be time-consuming.[45] Technological advancements inliquid chromatography,mass spectrometry and other techniques are helping to overcome these challenges.[45]
Implementing and enforcing bioprospecting-related treaties and legislation is not always easy.[2][41] Drug development is an inherently expensive and time-consuming process with low success rates, and this makes it difficult to quantify the value of potential products when drafting bioprospecting agreements.[2]Intellectual property rights may be difficult to award too. For example, legal rights to amedicinal plant may be disputable if it has been discovered by different people in different parts of the world at different times.[2]
Whilst the structural complexity of natural products is generally advantageous in drug discovery, it can make the subsequent manufacture of drug candidates difficult. This problem is sometimes resolvable by identifying the part of the natural product structure responsible for activity and developing a simplified synthetic analogue. This was necessary with the natural product halichondrin B, its simplified analogueeribulin now approved and marketed as ananticancer drug.[46]
Errors and oversights can occur at different steps in the bioprospecting process including collection of source material, screening source material forbioactivity, testing isolated compounds fortoxicity, and identification ofmechanism of action.
Prior to collectingbiological material ortraditional knowledge, the correct permissions must be obtained from the source country, land owner etc. Failure to do so can result incriminal proceedings and rejection of any subsequentpatent applications. It is also important to collect biological material in adequate quantities, to have biological material formallyidentified, and to deposit a voucher specimen with arepository for long-term preservation and storage. This helps ensure any important discoveries are reproducible.[10][14]
When testing extracts and isolated compounds for bioactivity and toxicity, the use ofstandard protocols (eg.CLSI,ISO,NIH,EURL ECVAM,OECD) is desirable because this improves test result accuracy and reproducibility. Also, if the source material is likely to contain known (previously discovered) active compounds (eg. streptomycin in the case of actinomycetes), then dereplication is necessary to exclude these extracts and compounds from the discovery pipeline as early as possible. In addition, it is important to considersolvent effects on the cells orcell lines being tested, to include reference compounds (ie. purechemical compounds for which accurate bioactivity and toxicity data are available), to set limits on cell line passage number (eg. 10–20 passages), to include all the necessary positive and negativecontrols, and to be aware of assay limitations. These steps help ensure assay results are accurate, reproducible and interpreted correctly.[10][14]
When attempting to elucidate the mechanism of action of an extract or isolated compound, it is important to use multiple orthogonal assays. Using just a single assay, especially a singlein vitro assay, gives a very incomplete picture of an extract or compound's effect on the human body.[47][48] In the case ofValeriana officinalis root extract, for example, thesleep-inducing effects of this extract are due to multiple compounds and mechanisms including interaction withGABA receptors andrelaxation ofsmooth muscle.[47] The mechanism of action of an isolated compound can also be misidentified if a single assay is used because some compoundsinterfere with assays. For example, the sulfhydryl-scavenging assay used to detecthistone acetyltransferase inhibition can give a false positive result if the test compound reacts covalently with cysteines.[48]
The termbiopiracy was coined byPat Mooney,[49] to describe a practice in which indigenous knowledge of nature, originating withindigenous peoples, is used by others for profit, without authorization or compensation to the indigenous people themselves.[50] For example, when bioprospectors draw on indigenous knowledge of medicinal plants which is laterpatented by medical companies without recognizing the fact that the knowledge is not new or invented by the patenter, this deprives the indigenous community of their potential rights to the commercial product derived from the technology that they themselves had developed.[51] Critics of this practice, such asGreenpeace,[52] claim these practices contribute to inequality between developing countries rich inbiodiversity, and developed countries hostingbiotech firms.[51]
In the 1990s many large pharmaceutical and drug discovery companies responded to charges of biopiracy by ceasing work on natural products, turning tocombinatorial chemistry to develop novel compounds.[49]
Therosy periwinkle case dates from the 1950s. The rosy periwinkle, while native toMadagascar, had been widely introduced into other tropical countries around the world well before the discovery ofvincristine. Different countries are reported as having acquired different beliefs about the medical properties of the plant.[53] This meant that researchers could obtain local knowledge from one country and plant samples from another. The use of the plant fordiabetes was the original stimulus for research. Effectiveness in the treatment of bothHodgkin lymphoma andleukemia were discovered instead.[54] The Hodgkin lymphoma chemotherapeutic drugvinblastine is derivable from the rosy periwinkle.[55]
TheMaya ICBG bioprospecting controversy took place in 1999–2000, when theInternational Cooperative Biodiversity Group led byethnobiologistBrent Berlin was accused of being engaged in unethical forms of bioprospecting by severalNGOs and indigenous organizations. The ICBG aimed to document the biodiversity ofChiapas,Mexico, and theethnobotanical knowledge of the indigenousMaya people – in order to ascertain whether there were possibilities of developing medical products based on any of the plants used by the indigenous groups.[56][57]
The Maya ICBG case was among the first to draw attention to the problems of distinguishing between benign forms of bioprospecting and unethical biopiracy, and to the difficulties of securing community participation and prior informed consent for would-be bioprospectors.[58]
In 1994, theU.S. Department of Agriculture andW. R. Grace and Company received a European patent on methods of controlling fungal infections in plants using a composition that included extracts from theneem tree (Azadirachta indica), which grows throughoutIndia andNepal.[59][60][61] In 2000 the patent was successfullyopposed by several groups from the EU and India including the EU Green Party,Vandana Shiva, and theInternational Federation of Organic Agriculture Movements (IFOAM) on the basis that the fungicidal activity of neem extract had long been known inIndian traditional medicine.[61] WR Grace appealed and lost in 2005.[62]
In 1997, the US corporationRiceTec (a subsidiary of RiceTec AG of Liechtenstein) attempted to patent certain hybrids ofbasmati rice and semidwarf long-grain rice.[63] The Indian government challenged this patent and, in 2002, fifteen of the patent's twenty claims were invalidated.[64]
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The Enola bean is a variety of Mexicanyellow bean, so called after the wife of the man who patented it in 1999.[65] The allegedly distinguishing feature of the variety is seeds of a specific shade of yellow. The patent-holder subsequently sued a large number of importers of Mexican yellow beans with the following result: "...export sales immediately dropped over 90% among importers that had been selling these beans for years, causing economic damage to more than 22,000 farmers in northern Mexico who depended on sales of this bean."[66] A lawsuit was filed on behalf of the farmers and, in 2005, the US-PTO ruled in favor of the farmers. In 2008, the patent was revoked.[67]
Hoodia gordonii, asucculent plant, originates from theKalahari Desert ofSouth Africa. For generations it has been known to the traditionally livingSan people as anappetite suppressant. In 1996 South Africa'sCouncil for Scientific and Industrial Research began working with companies, includingUnilever, to develop dietary supplements based onHoodia.[68][69][70][71] Originally the San people were not scheduled to receive any benefits from the commercialization of their traditional knowledge, but in 2003 the South African San Council made an agreement with CSIR in which they would receive from 6 to 8% of the revenue from the sale ofHoodia products.[72]
In 2008 after having invested €20 million in R&D onHoodia as a potential ingredient indietary supplements for weight loss, Unilever terminated the project because their clinical studies did not show thatHoodia was safe and effective enough to bring to market.[73]
The following is a selection of further recent cases of biopiracy. Most of them do not relate to traditional medicines.
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One common misunderstanding is that pharmaceutical companiespatent the plants they collect. While obtaining a patent on a naturally occurring organism as previously known or used is not possible, patents may be taken out on specific chemicals isolated or developed from plants. Often these patents are obtained with a stated and researched use of those chemicals.[citation needed] Generally the existence, structure and synthesis of those compounds is not a part of the indigenous medical knowledge that led researchers to analyze the plant in the first place. As a result, even if the indigenous medical knowledge is taken as prior art, that knowledge does not by itself make the active chemical compound "obvious," which is the standard applied under patent law.
In theUnited States,patent law can be used to protect "isolated and purified" compounds – even, in one instance, a new chemical element (see USP 3,156,523). In 1873,Louis Pasteur patented a "yeast" which was "free from disease" (patent #141072). Patents covering biological inventions have been treated similarly. In the 1980 case ofDiamond v. Chakrabarty, theSupreme Court upheld a patent on a bacterium that had been genetically modified to consume petroleum, reasoning that U.S. law permits patents on "anything under the sun that is made by man." TheUnited States Patent and Trademark Office (USPTO) has observed that "a patent on a gene covers the isolated and purified gene but does not cover the gene as it occurs in nature".[82]
Also possible under US law is patenting acultivar, a new variety of an existing organism. The patent on the Enola bean (now revoked)[83] was an example of this sort of patent. Theintellectual property laws of the US also recognizeplant breeders' rights under thePlant Variety Protection Act, 7 U.S.C. §§ 2321–2582.[84]
The Convention on Biological Diversity (CBD) came into force in 1993. It secured rights to control access togenetic resources for the countries in which those resources are located. One objective of the CBD is to enable lesser-developed countries to better benefit from their resources and traditional knowledge. Under the rules of the CBD, bioprospectors are required to obtaininformed consent to access such resources, and must share any benefits with the biodiversity-rich country.[86] However, some critics believe that the CBD has failed to establish appropriate regulations to prevent biopiracy.[87] Others claim that the main problem is the failure of national governments to pass appropriate laws implementing the provisions of the CBD.[88] TheNagoya Protocol to the CBD, which came into force in 2014, provides further regulations.[89] The CBD has been ratified, acceded or accepted by 196 countries and jurisdictions globally, with exceptions including theHoly See andUnited States.[85]
The requirements for bioprospecting as set by CBD has created a new branch of internationalpatent andtrade law, bioprospecting contracts.[2] Bioprospecting contracts lay down the rules of benefit sharing between researchers and countries, and can bring royalties tolesser-developed countries. However, although these contracts are based on prior informed consent and compensation (unlike biopiracy), every owner or carrier of an indigenous knowledge and resources are not always consulted or compensated,[90] as it would be difficult to ensure every individual is included.[91] Because of this, some have proposed that the indigenous or other communities form a type of representative micro-government that would negotiate with researchers to form contracts in such a way that the community benefits from the arrangements.[91] Unethical bioprospecting contracts (as distinct from ethical ones) can be viewed as a new form of biopiracy.[87]
An example of a bioprospecting contract is the agreement betweenMerck andINBio ofCosta Rica.[92]
Due to previous cases of biopiracy and to prevent further cases, the Government of India has convertedtraditional Indian medicinal information from ancient manuscripts and other resources into an electronic resource; this resulted in theTraditional Knowledge Digital Library in 2001.[93] The texts are being recorded fromTamil,Sanskrit,Urdu,Persian andArabic; made available to patent offices in English, German, French, Japanese and Spanish. The aim is to protect India's heritage from being exploited by foreign companies.[94] Hundreds ofyoga poses are also kept in the collection.[94] The library has also signed agreements with leading internationalpatent offices such asEuropean Patent Office (EPO),United Kingdom Trademark & Patent Office (UKTPO) and theUnited States Patent and Trademark Office to protecttraditional knowledge from biopiracy as it allowspatent examiners at International Patent Offices to access TKDL databases for patent search and examination purposes.[79][95][96]
{{cite book}}: CS1 maint: location missing publisher (link){{cite book}}: CS1 maint: location missing publisher (link){{cite book}}: CS1 maint: location missing publisher (link)CBD stating that the benefits arising from the use of genetic resources should be shared in a fair and equitable way (Rau, 2010)
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