Bioprospecting (also known as biodiversity prospecting) is the exploration of natural sources for small molecules, macromolecules and biochemical and genetic information that could be developed into commercially valuable products for the agricultural, aquaculture, bioremediation, cosmetics, nanotechnology, or pharmaceutical industries. In the pharmaceutical industry, for example, almost one third of all small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) between 1981 and 2014 were either natural products or compounds derived from natural products.
Terrestrial plants, fungi and actinobacteria have been the focus of many past bioprospecting programs, but interest is growing in less explored ecosystems (e.g. seas and oceans, caves and polar regions) and organisms (e.g. extremophiles, tropical corals and necrophages) as a means of identifying new molecules with novel biological activities. Species may be randomly screened for bioactivity or rationally selected and screened based on ecological, ethnobiological, ethnomedical, historical or genomic information.
When a region's biological resources or indigenous knowledge are unethically appropriated or commercially exploited without providing fair compensation, this is known as biopiracy. 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 the UN Convention on Biological Diversity and the Nagoya Protocol. The WIPO is currently negotiating more treaties to bridge gaps in this field.
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 US Marine Mammal Protection Act and US Endangered Species Act, and international treaties such as the UN Convention on Biological Diversity, the UN Convention on the Law of the Sea, the Biodiversity Beyond National Jurisdictions Treaty, and the Antarctic Treaty.
Bioprospecting-derived resources and products Agriculture
Bioprospecting-derived resources and products used in agriculture include biofertilizers, biopesticides and veterinary antibiotics. Rhizobium is a genus of soil bacteria used as biofertilizers, Bacillus thuringiensis (also called Bt) is a biopesticide, and valnemulin and tiamulin (discovered and developed from the basidiomycete fungi Omphalina mutila and Clitopilus passeckerianus) are examples of veterinary antibiotics.
Bioremediation Examples of bioprospecting products used in bioremediation include Coriolopsis gallica- and Phanerochaete chrysosporium-derived laccase enzymes, used for treating beer factory wastewater and for dechlorinating and decolorizing paper mill effluent.
Cosmetics and personal care Cosmetics and personal care products obtained from bioprospecting include Porphyridium cruentum-derived oligosaccharide and oligoelement blends used to treat erythema (rosacea, flushing and dark circles), Xanthobacter autotrophicus-derived zeaxanthin used for skin hydration and UV protection, Clostridium histolyticum-derived collagenases used for skin regeneration, and Microsporum-derived keratinases used for hair removal.
Nanotechnology and biosensors Because microbial laccases have a broad substrate range, they can be used in biosensor technology to detect a wide range of organic compounds. For example, laccase-containing electrodes are used to detect polyphenolic compounds in wine, and lignins and phenols in wastewater.
Pharmaceuticals
Many of the antibacterial drugs in current clinical use were discovered through bioprospecting including the aminoglycosides, tetracyclines, amphenicols, polymyxins, cephalosporins and other β-lactam antibiotics, macrolides, pleuromutilins, glycopeptides, rifamycins, lincosamides, streptogramins, and phosphonic acid antibiotics. The aminoglycoside antibiotic streptomycin, for example, was discovered from the soil bacterium Streptomyces griseus, the fusidane antibiotic fusidic acid was discovered from the soil fungus Acremonium fusidioides, and the pleuromutilin antibiotics (eg. lefamulin) were discovered and developed from the basidiomycete fungi Omphalina mutila and Clitopilus passeckerianus.
Other examples of bioprospecting-derived anti-infective drugs include the antifungal drug griseofulvin (discovered from the soil fungus Penicillium griseofulvum), the antifungal and antileishmanial drug amphotericin B (discovered from the soil bacterium Streptomyces nodosus), the antimalarial drug artemisinin (discovered from the plant Artemisia annua), and the antihelminthic drug ivermectin (developed from the soil bacterium Streptomyces avermitilis).
Bioprospecting-derived pharmaceuticals have been developed for the treatment of non-communicable diseases and conditions too. These include the anticancer drug bleomycin (obtained from the soil bacterium Streptomyces verticillus), the immunosuppressant drug ciclosporin used to treat autoimmune diseases such as rheumatoid arthritis and psoriasis (obtained from the soil fungus Tolypocladium inflatum), the anti-inflammatory drug colchicine used to treat and prevent gout flares (obtained from the plant Colchicum autumnale), the analgesic drug ziconotide (developed from the cone snail Conus magus), and the acetylcholinesterase inhibitor galantamine used to treat Alzheimer's disease (obtained from plants in the Galanthus genus).
Bioprospecting as a discovery strategy Bioprospecting has both strengths and weaknesses as a strategy for discovering new genes, molecules, and organisms suitable for development and commercialization.
Strengths
Bioprospecting-derived small molecules (also known as natural products) are more structurally complex than synthetic chemicals, and therefore show greater specificity towards biological targets. This is a big advantage in drug discovery and development, especially pharmacological aspects of drug discovery and development, where off-target effects can cause adverse drug reactions.
Natural products are also more amenable to membrane transport than synthetic compounds. This is advantageous when developing antibacterial drugs, which may need to traverse both an outer membrane and plasma membrane to reach their target.
For some biotechnological innovations to work, it is important to have enzymes that function at unusually high or low temperatures. An example of this is the polymerase chain reaction (PCR), which is dependent on a DNA polymerase that can operate at 60 °C and above. In other situations, for example dephosphorylation, it can be desirable to run the reaction at low temperature. Extremophile bioprospecting is an important source of such enzymes, yielding thermostable enzymes such as Taq polymerase (from Thermus aquaticus), and cold-adapted enzymes such as shrimp alkaline phosphatase (from Pandalus borealis).
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).
For useful molecules identified through microbial bioprospecting, scale up of production is feasible at reasonable cost because the producing microorganism can be cultured in a bioreactor.
Weaknesses
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. This problem may be resolvable by genetically manipulating easier-to-culture organisms such as Escherichia coli or Streptomyces coelicolor to express the gene cluster responsible for the desired activity.
Isolating and identifying the compound(s) responsible for a biological extract's activity can be difficult. Also, subsequent elucidation of the mechanism of action of the isolated compound can be time-consuming. Technological advancements in liquid chromatography, mass spectrometry and other techniques are helping to overcome these challenges.
Implementing and enforcing bioprospecting-related treaties and legislation is not always easy. 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. Intellectual property rights may be difficult to award too. For example, legal rights to a medicinal plant may be disputable if it has been discovered by different people in different parts of the world at different times.
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 analogue eribulin now approved and marketed as an anticancer drug.
Bioprospecting pitfalls Errors and oversights can occur at different steps in the bioprospecting process including collection of source material, screening source material for bioactivity, testing isolated compounds for toxicity, and identification of mechanism of action.
Collection of source material
Prior to collecting biological material or traditional knowledge, the correct permissions must be obtained from the source country, land owner etc. Failure to do so can result in criminal proceedings and rejection of any subsequent patent applications. It is also important to collect biological material in adequate quantities, to have biological material formally identified, and to deposit a voucher specimen with a repository for long-term preservation and storage. This helps ensure any important discoveries are reproducible. Environmental impacts must also be considered as the over-harvesting of desirable species can put them at risk of extinction.
Bioactivity and toxicity testing When testing extracts and isolated compounds for bioactivity and toxicity, the use of standard 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 consider solvent effects on the cells or cell lines being tested, to include reference compounds (ie. pure chemical 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 negative controls, and to be aware of assay limitations. These steps help ensure assay results are accurate, reproducible and interpreted correctly.
Identification of mechanism of action