0482-B1
Michel Cusson[1]
Through two examples, the present paper examines the various practical hurdles - registration, intellectual property, public acceptance, commercial potential - currently facing forest pest control products developed through biotechnology, and explores ways of facilitating their deployment.
The need to reduce or eliminate the use of conventional chemical pesticides, both in agriculture and forestry, has fostered a search for alternative products and strategies that have a much lower impact on human health and the environment. Naturally occurring biological control agents, plant-derived target-specific insecticides, and pest-resistant plants obtained through conventional breeding are among the better-known and most accepted alternatives. However, because effective biopesticides, pest-specific compounds and resistant crops or trees are not always readily available for the management of a given pest, scientists have harnessed the power of biotechnology in an effort to improve the efficacy of existing biocontrol agents, to identify target sites in pest insects and to introduce resistance genes into host plants.
Given the original and noble goal of these efforts - i.e., the development of environmentally friendly pest control tools -, it seems somewhat ironic that the products of pest control biotechnology are the subject of greater scrutiny and fear than their highly toxic chemical predecessors, at least at the time the latter were first being considered for registration. This situation apparently reflects a heightened environmental awareness, both in the general public and among environmental advocacy groups, which has its roots in various publications that started pointing out, in the 1960’s, the threats posed by chemical pesticides (e.g., Carson 1962). Along with this awareness is a perception that - rightly or wrongly - pest control tools derived from biotechnology carry more risk for the environment than conventional products.
The purpose of the present paper is not to review recent biotechnological progress relating to forest pest management, but rather to examine the various hurdles - registration, intellectual property, public acceptance, commercial potential - currently facing pest control tools developed through biotechnology. Emphasis is put on two selected insect control strategies (genetically modified baculoviruses and “biorationals”), including some comparisons of the issues that are specific to trees and the forest environment with those particular to crops in agro-ecosystems. I also explore ways of facilitating the deployment of these pest control tools.
Baculoviruses are DNA viruses that occur naturally among populations of many insect species, predominantly lepidopterans (caterpillars). Larvae become infected while feeding on contaminated foliage and typically undergo liquefaction upon death, thereby releasing virus onto the host plant and allowing the infection cycle to start all over again. The principal attraction - from an environmental standpoint - in using these viruses for biopesticide development is their very narrow host range: most baculoviruses have the ability to infect only a few closely-related species, and are totally harmless to other organisms in the treated environment. Some naturally occurring (i.e., unaltered) baculoviruses have indeed been registered as pest control products in the USA, including one aimed at the gypsy moth (“Gypcheck”). However, despite their environmental advantages, these viral insecticides have not been commercially successful, largely due to their relatively high cost and slow action (they take up to 10 days to kill an insect pest; Wood et al. 1990).
The slow action of baculoviruses has been the main focus of research efforts aimed at improving their efficacy through genetic engineering. Interestingly, some features of baculoviruses make it possible to introduce foreign genes (e.g., an insect-specific toxin) into their genomes in such a way that they are expressed at very high levels; the proteins produced as a result of expression of the introduced genes are chosen with the intention of causing significant physiological disruption in the host, thereby bringing about feeding cessation and death earlier than in insects infected with the wild-type virus.
Over the past ~15 years, many genetically modified baculoviruses have been developed in various laboratories, with some displaying improved efficacy relative to the progenitor wild-type virus. For such candidates, it is customary to seek patent protection, particularly if the type of physiological perturbation caused by the inserted gene is novel. The cost of international patent protection may, however, be prohibitive, given the limitations that the virus’ narrow host range imposes on the product’s commercial potential - a consideration that may be even more important for viruses aimed at forest pests due to the often cyclical nature of their outbreaks, with long endemic periods during which the viral insecticide is likely to remain on the shelf. Thus, with respect to commercial viability, the host specificity of baculoviruses should be viewed more as an impediment than an advantage. In this context, it appears appropriate to search for ways of achieving a compromise between an environmentally desirable degree of host specificity and a host range that is broad enough to attract commercial interest. Research activities aimed at extending baculovirus host range to a greater number of lepidopteran species are, therefore, strategically important, particularly for viruses targeting forest pests. Recent progress has been made in this area through the insertion of genes from another group of viruses (the polydnaviruses) into the baculovirus genome; these foreign genes encode proteins that suppress the host caterpillar’s immune response, thereby allowing a given baculovirus to replicate in an otherwise non-permissive host (Webb and Cui 1998). Similarly, the identification of genes, within baculovirus genomes, dictating host specificity may allow scientists to manipulate the host range of a given virus through genetic manipulation.
For registration in Canada and the United States, genetically engineered baculovirus-based insecticides are subject to the same regulations and data requirements as conventional microbial pesticides, but with the following additional considerations: (i) effects (health, environment, etc.) of the pesticidal substance produced by the inserted gene, (ii) possible modification of host range (namely broadening to the point of being infectious to other types of organisms, including mammals), (iii) the stability and persistence of the recombinant virus in the environment (particularly, the possibility that it may displace the wild-type virus), and (iv) the potential for genetic exchange of the foreign insecticidal gene with other naturally occurring microbes (McClintock et al. 2000).
Small-scale field releases of genetically modified baculoviruses, in agricultural settings, have been approved and carried out in the United Kingdom (Bishop 1989; Cory et al. 1994), in the United States (Woods et al. 1994; see also McClintock et al. 2000), as well as in Canada (Mulock and Faulkner 1997). China has also been active, recently, in this area of research, and has established a well-structured body, the “National Biosafety Committee” (NBC), to oversee applications for environmental releases and industrial-scale trials involving genetically modified organisms (GMOs) (Z. Hu, personal communication). Some of the field trials conducted so far involved viruses carrying only a marker gene and/or with a gene deletion, with the simple aim of assessing persistence and spread in the environment of a genetically altered virus, whereas others were carried out to assess the field efficacy of a virus modified to express an insect-selective toxin gene. In the latter case, the modified baculovirus was shown to kill faster, resulting in reduced crop damage relative to controls and wild-type-virus-treated plants (Cory et al. 1994); in the former case, persistence and spread of the modified virus were shown to be lower than for the corresponding wild-type microbe (Mulock and Faulkner 1997), giving support to the claim that a genetically modified virus will be less persistent in the environment than the naturally occurring parent virus. From theoretical considerations alone, a strong case can be made for the lower persistence of recombinant baculoviruses based on the fact that they kill the host faster than the wild-type virus, giving it less time to replicate and, therefore, leaving a smaller secondary inoculum on the foliage (McClintock et al. 2000). For a discussion of other environmental and health concerns associated with the use of genetically modified baculoviruses, the reader is referred to McClintock et al. (2000) who summarized the data presented by DuPont Agricultural Products to the US Environmental Protection Agency (EPA) in the context of a permit application for a field release of a recombinant baculovirus, and for which the company was able to make a strong case for the overall safety of the genetically modified agent, presenting both experimental data and theoretical arguments.
With respect to the control of forest insect pests, the only baculovirus that has so far been the subject of genetic modifications is the one specific to the spruce budworm, Choristoneura fumiferana (CfMNPV), the most destructive pest of conifers in eastern Canada. Among the various genetic modifications attempted, one has proven to be rather promising; in this particular case, the gene inserted into the viral genome does not encode a toxin, but a molt-related protein found in the host C. fumiferana. Untimely expression of this gene in infected hosts causes an incomplete molt that results in death of the insect (Palli et al. 1999). Small-scale field releases of this virus have not yet been conducted (assessment of the efficacy of this virus is at the green-house trial stage); obtaining permits for such releases could prove somewhat more challenging than for agents aimed at agricultural pests given that containment issues for pesticide applications over tall trees, whether aerial or from the ground, are greater than for low-lying crops.
Thus, none of the recombinant baculoviruses developed since the late 1980’s have yet been registered for use anywhere in the world and, as a consequence, none are currently part of operational pest management programs, either in agriculture or forestry. In addition, given the bad press given to GMOs in recent years, applications for registration of genetically modified baculoviruses are not being given a high priority status by regulatory agencies (J. Drolet, personal communication). In spite of these considerations, recombinant baculoviruses constitute a pest control avenue that is well worth pursuing, particularly for the management of forest insect pests, where control options are often severely limited and where target specificity may be of major importance considering the greater complexity of the natural forest ecosystem relative to the simpler monoculture-based agro-ecosystems. As is probably true of many new technologies, once a precedent will have been set for the registration of a genetically modified baculovirus, subsequent registrations will likely be easier given that applicants will then be able to draw upon the similarities within this virus family to build a strong case in favor of their overall safety. In the meantime, the adoption of certain research and development strategies could lead to products that have a shorter transit time in the registration pipeline.
First, it is probably wise to choose the foreign gene for insertion among organisms present in the target pest’s ecosystem, as was the case for the aforementioned recombinant virus developed against the spruce budworm. In terms of perceived risks of this technology by the general public, a caterpillar gene involved in molt regulation may seem less threatening than a toxin gene obtained from scorpions, even though the toxin has been shown to be specific to insects and the virus is known to be unable to replicate in mammals. Thus, the search for new genes originating either in the pest itself or in other organisms in its ecosystem should be encouraged. On the issue of risk assessment, scientists will have to develop effective communication strategies aimed at dealing with objections relative to the deployment of these organisms, particularly those that are not based on sound science, while showing respect for legitimate concerns. Past experience with an experimental field release of a genetically modified baculovirus in Canada suggests that a good communication plan can do much to reduce or eliminate public resistance directed at the use of such genetically modified viruses (B. Mulock, personal communication).
Notwithstanding the efforts to further enhance the efficacy and increase the host range of baculoviruses through genetic manipulations-both of which should increase their commercial potential-the success of these viruses may ultimately depend on our ability to mass produce them more cheaply and more efficiently. Efforts are being made to replace the current in vivo virus production methods with in vitro approaches using insect cell lines in large bioreactors. Once these methods have been perfected, it should become possible to produce recombinant baculoviruses of more uniform quality and at lower cost, therefore making them more attractive from a commercial standpoint. For the control of forest insects, there will be cases where commercial viability remains unlikely due to the sporadic nature of the pest and the relative target specificity of the virus; in such instances, it may not be unreasonable for governmental research agencies to consider using public funds for virus production and application, particularly if the forest is on public land.
Biorational insecticides may be defined as chemicals that aim at disrupting a physiological function specific to insects or a group of insects. Although the active ingredient of these insecticides is a chemical compound, their insect specificity and mode of action (they usually act through a non-toxic mechanism) make them far more environmentally friendly than conventional chemical insecticides. Some of these molecules are obtained from natural sources or are synthetic analogs of the natural compounds. In these instances, they are often referred to as “biochemical pesticides” (McClintock et al. 2000). Others, however, may bear little resemblance to naturally occurring substances but are chosen on the basis that they inhibit or antagonize a biochemical function specific to insects. The identification of such compounds can be greatly aided by biotechnology, whereby the genes encoding insect proteins believed to be suitable targets for inhibition (e.g., enzymes) or antagonistic interactions (e.g., hormone receptors) are cloned and used for the development of in vitro screening systems. Where the three-dimensional structure of the protein can be determined, computer-assisted design can be used to help identify suitable inhibitors and antagonists in an approach similar to that currently employed for drug discovery.
A good example of a recently developed and registered biorational insecticide is tebufenozide, which disrupts the molt of caterpillars by targeting the receptor of the molting hormone, ecdysone. Although this compound is specific to the Lepidoptera, it is far less specific than the baculoviruses discussed above-and, in this respect, less environmentally desirable than baculoviruses; yet, because it does not come under the “GMO” category and, as such, does not carry such risks as genetic exchange of foreign insecticidal genes with other naturally occurring organisms, it made it through the registration process in North America. Thus, it can be seen that if biotechnology can be used to help identify target-specific pest control molecules, these may have a greater chance than recombinant baculoviruses of becoming registered rapidly. In addition, they will likely display a degree of target specificity intermediate between conventional chemical insecticides and baculoviruses, conferring on them a somewhat higher commercial potential.
It can be seen from the two examples discussed here that biotechnology can be used in very different ways to generate novel pest control products. While genetically modified baculoviruses probably constitute one the most environmentally benign options for the management of forest insect pests, the current debate on the risks associated with the deployment of GMOs will continue to have a negative impact on the registration of these products. In addition, the narrow host range and high production costs of baculoviruses make them less commercially appealing than some other competing products. However, most of these difficulties can likely be overcome through the development of effective communication strategies and well-targeted research. In the meantime, the use of biotechnology to identify molecules that can disrupt insect-specific physiological functions will likely generate products that can be more easily commercialized. The application of biotechnology to the development of forest pest management tools is, of course, not limited to the two examples given here. Plant-pesticides, also known as pest-resistant transgenic trees, are among the promising avenues of forest pest management biotechnology. For a detailed discussion of the various issues relating to the operational use of transgenic trees in plantation forestry, the reader is referred to Strauss and Bradshaw (2001).
I am indebted to Dr. B.A. Arif (Canadian Forest Service, Sault Ste. Marie, Canada), Dr. J. Drolet (Pest Management Regulatory Agency, Ottawa, Canada), Dr. Z. Hu (Wuhan Institute of Virology, Wuhan, China) and Dr. J. Charity (Forest Research, Rotorua, New Zealand) for their insightful input.
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| [1] Natural Resources Canada,
Canadian Forest Service, Laurentian Forestry Centre, 1055 du P.E.P.S., P.O.
Box 3800, Sainte-Foy, Québec, G1V 4C7, Canada. Tel: 418-648-3944;
Email: [email protected];
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