Presentation Summary

Like several other companies with large crop protection businesses, Zeneca initiated research during the late 1980’s to investigate the potential of biopesticides to complement and extend our product range. The key drivers were:

• A need to limit the use of established products in some market segments to control possible resistance development.
• The potential that biopesticides could capture a significant portion of some insect control markets.
• Pull from many of our National Companies for products which offered farmers and growers alternative technology.
• The promise of emerging technology to facilitate improved performance for natural biopesticides.

Areas outside insect control, for instance a potential biofungicide for soilborne disease control, were also investigated, but I will limit my comments to insect control where I can speak more expertly to the business drivers.

Attention of Zeneca’s R&D was quickly drawn to the potential of baculoviruses for insect control, mostly due to research in the academic community and government organizations such as the USDA. Nevertheless, several weaknesses were readily apparent in the wild type viruses. These included:

• Lack of spectrum. Wild type organisms were often very species specific in their effect.
• Slow speed of kill. Again, wild type organisms, due to their need to reproduce, required days to weeks to kill the host insect. During this period the larvae continue to grow and feed.
• As a consequence of the above, often substandard effects - even in susceptible species - when compared to chemical control, particularly in regard to consistency/reliability of control.
• Rudimentary methods of production that did not readily lend themselves to production in the large volumes required for substantial applications or with the consistent quality desired for our products which would likely constrain profitability.
• The intrinsic instability of biological materials require methods to maintain their effectiveness under environmental conditions and during shipment and storage.

There are no doubt balancing advantages to biopesticides as well, such as substantially reduced costs associated with registration to bring these control methods to market.

Considerable R&D resource was expended by Zeneca during the early-mid 1990’s in developing a capability to genetically modify baculoviruses to improve performance. A number of collaborations with universities and other organizations were developed to foster this effort. Working together with outside organizations was necessitated by our R&D Strategy which recognized core internal competencies, e.g. field biology, and suggested a collaborative approach to acquiring technology or capability outside of those areas of internal strength, until which time a clear need to develop an internal competence was obvious.

A number of streams of technology and capability development needed to come together to provide and advance a genetically modified baculovirus with the potential to meet our business targets (vide infra):

• A "warhead" was required to improve the speed and effect provided by the natural baculovirus. This would likely be an insect specific protein toxin.
• A method to produce sufficient quantities of the engineered virus with consistent quality cost effectively. This requirement was believed to stipulate in vitro production methodology with many associated challenges, e.g. use of insect cell cultures on large scale under sterile conditions, chiefly driven by an assumption that traditional in vivo methods would not be applicable when the larvae died much more quickly.
• Robust formulation technology. Once again, associated with the formidable task of working with biological materials.
• Internal capabilities in Molecular Biology to build the modified organisms and Lab and Field Biology to assess the effects.
• Associated development in Toxicology and Environmental Sciences to facilitate field release and registration of a genetically modified organism.

In parallel, an understanding of how such products would be marketed and a preliminary model for what level of sales would be required to justify development costs were essential to be able to evaluate the profile of any possible products which emerged from this effort.

To model sales of a genetically modified baculovirus, the following assumptions were made:

• An adequate effect on lepidopteran pests in cotton, vegetables, and some other crops (e.g. corn). To achieve the requisite spectrum, two profiles were assumed - that of alfalfa looper virus (AcMNPV) and the related celery looper virus (AfMNPV).
• That the achievable effect was equivalent to chemical standards on the least effective end of the spectrum for control of the target pests, e.g. thiodicarb in cotton.
• There were no issues around production, formulation or registration.

With these assumptions, a NPV model suggested that a genetically modified virus would need to achieve sales of $40m in order to justify and R&D expenditure of $15m.

This research effort was terminated when it became apparent that genetically modified viruses were not likely to be capable of fully meeting Zeneca’s business objectives. This is clearly the key weakness of biopesticides for large crop protection businesses. The most obvious drawbacks to baculoviruses were the lack of spectrum, a consequent small market value judged insufficient to justify development costs, and the substantial R&D effort required to bring them to market, particularly in the development of in vitro production technology. Although a number of feasible means to broaden virus spectrum were identified, the rather large R&D investments required to pursue these compelled Zeneca to make the decision that alternative feasible new insect control technologies were preferred R&D investments. This reasoning applies equally, if not more so, to wild-type viruses, decreasing their commercial attractiveness for a large company.

Nevertheless, there is no doubt the future will witness a better balance of chemical, biotechnological and biological control based products for the control of insects. It is also clear that achieving this balance will be facilitated by superior monitoring and information techniques which will allow these products to be selectively and precisely brought to bear to fight pest infestations in an optimal way and to preserve the useful life of individual products. It is therefore timely to consider alternative paradigms for commercializing biological control agents to enable biopesticides to become a practical part of the requisite new control strategies.

There, however, remain many issues which must be grappled with and solved before sufficient balance is achieved between the efficacy the growers are happy with and an practical ability to make biopesticides available to these growers. Some of these have been alluded to in this paper. Although a needed first step, this workshop is only one piece of the puzzle.

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