ENGINEERED BT: FROM PEST TO MARKET CONTROL

December 1995

ENGINEERED BT: FROM PEST TO MARKET CONTROL

Bacillus thuringiensis (in short: Bt) is a bacterium which normally lives in the soil. It produces a crystal protein that has the ability to disintegrate the gut wall of some insects (particularly that of beetles and caterpillars) but is innocuous for most of living organisms. Due to these properties, Bt has been used as a biological pesticide by organic farmers since the early 1960s. It has been the environmental friendliness of Bt that has caught the eyes — and investments — of large agrochemical companies that increasingly face both regulatory and consumer's constraints for the expansion of their conventional chemical pesticides. Also many of the smaller and specialised biotech companies have thrown their weight behind Bt research, hoping to be able to corner part of the expected benefits. So, what's new, if organic farmers have been spraying this biopesticide for many decades? New is that genetic engineering allows to pull the genes that produce the Bt killer protein out of the bacteria and insert them into the crops one wants to protect against the pests that the Bt protein could kill. Several other approaches are being taken. Also new is the tremendous amount of money being invested to engineer Bt genes into virtually any crop worthwhile investing in.

Single solution approaches

In a world where the dangers and real price of chemical pesticides are increasingly being acknowledged, large agrochemical companies are striving to adapt to (and control) the new situation. The stakes are high: Ciba Geigy has estimated that 10% of all pesticides will be biologically-based by year 2000 representing some US$ 3 billion in world sales, compared to the US$ 130-140 million market for biopesticides today. However shifting from chemical to biological pesticides does not necessarily mean a change for the better, if everything else remains the same. Industry continues with its global-solutions approach (those with a big market) to particular and complex problems. The case of biopesticides in general, and Bt in particular clearly mirrors this trend.

For our June 1992 article on Bt, we conducted a survey on research reports on biological control agents as listed in Derwent Biotechnology Abstracts  in 1989. We have repeated the exercise for 1994. As it may be seen in the Graph on "Research on Microbiological Control Agents", the picture is not very different today. Despite all discussions on resistance problems and on the need for diversification of the sources for pest resistance, Bt continues to concentrate over one third of all research on microbiological control agents. If one takes the whole Bacillus family, this figure goes up to 46%. Bt genes are also engineered into other Bacillus species, as well as into other microbial genera such as Pseudomonas spp. If one takes the number of published research reports as a guide, the conclusion is that out of the thousands of possible approaches to biological control of crop pests, well over half (56%) of all biotech research on microbial control agents focuses on two single genera: Bacillus and Pseudomonas. The trend to concentrate research on a very narrow range of genes and organisms remains unchecked — and is increasing. Some sources indicate that currently 95% of all biotech research to develop microbial insecticides is directed at the Bt bacterium.

The "miracle gene" is being built into virtually any crop of significance. At the last count no less than 14 crops and trees had been field tested in the USA, and many others are being researched but not yet in the testing phase. (See Table "Too much of a Good Thing?") Corn is target number one for most companies, as it is a widely planted crop and the first money maker of the seeds industry. According to Ciba-Geigy, Bt genetically engineered corn will have 75% of market share in the (US) western corn belt within ten years, and 50% market share in other parts of the corn belt. It is thus not surprising that corn is at the heart of the industry's research efforts on Bt engineered plants (particularly of those of major corn breeders such as Ciba-Geigy and Pioneer Hi Bred). Many of the big Bt players are involved in corn Bt technology: Ecogen is working on bioinsecticides; Zeneca (former ICI seeds), on the inoculation of bacteria genetically engineered to contain Bt; and Mycogen, Plant Genetic Systems, Ciba-Geigy and Monsanto are focusing their efforts on building Bt gene into corn. Marketing agreements also involve other large companies such as Sandoz. Some of these companies are working with the whole range of options.

But then, corn is not the only focus. Monsanto's Bt potatoes and cotton have already been granted commercial approval. The International Rice Research Institute (IRRI) is developing rice varieties resistant to yellow stem borer from genetically engineered rice containing a synthetic Bt gene patented by Ciba-Geigy (see Seedling Vol 12, No 3, October 1995). Other crops are under way: soya, wheat, tomato, brassica, and even white spruce and hybrid poplar tree. However, for most of these strategically secondary crops, the use of Bt in the form of bioinsecticides seems to be the prevailing approach. With so many different plants being inoculated with the same medicine, the question is indeed, as the Union of Concerned Scientists puts it, Too much of a Good Thing?

Concentrating control ..... and profits

Not only is the scope of the solutions the industry is promising us for a sustainable agriculture very limited (one or two microbes do it all), so is the number of actors who are to bring the solutions to the farmers fields. A good indication on who is involved in Bt research is by looking at Bt related patents and patent applications. By March 1995 there were no less than 440 either granted or pending patents related to our poor little Bt bacteria, according to Derwent's World Patent Index. (see Graph "Who controls Bt?") Such an impressive amount of monopoly titles related to this single organism already indicates the struggle going on amongst the industrial giants to control any benefits originating from it. The public sector with some 12% of the patents is virtually absent from the scene. The top ten Bt companies, including chemical giants as Ciba Geigy, ICI, Monsanto and Sandoz, control a full 44% of all patents and applications for patents. A single company, Mycogen Corp, accounts for 16% of all of them, while a number of other specialised biotech companies, such as PGS and Ecogen, are also actively present.

While the concentration of Bt patents with the top few companies is surely an indication of who are the main players of the game, it hides the enormous confusion on who has the right to develop what. Patents are issues on a case by case basis, and many are either overlapping or conflicting. Patents have been applied — and granted — on Bt isolates, strains, genes and on specific proteins toxic to a given insect class or pest. For example, Mycogen owns two patents on both a Bt isolate and a gene active against lepidopteran pests. Apart from patenting Bt genetic resources, companies have also sought process patents allowing them to control key technology - especially in the obtention of efficient Bt engineered plants. This has been one of Mycogen's strategies: it owns a US patent on synthesising Bt genes to optimise expression of insecticidal proteins in plants, a technique very widely used to increase the expression of insecticidal proteins in plants. However, DowElanco has recently developed a new technology - modifying Bt genes so that they resemble the plant in which they are to be inserted. At the same time Plant Genetic Systems has been granted a US patent covering all transgenic plants containing Bt, and Mycogen has been issued a European patent which covers the insertion of any insecticidal gene in any plant... It will take a while before the patent dust settles and we know who is infringing upon whose patent. Clear is, however, that the future surviving suppliers of the Bt miracle are going to be as few in number and as uniform in approach as the size of the market and the strength of the players will allow.

Nevertheless, while they fight each other on the patent front, the same companies form alliances to get hold of missing pieces of technology, or to get the technology to the market. It is striking that most of the alliances are developed within the group that is already strong in Bt technology, thus ensuring that no unwanted newcomers enter into this field. For example, Mycogen has cross licensing agreements with Ciba Geigy and with Pioneer Hi Bred to work on Bt corn. In turn, Pioneer buys 13% of Mycogen's shares. Monsanto has licensed Bt technology from Novo Nordisk (for their Bt potatoes), while it allows Sandoz to commercialise Monsanto's Bt corn. Basically, licensing and co-operation agreements are meant to create some order and division of labour in the Bt arena. Often the agreements are between large agrochemical corporations with direct access to the market (through their pesticides and seeds subsidiaries...) and specialised biotech companies without a seeds infrastructure to get their products to the market, using their intellectual property rights portfolio to bargain joint ventures with seeds companies or to earn royalties from licensing. The accompanying Table gives some information on the activities of the main players, and the agreements between them.

Developing resistance?

For the last 10 years concerned scientists and NGO's have called attention to the dangers involved in the phenomenal widespread use of the Bt toxin, which would result from the current direction of biotech investments and research. The development of insect resistance — which has already been documented in diamondback moths, and is known to be potential in other insects — is the most outstanding issue, due to its potential to render a currently effective bio-insecticide useless. But insect resistance is just on other factors of concern. The possibility of Bt affecting beneficial insects and other life forms — some of them as important for agriculture as earthworms — the transfer of Bt genes from genetically engineered plants and microbes to weeds, and even the dangers of its use for human health (the genus Bacillus includes highly pathogenic species), remain potential and unadressed risks.

As a response to the criticisms raising the issue of resistance development, six years ago fifteen companies heavily involved in Bt research (including Monsanto, Sandoz, Calgene and Abbott Laboratories) created the Bt Management Working Group (BtMGW). With a US$ 250.000 budget for four years, the group has funded research on the molecular and cellular basis of Bt toxicity and resistance. The group has also funded experimental tests of strategies for minimising the threat of resistance, such as field experiments involving transgenic corn plants resistant to the European corn borer, and the use of computer modelling to determine if mixtures of genetically modified and "normal" corn could slow or avoid Bt resistance. However, as Bruce Tabashnik (an entomologist and expert on resistance based at the University of Hawaii) points out, the conclusions of such exercises are only as good as the assumptions that underlie them. In fact, little is known about which tactics work to prevent resistance and which don't.

One of the means proposed by the industry in order to halt or delay resistance was to use different Bt strains in the expectation that insects with resistance to one toxin would still be stopped by another. Biotech companies have bioprospected for different Bt strains. However, in 1992 it was found out that insects that developed resistance to one type of Bt toxin are often also resistant to other types of the toxin to which they have not been exposed. How exactly the insects manage this is beyond the scientists' understanding, but the appearance of this type of "cross resistance" would mean that the recommended strategy to mix different Bt strains and toxins is rendered useless. Tabashnik, who has been studying Bt resistance for many years, considers that varying the sprayed toxins (or the engineered plants) may actually increase the evolutionary pressure on the pests to develop general resistance mechanisms.

Another approach which at first sight seems to be more promising is using Bt selectively in the framework of an Integrated Pest Management (IPM) scheme. Plants with Bt genes and plants without them are planted in the same field. The idea is that whilst a part of the pest population should be exposed to high doses of toxin, another part should be left in "reservoirs", so that the surviving resistant insect's genes match with normal individuals and the resistance trend dilutes. But this is easy-to-say and difficult to take into practice, given biological factors (some insects like to taste a bit of every plant; some others prefer to stay at home; some like to eat any part of the plant, but the "gourmets" like to feed in a given part only).The entomologists working in the industry's programmes face problems so complex that some of them think, as Wendy Gelernter of the Mycogen Corporation: "We can model and we can discuss, and we can try to run lab experiments, but everyone agrees that you can't do that sufficiently to come up with an answer that will make us all comfortable".

In any case, the industry itself is not conformable with the idea of reservoirs, which means selling mixtures of genetically-engineered and normal crop seeds, because this creates competition problems. Why would a farmer sacrify part of this seasons harvest for the doubtful benefit that resistance might take longer to build up? There would always be a company that would sell the 100% Bt plants.... as long as possible.

After six years of researching and discussing, the industry working group on Bt still has to come with a convincing argument on how to move forward. Susan Macintosh, from Novo Nordisk Entotech and Chair of the BtMGW, is very frank about the situation: "What is the best strategy? I can't tell you that. I don't think anyone can". However, this recognition has not prevented the BtMGW from concluding that the risk of resistance to Bt is minimal as part of integrated pest management programmes. Confronted with the uncertainties, the industry's position is very well expressed by Wendy Gelernter of Mycogen: "It's almost like you need to try several alternatives on some limited commercial scale and see what happens". In other words, after years of resistance management research, the industry has come to the conclusion, that we don't really know, and that we just need to go ahead, sell it to the farmers, and see what happens. The EPA seems to agree. In fact, when the Agency granted a permit to Monsanto to sell Bt potatoes, it endorsed the need for resistance management strategies, but offered no plan.

The results of the industry's efforts to manage Bt resistance come as no surprise. The research conducted by the BtMWG has not been the industry's assessment on whether or not it was worth (let alone environmentally safe) to invest in Bt. Instead, it has been an effort to justify and to "sell" a technology that was already being developed and that is presented as unavoidable progress. In this sense, the BtMWG has essentially conducted a public relations work for its members.

Resistance development has been perceived by the Union of Concerned Scientists as a serious enough problem that they have issued an Action Alert. Under the slogan "Save Bt for organic and sustainable farmers", The Union argues that massive introduction of Bt engineneered crops will accelerate the development of resistance to Bt, and that therefore organic farmers, who have been using non-engineered Bt for decades, would lose a valuable tool in their farming systems. Some farmers would be thrown back to synthetic insecticides. The July 1995 issue of "The Gene-Exchange" newsletter calls upon its readers to demand the EPA and the USDA to delay any Bt crops approvals until satisfactory strategies have been developed to avoid the building up of resistance against the Bt toxin.

Bt: silver bullet or part of a solution?

The important concentration of the industry's research on agricultural biological control around Bt is due to the opportunities of control and economic profit that it offers to the industry as much as to its efficacy. And this possibility of control relies both in enforceable intellectual property rights and in ensuring that the obtained products are going to be perceived as "necessary" and thus demanded. For the industry, this demand must come from the progressive substitution of chemical pesticides. Mycogen put it clearly when it declared that it expected to have "an important part" in the Clinton administration's goal to have 75% of the US farms using Integrated Pest Management (IPM) techniques to reduce the use of chemical pesticides by the year 2000.

But, in order to substitute one big market by another, the first priority is to maintain the rest of the system as untouched as possible: the need for external agricultural inputs, the uniformity of the marketable crops, the control on distribution and on transformation of agricultural products must absolutely be maintained, and even strengthened. Bt (and other industrially-controlled biological control agents) must become the alternative to the excessive dependency on pesticides in industrialised agriculture.

This is a diametrically opposed approach to that of the many organic farmers and environmental NGOs who where the first to denounce the use of pesticides. For many of them, the use of pesticides inputs is merely one of the symptoms of unsustainable agricultural practices that rely on high-external energetic and chemical inputs, irrigation and monocropping to provide uniform harvests. If true sustainability — not just mechanisms to minimise environmental damage while mantaining coprporate control— is to be achieved, it is a matter of urgency to re-think agriculture in order to make it environmentally sound, socially just and economically "viable".

Sustainable agriculture should be built upon the full realisation of agroecosystem potentialities and synergies — including farmers' work and creativity — rather than on the piecemeal action of external elements. For example, a simple and proven alternative to Monsanto's Bt-potato, in controlling the damaging Colorado Potato Beetle, is to use a number of cultural practices such as crop rotation, trap cropping, mulching and late planting. Yet the problem for the industry is that none of these measures provide for an uniform and extensive market. With these integrated approaches, pests are "integratedly managed", given that different aspects of the agroecosystem (multicropping, the use of different plant varieties, crop rotations, soil health, the presence of predator populations, genetic diversity) interact and limit pest proliferation. This kind of sustainable agriculture could also admit punctual input of external elements such as biopesticides, but without putting all the eggs in the Bt basket.

Sources:

* Abstracts on BioCommerce 1993-1995. BioCommerced Data Ltd, Berkshire, UK.

* Biotech Reporter (incorporating AgBiotechnology News) ISSN 1069 4773. Cedar Falls, USA.

* Biotechnology Abstracts 1994. Derwent Information Limited, London, UK.

* Holmes, B., 1993. "The perils of planting pesticides", New Scientist, 1888: 34-37

* The Gene Exchange, Union of Concerned Scientists, Washington, July 1995

* World Patent Index, Derwent Information Limited, London, UK