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Cornell Community Conference on Biological Control - April 11-13, 1996

Present and Future Prospects of Biological Insecticides

Ramon Georgis
biosys
10150 Old Columbia Road
Columbia, Maryland 21046

(prepared from the videotaped presentation*)

I am delighted to be here and I very much appreciate the invitation.

There are many different definitions of biological insecticides. The most common one refers mainly to the fungi, baculoviruses, nematodes, protozoa and Bts as biological insecticides. However, in my presentation, I will define bioinsecticides as follows: naturally occurring organisms (such as fungi, baculoviruses) their byproducts (such as chemicals derived from Actinomyces  and Streptomyces ) products derived from insects (such as pheromones); and products derived from plants (such as azadirachtin or neem). Some of the biological insecticides may be used as foliar applications and others as a soil applications.

The global insecticide market is estimated at 8 billion dollars per year and there is a very strong indication that biological insecticides will account for almost $500 million by the year 2000. However a number of technological breakthroughs will be needed to reach this level of market share.

The future of biological insecticides will largely depend on the financial strength of the companies involved in producing these products. the initial domination was by pharmaceutical companies such as Sandoz and Abbott.

In the eighties there were a number of biotechnology firms that were established and funded. Each company spent between 20 and 60 million dollars in R&D to develop a single technology. For example, biosys has spent 35 million dollars to develop the use of nematodes for the control of soil insects.

Most of these biotechnology companies have focused on one technology, all of them very high risk. However, in the last 2-3 years, the industry has begun to change; it became obvious that companies should have more than one product line to become established in the marketplace. For instance, biosys' consolidation effort has led to the acquisition of three companies: AgriSense in 1992 (pheromone technology), CGI in 1995 (virus technology), and AgriDyne in 1996 (azadirachtin technology).

A joint R&D venture was another approach that some companies have adopted to strengthen their position. For example, Ecogen is working with Monsanto, and Mycogen is working with Dow Elanco. It is anticipated that the consolidation will create the critical mass of products that is needed to generate the target revenues.

Many major companies in the United States are involved in developing bioinsecticides. Most agrochemical companies are mainly working on Bt. This technology is well established and it does not require a high investment. Other companies are involved in nematode, virus, fungus, azadirachtin and pheromone technologies.

Most of the major breakthroughs in bioinsecticide development were achieved in the last 10 years. As a result, a number of products were introduced into the market. The progress in mass production through fermentation (nematodes, Bt), in vivo  (baculoviruses), extraction and purification (azadirachtin) and synthesis routes (pheromones) were instrumental in marketing these products. Research efforts are in progress to develop o optimize the in vitro  production process for baculoviruses and fungi.

In my presentation I will focus on four technologies: nematodes; baculoviruses; pheromones; and azadirachtin. A brief analysis of other technologies will also be presented. Each technology has a different active ingredient, has a different mode of action,

and has a different application technique or methodology.

Bt, Fungi and Biologically Derived Products

Bt is the most widely used biological insecticide. It's very important to realize that the impression about Bt is that there is no significant gap between classical Bt and genetically engineered Bt, and that it is slow in killing the insect. However, Bt technology has been developed to the point that it's being used correctly in insect control programs. As a result, Bt is capable of protecting crops from insect damage. Certainly the introduction of Bt transgenic plants will have an impact on the market share of Bt sprays, especially in the cotton market.

Fungi are potential bioinsecticides. The commercial reality is there and there are a number of fungi such as Beauvaria  and Metarhyzium  that are widely used, especially in greenhouses. technological breakthroughs will also be needed, especially in production and formulation, to extend their usage to large acreage areas.

Other biological insecticides are those derived from organisms such as Actinomyces  and Streptomyces . This line of products, in the opinion of many people, are chemicals, not biologicals. Product characteristics are identical to chemical insecticides.

Insect Parasitic Nematodes

The active ingredient of parasitic nematodes is the third stage infective juvenile (J3) which is about 500 microns long and 20 microns wide.

A pathogenic bacterium lives in the gut of these nematodes. The infective stage enters the insect through its natural opening, releases the bacteria which multiply and, as a result, insect mortality occurs within 48 hours. The nematode develops inside the dead insect and emerges as J3 into the environment seeking other insects.

What are the major breakthroughs in this technology? In 1988, nematodes became commercially available through the success of production in 80,000 liter fermenters. In 1992 a reliable formulation was developed. Nematodes are living organisms, and the only way to reduce their metabolism is to lower their water content. Research efforts have succeeded in lowering their water content, inducing them to enter into a partially desiccated phase. And, finally, between 1988 and 1993, five nematode species were introduced into the marketplace. Each species is effective against certain insect groups.

It requires 14-16 days in the main fermenter to produce nematodes compared to only 2 required for the production of Bt. The longer the fermentation period, the higher the opportunity for contamination. therefore, a well-developed process is needed to achieve predictable nematode production.

Concerning shelf life, the water dispersible granule is the most advanced formulation. Basically, nematode droplets are sprayed on a rotating pan containing granular powder material. Immediately, the powder surrounds the nematodes and creates a 5-10 mm in diameter granule that contains about 40,000 nematodes. Within a few days of exposure to certain temperatures, the nematodes gradually lose their water content and enter into a partially desiccated phase. At this phase, moisture and oxygen are still needed by the nematodes for survival. The granule's material has the capability of maintaining adequate moisture levels as well as allowing gas exchanges.

The five species of nematode on the market are Steinernema carpocapsae, S. riobravis, S. feltiae, Heterorhabditis bacteriophora, and H. megidis.  In general, these nematodes are available in medium to high value markets.

Considerable efforts and resources were used in the development of nematode efficacy against corn rootworm, root maggots, and wireworms. These insects are considered the true soil insects, and they are the key target for nematode entry into the agricultural market. Failure of the nematodes to achieve successful and predictable results against these insects have significantly reduced their market potential in this market segment. Therefore, the prediction of reaching >$100 million in annual sales presently appears impossible. Against white grubs in turfgrass, nematode performance is inconsistent and expensive compared to standard insecticides. Cockroaches are the most susceptible insect to the nematodes. However, failure to develop a nematode-bait station with more than a twelve month shelf life has shattered its commercial introduction.

The key elements needed to expand the market share of nematode products are:

  1. Identifying new nematode species and strains. There are many species in the soil that have yet to be discovered.
  2. Advanced research in production and formulation of the current non-commercial species/strains.
  3. Improving temperature and desiccation tolerance of current formulations through genetic engineering.
  4. Introducing nematodes into IPM programs.

In general, the cost of nematode products in non-agricultural markets (e.g., lawn and garden, turfgrass, citrus, mint, mushrooms, greenhouses) is comparable to standard insecticides. In agriculture, the cost of most chemical insecticides ranges between $6.00 and $9.00 per acre. With the current technology, the cost of nematode products for the agriculture market will exceed $30.00 per acre.

Baculoviruses

Baculoviruses are ingested by the insect larvae causing infection of the insect's cells and its death occurs in 3 to 8 days, depending on the larval species and instar.

These organisms are known to be very slow in killing the insect, and this is one of the major issues affecting their expansion in insect control programs. However, the probability is high for the development of genetically engineered viruses that carry a specific toxin to the target insect. Increases in the speed of kill of up to 60% have been reported by various researchers.

The major breakthroughs in this technology from the industry's perspective are:

NPV
The two products released in the US. are Hz NPV and its major hosts are Heliothis/Heliocoverpa  in cotton, tomatoes and legumes, and Se NPV against Spodoptera exigua  in cotton, vegetables, grapes, flowers and ornamentals. The cost is $6-10/acre treatment. At this cost, virus products are competitive with standards. (For example, in cotton and vegetables, the pyrethroids cost is $5-7/acre treatment and larvin® is $8-10.)

Current products are produced in vivo.  This method of production is predictable and various stages of the process have been automated, which makes it a practical approach for baculovirus production. Extension efforts in using insect cell lines for virus production in fermenters are in progress by various commercial companies. An inexpensive medium that support cell growth has been defined by most companies and successful runs have been reported at 300 to 1000 liter fermenters. The possibility of production at a commercial scale is under investigation.

There is a very good justification for using in vivo  as long as the market size doesn't exceed 2 million acres. Also, it appears that the fermentation technology is the idea approach for the production of genetically engineered viruses., These viruses will kill the insects faster than the wild type, making the in vivo  process an inefficient approach.

The major requirements of expanding the market potential of baculoviruses are:

  1. Improving the speed of kill by 50% through genetic engineering.
  2. Improving the residual activity of the virus formulation from 2-4 days to >7 days.
  3. Strengthening the role of baculoviruses in IPM programs.
  4. Developing cost-effective cell culture for mass production of both the wild type and genetically engineered baculoviruses.

Pheromones

Insects can only mate once the male and female have found each other at the same time. One of the more important functions of pheromones is to assist in this process. If an area is saturated with the pheromone of the pest insect, the message given out by individual insects is swamped. Mating then occurs only by the chance meeting of males and females. As a result, eggs are not laid, or the eggs that are laid are infertile.

Successful mating disruption needs:

  1. The pheromone to be well distributed throughout the crop area being protected.
  2. Treatment to start early in the season when insect populations are low.
  3. The pheromone effect to be maintained throughout the mating season.
  4. A controlled release system that prevents breakdown/degradation of the pheromone while allowing slow release into the atmosphere at effective concentrations.

As with any young and evolving technology, a very wide range of issues has been encountered and resolved. To develop any pheromone, the tiny quantity released by an insect must first be captured. Only then can powerful analytical techniques be used to identify the chemical. This may involve detecting concentrations equivalent to a grain of salt in a swimming pool.

The pheromone from every insect is different, and some are mixtures of complex molecules. Most of the pheromones are unsaturated long straight-chain acetates, alcohols, aldehydes or epoxides. Chemists then find ways of making the pheromone in a laboratory. Often this involves years of study and the use of many chemicals like building blocks which have to be assembled in one very precise way. Even when the pheromone can be made in the laboratory, it must be formulated in a way that gives maximum effect over the desired release period.

Various hand placement and sprayable devices are used as pheromone controlled release systems.

While the chemists are making the pheromone, teams of biologists study the habits of the pest and its life cycle. Only then can the best trapping systems be designed and manufactured.

Sometimes laboratory synthesis of pheromones may be too difficult and expensive to be practical. The pheromone may possibly be chemically unstable or impossible to formulate. In such circumstances, it may be possible to make a closely related compound with similar effects that can be more easily made and is thus more suited to field use.

Current products are sold at $25-30/acre. At these prices, growers are willing to purchase these products. Their aim is to use less standard insecticides due to low insect populations caused by mating disruption pheromones.

The key elements to the success of pheromones are:

  1. Optimize residual activity/controlled release of sprayable formulations from 1-2 weeks to >4 weeks.
  2. Develop new synthesis routes that lead to production of low-cost active ingredients.
  3. Advanced research in the "Lure and Kill" concept (including an insecticide with the pheromone/attractant materials that kills the attracted insects).

Azadirachtin

Neem grows wild in more than 50 countries worldwide, including India and on much of the African continent. So many medicinal and agricultural uses have been attributed to neem that it is often called "nature's pharmacy" by those who have studied its uses. After more than 20 years of research, scientists are just beginning to understand some of the attributes that make neem such an exciting plant.

One noteworthy compound found in neem is azadirachtin. Composed only of carbon, hydrogen and oxygen, azadirachtin woks as a broad spectrum insect growth regulator by disrupting molting during an insect's larval, or juvenile, stage. By altering insect metamorphosis, azadirachtin prevents larvae from developing into adults and producing a subsequent generation of insect pests.

In addition, many insects are strongly repelled by the anti-feedant properties of azadirachtin, so much so that dozens of leaf-eating species will starve to death rather than eat leaves treated with azadirachtin. these combined modes of action are unique among currently available synthetic chemical and microbial insecticides. Proprietary methods have been developed for extracting the insecticidal components from neem oil. The resulting "neem extract" contains the essential natural insecticide azadirachtin.

The key elements for the success of azadirachtin are:

  1. Development of a hydrogenation process and advance formulation to enhance the field stability of current products from 3-5 days to >7days.
  2. Development of advanced cost efficient purification and extraction manufacturing processes.

Conclusion

Biological insecticides are currently sold in various market segments.

Market penetration was possible due to competitive prices, reliable formulations and efficacy comparable to standards. Advances in IPM programs will increase the usage of biological insecticides, especially in situations where the performance of biological insecticides are below the standard insecticides due to high insect pressure. Advancements in genetic engineering and manufacturing processes (fermentation, synthesis, formulation) will strengthen the position of biological insecticides in the marketplace.


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