BACK TO INDUSTRY INSIDER

The world's population is growing, yet farmland is limited. To feed the world, farmers must improve the yield and quality of crops and reduce the losses to pests. So, following a period of consolidation in the 1990s, crop-protection companies are once again hiring scientists to meet the increasing demand for safer, more environmentally friendly agrochemicals.

Although world agrochemical sales in 2002 fell slightly (to US$27.7bn), particularly in the Americas and Asia-Pacific areas, Western Europe saw sales rise by over 7 %, to US$6.3bn (about ?6.3bn). The largest market segments last year were herbicides (51%), insecticides (25%), and fungicides (20%).

All six of the global giants that dominate crop protection--Syngenta, Bayer, Monsanto, BASF, Dow, and DuPont--are active in each of these main areas and for all the major crops. They have expanded by mergers, and all have, to some extent, adopted the life-science business model, selling both conventional agrochemicals and genetically modified (GM) seeds. Monsanto has taken this approach the farthest by concentrating on chemicals that complement its GM seeds.

For other companies, the chemical and seed businesses are less intimately related. Dave Hughes, a project leader for Syngenta at its Jealott's Hill International Research Centre in the United Kingdom, explains that chemicals are more flexible: "If you buy a seed that has been modified to have a crop-protection trait, then you are locked into that strategy." Introducing protection also means compromising yield, because the plant's resources are diverted into doing something it normally wouldn't, "such as producing a protein that is tolerant to a herbicide," explains Hughes. Many in the industry now see GM's role as improving crop quality, and they're sticking with chemicals to fight pests.

Drivers of Innovation

But if chemicals are reasserting their importance in agribusiness, you can't afford to rely on the tried and trusted. "Pests in general are really nasty, virulent, horrible organisms," Hughes points out. "It's tricky to take these guys on--you're fighting Mother Nature, and she's quite a difficult opponent. It's an evolutionary inevitability that resistance will build up at some point, [because] we're applying a selection pressure, and the pests will respond."

Just as bacteria become resistant to antibiotics, so insects, weeds, and fungi develop resistance to commonly used treatments. Hughes explains that "150 years after the Irish potato famine, we still haven't got [potato blight] cracked. It has evolved resistance to every chemical we've thrown at it so far." Similarly, Lolium rigidum, a type of ryegrass that was introduced deliberately into Australia as a vigorous pastureland grass for livestock, "is now a major-league pain in the neck for Australian arable farmers" because of its propensity to develop herbicide resistance. "Resistance is the major supplier of unsolved problems to the industry," Hughes adds.

Research

Fortunately for farmers, the pests don't hold all the aces. Industry is throwing plenty of high technology and cash--global spending on crop-protection R&D is now over ?2 billion a year--at the problem. Discovery research, often in conjunction with academic researchers, increasingly involves genomics, informatics, and screening of libraries of natural and synthetic chemicals. "We're flying on the back of the genomics revolution," says Hughes. But unlike the pharmaceutical industry, "when we work on early leads, we often don't know how they work biochemically. Pharmaceutical researchers pick some kind of protein or receptor and target chemicals that interact with it. We do it totally the other way round. We test on whole organisms and look for effects." (See accompanying profile of Patrice Sellës.) However, if the biochemists can discover the mode of action, this speeds up the next stages of research, through lead finding, optimisation, and formulation.

On average, it costs ?200m and takes 9 years to discover, develop, and register a new crop-protection chemical. About 140,000 molecules have to be screened to find one, and the sector uses the same technologies as pharmaceutical labs do for accelerated screening. Bayer's agricultural centre in Monheim, Germany, is testing 30,000 compounds a day with high-throughput screening (HTS), and the staff people there hope to move soon to ultra-HTS: 150,000 compounds a day. At this rate of testing, generating libraries of compounds becomes a challenge. DuPont has collaborations with Affymax and Discovery to access their pharmaceutical-derived expertise in combinatorial synthesis and HTS. Other new techniques, such as high-throughput crystallography, are on the horizon.

Formulation

The big six work with smaller companies in other areas, too--particularly formulation. The product a farmer applies to a crop is more than just the active chemical. Depending on whether it is applied as liquid or granules, it will include adjuvants, dispersants, or emulsifiers, controlled-release coatings, and many other substances. Without these inert additives, the product would not be effective, so a great deal of effort goes into product formulation.

Several chemical suppliers specialise in inert ingredients. An innovation in this area can improve efficiency and environmental impact as easily as a new active compound can. For example, two subsidiaries of the ICI chemical group, Uniqema and National Starch, supply polymers that help control release of the active compounds and improve their solubility. Similarly, the French drug-delivery firm Flamel is working with Monsanto to develop nanoencapsulated formulations of a herbicide called Roundup. Crompton makes surfactants to improve spreading and wetting properties for a range of insecticides. Interagro is a U.K.-based maker of brand-name adjuvants that are widely used by formulators.

Agrochemical companies often outsource bulk manufacture of their active ingredients or key intermediates to specialist firms--usually companies that do the same work for drug manufacturers. In Europe, these include Avecia (U.K.), Contract Chemicals (U.K.), Degussa (Germany), Lonza (Switzerland), Rhodia (France), and many others. Sometimes, these interactions can introduce expertise from unrelated industries. Japan's Asahi Glass, for example, has extended its fluorochemical business to make agrochemical intermediates, and with Mitsubishi's Italian fluorochemical subsidiary, Mitena, it now owns F2 Chemicals, a spinoff of British Nuclear Fuels. And the U.S. biopharmaceutical company Celgene is offering enzymatic chiral synthesis technology to agrochemical manufacturers through its Celgro subsidiary. Celgro estimates that about $6 billion of the world agrochemical market is now for single-isomer compounds that--in the many instances in which a single isomer is biologically active--double efficacy and improve the safety margin.

Safety

Safety tests are a major R&D cost. Many in the industry claim crop-protection chemicals are more tightly regulated than human medicines are. Not only are they tested for efficacy against the disease or pest, and for the safety of the patient (i.e., the crop), but they must also be safe for the farmer, the consumer of the food, and the environment. Testing all these attributes involves a range of disciplines, including chemical analysis, metabolic studies, toxicology, and ecobiology. The costs of testing and documenting a new product are enormous, the requirements are getting tighter, and older products must be reregistered or scrapped. Manufacturers are putting ever more scientific effort into this work, either in their own or contract labs (Bayer has 1000 people working in environmental science), and this applies to formulators and manufacturers of generic as well as the research-based companies. However, safety can be a major driver for product innovation.

Employment

With all of this innovation going on, what is the job market in agrochemicals really like? Research employment shrank with the closure of labs after mergers in the 1990s. Syngenta effectively froze recruitment of project leaders when it was formed from the agrochemical businesses of AstraZeneca and Novartis in 2000. Now, with an ageing research workforce, it is looking toward hiring the next generation of leaders and is funding scholarships for final-year Ph.D. students in the United Kingdom in order to attract future recruits. New lab techniques, increased numbers of compounds to screen, and expanding toxicology and environmental programmes are other reasons for companies to hire extra scientists.

Agrochemicals: Some Recruitment Sites

The Big Six

Up and Coming

Outsourcing: Bulk Manufacturers

Outsourcing: Chemical Leads/Technologies

Suppliers of Formulation Chemicals/Technologies

And it's not just the major multinationals that are growing (see profile of Harry Teicher). Agrochem has a second tier of companies with big ambitions. Nufarm (based in Australia), Arysta (Japan), and Makhteshim-Agan (Israel) have expanded by acquiring European products and markets given up by Bayer to satisfy competition law. Similarly, Cheminova (Denmark) bought the rights to a Syngenta fungicide.

Syngenta has some 20,000 employees around the world, about 5000 of them in research, technology, and development. Smaller companies must concentrate on fewer areas. Cheminova has 1500 employees (850 in Denmark), of whom 80 work in the development department at Harboøre--and this number is rising. Agrisense in South Wales, U.K., has just 55 employees, of whom five are scientists. Companies this small cannot do basic research, but Agrisense is active in research collaborations with universities and companies around Europe, just as larger firms are.

What do companies look for? According to Hughes, you need expertise in your particular discipline (chemistry, biology, toxicology, or process engineering, for example) but also a broader scientific base.- You need an interest in other aspects of science, because you'll be working with people from the other branches. As a rule, Syngenta recruits research chemists at the B.Sc. or Ph.D. level, and it looks for Ph.D.s and postdocs when hiring team leaders. And, says Hughes, "you need to communicate your ideas to people within your project team, people working for you, perhaps--even more importantly--the people you work for, and sometimes [you need to] even go out and talk to the public".

Greenness

Given that the industry is so often under attack by pressure groups, perhaps this last need is a particularly urgent requirement for crop-protection scientists. They argue that if consumers want the choice they can have it, but few regard organic farming as serious competition. They cannot see it meeting consumer requirements for quality, quantity, and affordability. What's more, they point out, customers ought to be aware that toxins from untreated fungal disease are probably more harmful than pesticide residues are, and that plants themselves produce chemicals designed to protect them against pests.

Indeed, many crop-protection chemicals were first isolated from natural sources, including the widely used pyrethroid insecticides (from chrysanthemums), Syngenta's best-selling fungicide azoxystrubin (from mushrooms), and Dow's insecticide spinosad (from a microorganism), which won a U.S. Presidential Green Chemistry Award. Nufarm has rights to develop potential herbicides emerging from an academic project to screen marine organisms on Australia's Great Barrier Reef.

Other biological agents adopted by the conventional crop-protection industry include plant-growth regulators, which are analogues of natural plant hormones, and insect sex attractants (pheromones) used to attract pests to traps or to disrupt their mating. Enzo Casagrande of Agrisense explains that these are usually made on scales of kilograms or even grams, but a few are now so widely used that tonnes are made worldwide. "Although the compounds are synthetic--you would have to crush a lot of insects to extract a usable amount of a pheromone--they are regarded as biological agents," he explains.

Worried by their bad reputations--which, they argue, are long out of date--crop protection companies embrace concepts such as integrated pest management (using combinations of appropriate control measures to reduce harm) and sustainability. It may seem odd to hear manufacturers trumpeting reductions in the use of their products, but when this is the result of improved compounds, formulation, or application methods, their scientists can take the credit.