Traditional ‘Chemical-Based’ Discovery and Screening

Until the last 15 years or so, the only way that herbicides (and other agrichemicals) were discovered was to individually apply a small amount of a collection of chemicals to a few target weeds, and visually assess their efficacy.  Chemical collections were developed by many companies, mostly manufacturers of petroleum-based products like paint, rubber goods, and plastics.  Pharmaceutical companies, who are often considered the ‘rich cousins’ of agrichemical industries, have traditionally maintained large chemical synthesis divisions.  Naturally, agrichemical industries also synthesized their own collections, or they could purchase them from others.  While this approach is sometimes denigrated (“spray and pray”), it has been highly successful and it has certain advantages.  

The major advantage of this approach is that testing unknown compounds on whole plants integrates all the requirements for herbicide performance into a single assay, including uptake, translocationmetabolism, and the ability to inhibit a potentially lethal physiological step.  Previous knowledge about the biochemical or enzymatic target site is completely unnecessary.  Once a lead compound is identified, extensive chemical research may be used to identify and modify its structure, usually in an attempt to improve its performance.  The subsequent availability of relatively large amounts of the synthesized compound allows studies on its mechanism of action, toxicology, and environmental compatibility.

This traditional approach has been largely ‘chemical-based,’ by starting with screens of unknown or novel chemicals and serendipitously discovering herbicidal activity.  The discovery of herbicides that are selective (do not injure certain crops) or nonselective (lethal to all plants) is similarly random.  Some authors have estimated that more than 30,000 compounds must be screened to identify one crop-selective herbicide.  Using this process, agrichemical industries require 10 to 12 years to develop a lead compound into a commercialized herbicide, with associated costs recently estimated at $180 million.  

A necessary part of the commercialization process for a new herbicide is its registration with the Environmental Protection Agency (EPA).  The basis of pesticide registration in the U.S. is the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) that was enacted in 1947 as a product reliability law.  FIFRA was amended in 1972 and 1988 to include toxicity and environmental hazard testing.  In 1996, Congress passed new pesticide legislation, the Food Quality Protection Act, that required testing for pesticide residues on food and mandated that registrations be reviewed every 15 years.  The registration process itself involves comprehensive testing of the herbicide’s efficacy, toxicity to nontarget organisms, effects on human health, and its potential for environmental hazard.  Some have argued that the registration process is inadequate, claiming that it is too focused on financial issues and neglects long-term human health concerns.

Starting in the late 1980’s, the shortcomings of the traditional discovery process started to become apparent, for several reasons.  First, more stringent regulatory constraints imposed in the 1980’s substantially reduced the number of compounds that had herbicidal activity and yet were able to meet numerous environmental and toxicological requirements.  Second, the number of compounds discovered through this empirical approach was rapidly dwindling, likely as a direct result of the discovery process itself.  In other words, only a certain number of compounds can fulfill all of the performance requirements noted above for whole plant screening assays.  This constraint may also help answer the question posed in the Introduction; namely, why only a relatively few target sites are acted upon by commercial herbicides.  These realities, along with the recent breakthroughs in all types of molecular technologies, have led agrichemical companies to vigorously explore new methods of herbicide discovery.