In the second week of November, central Indiana is a patchwork of tawny and black: here a field covered with a stubble of dried corn and soybean plants; a little far­ther on, bare earth where the farmer has plowed under the residue of last summer’s crop. This is soil that wants to grow things, and already if you look closely you can see some shoots of fall weeds: chickweed, cressleaf and purple nettle. In a greenhouse on the campus of Purdue University, Chad Brabham, a soft-spoken grad student in weed science, selects two pots, each holding one 18-inch-high plant, bearing serrated, three-lobed leaves on a coarse stem. If the plants look familiar, you might have seen them growing in a vacant lot or by a roadside almost anywhere in the lower 48 states. They are Ambrosia trifida, or giant ragweed—a plant as ugly as its name and as useless, well, as its cousin, common ragweed, A. artemisiifolia, a machine for sucking up water and spewing out highly allergenic pollen. If the farmers stopped farming, it would not take more than a few years before this part of Indiana would live up to the nickname that agronomists joke should appear on its license plates: Giant Ragweed National Forest.

Over the past half a century or so, that fate has been kept at bay primarily by chemical herbicides. One of the most widely used is glyphosate, best known as the active ingredient in Monsanto’s Roundup weed killers, among others. Brabham positions the two pots in a spray chamber and fills a small tank with a solution of the potassium salt of glyphosate. A traveling spray head swiftly traverses the length of the chamber and soaks the drab-green leaves with what by all rights should be a lethal dose. Brabham removes the pots and returns them to the growing table. What happens to these weeds in the next 24 hours will show, in microcosm, what farmers will face across the Midwest this growing season.

Glyphosate has taken center stage in an emerging drama in which the weed killer is the protagonist. “I wouldn’t use the word ‘catastrophe,’ but there are people saying it could be the worst thing for cotton growers since the boll weevil.” So says Doug Gurian-Sherman, a plant pathologist and senior scientist at the Union of Concerned Scientists, discussing the spread of glyphosate-resistant weeds—aka “superweeds”—which in the past decade have expanded their range in the U.S. from a few scattered occurrences to as much as 11 million acres. This coverage is still a small fraction of the 400 million acres of U.S. cropland, but it represents a fivefold increase just since 2007. “That’s a huge jump in the extent of those plants, and I don’t think anyone was expecting that,” says David Mortensen, a weed ecologist at Pennsylvania State University. And as he testified at a congressional hearing last summer—called by Representative Dennis J. Kucinich of Ohio to investigate the U.S. Department of Agriculture’s regulation of genetically engineered seeds—“there is reason to believe this trend will continue.” If superweeds do rise to the level of a catastrophe, it will be one that could not only have been predicted but that was also even foreseen. Like the antibiotic-resistant bacteria that have infectious disease specialists fearing the worst, it is a problem we have brought on ourselves, a reminder of the futility of attempting to outrun evolution. And more weeds are what we least need in a world that may be bumping up against the limits of technology to expand food production.

The Making of Killer Ragweed
Those who mostly view cornfields from an airplane window probably do not appreciate how much of farming consists of keeping weeds away from crops. The very word “cultivate” means not only to make something grow but also to plow or till the soil, which was the original method of weed control—uprooting unwanted plants and burying their seeds. Weeds lack the stealth and single-minded lethality of insects and microbes, which can strike seemingly out of nowhere and wipe out a crop in a matter of days. They grow in plain sight and attack their neighbors indirectly, robbing those plants of nutrients, water and, crucially, sunlight. But bugs and disease are typically sporadic, hit-or-miss events, whereas weeds are ubiquitous. Unchecked, a single giant ragweed plant can reduce the yield in an area holding 30 soybean plants by as much as half.

Which is why agronomists have been keeping a close eye on the weed species—10 at last count in the U.S. and about an equal number in the rest of the world—in which certain populations have evolved the ability to withstand an ordinarily lethal dose of glyphosate. As Monsanto spokespeople are quick to point out, that leaves more than 300 species still vulnerable to Roundup. But the 10 include some of the most prolific and intractable pests infesting cotton, corn and soybean fields: giant and common ragweed, horseweed, Johnsongrass, waterhemp and Palmer amaranth. The last, also known as pigweed, is the Paul Bun­yan of weeds, able to grow a stalk as thick as a baseball bat and tough enough to disable a combine that has the misfortune to encounter it. In its herbicide-resistant form, “it’s about the closest thing out there to a weed we can’t control,” says Thomas T. Bauman, a weed scientist at Purdue. “It makes giant ragweed [which itself can exceed 10 feet] look small, and it germinates all season, so after you think you’ve killed it off, it comes up again the next time it rains.” Some cotton growers have had to abandon their fields where pigweed has taken hold. Others have turned back the clock on agriculture by a century and are sending crews into their fields to whack at it with hoes. “I’ve seen more hoe crews in the fields [in 2010] than the past 15 years combined,” says David R. Shaw, vice president for research and development at Mississippi State University. “It’s incredibly hard work,” he adds, “and extremely difficult to make a profit.”

It is also work that farmers in the developed world thought they had left behind, with the coming on the scene of organic herbicides after World War II. Among the earliest was 2,4-d, the first of a large class of herbicides that mimic the hormone auxin and send the plant into a lethal frenzy of uncoordinated growth. Other classes of herbicides attack other processes, such as photosynthesis or nutrient transport. Glyphosate inhibits an enzyme called EPSPS (5-enolpyruvylshikimate-3-phosphate synthase) that builds three essential amino acids in plants and bacteria but, crucial to its widespread adoption, not in animals. The chemical attacks cells in the meristem, the growth bud at the tip of the plant. Within a day of application the plant stops growing, and death typically follows within a week or two.

Unlike the auxin mimics, which selectively kill broadleaf plants but are relatively harmless to grasses, glyphosate attacks anything green. And unlike herbicides that can be spread on the soil before weeds emerge in the spring, it must be applied directly to the leaves of whatever you are trying to kill. These traits limited glyphosate’s usefulness for several decades after its discovery in 1970. Farmers generally could use it only in the early spring, between the appearance of the first weeds and the sprouting of the crop, or during the growing season by the labor-intensive method of squirting it between the crop plants directly onto individual weeds. Micheal Owen, an agronomist at Iowa State University, describes weed management in those years as both art and science, a continuous juggling of herbicide application, crop rotation, and fall and spring tillage to various depths, each with a price in money and time to be weighed against the potential yield loss averted. Each technique also tended to control a different suite of weeds or, to put it another way, selected for the ones it did not kill. Those able to survive the onslaught flourished under the attack regimen. Weed problems are cumulative, as seeds mount up year after year, so the way to stay ahead was to use different techniques and change them often. Weeds thrive on predictability.

Readying a Revolution
All that changed in the early 1990s, when Monsanto perfected the technology to breed crops that could resist glyphosate. Whatever else one could say about this innovation, it was a scientific triumph that took, by Monsanto’s estimates, 700,000 person-hours of research time. A seven-year search for the right gene ended in an outflow pipe from a Monsanto facility in Louisiana. There researchers looking for organisms that could survive amid the glyphosate runoff discovered a bacterium that had mutated to produce a slightly altered form of the EPSPS enzyme. The altered enzyme made the same three amino acids but was unaffected by glyphosate. Scientists isolated the gene that coded for it and, along with various housekeeping genes (for control and insertion of the gene for the enzyme) collected from three other organisms, implanted it in soybean cells with a gene gun.

This is a brute-force technology in which the selected DNA is wrapped around microscopic specks of gold that are blasted at soybean embryos, in hopes that at least a few will find their way to the right place on a chromosome. Tens of thousands of trials resulted in a handful of plants that could withstand glyphosate and pass the trait down to their descendants. Starting in 1996, Monsanto began selling these soybean seeds as Roundup Ready. Seeds for glyphosate-resistant cotton, canola and corn followed soon after.

It also was a commercial triumph. Roundup Ready seeds revolutionized the farming of commodity crops in the U.S. and around the world, particularly in Argentina and Brazil. Encouraged by Monsanto’s advertising, farmers basically outsourced their weed problems, planting Roundup Ready seeds and dousing their fields with glyphosate at the first (and second and third) appearance of weeds. Last year in the U.S., 93 percent of soybean acres, and a large majority of corn and cotton, were planted with Roundup Ready seeds. Estimates of global demand in 2010 ranged up to almost one million tons.

Whether this technology has actually helped farmers produce more food is in dispute. The biotech industry likes to claim that it has, but a study by the Union of Concerned Scientists in 2009 concluded that any gains were small and far outstripped by the progress wrought by conventional breeding, at a small fraction of the cost. But the Roundup Ready system had other advantages as well. Most experts agree that among synthetic organic pesticides, glyphosate is one of the least toxic and persistent. And its effectiveness when used on Roundup Ready crops meant farmers had less need for tillage. No-till or low-till farming, a trend that began in the 1980s, saves fuel and reduces erosion and nutrient runoff into waterways. Glyphosate “is an incredibly effective chemical for killing plants,” says John Lydon, chief weed scientist at the usda, “and one of the most benign agricultural chemicals in use.”

That state of affairs was, of course, too good to last. “Weeds are constantly evolving by adapting to high selection pressures imposed by crop production practices,” says Purdue horticulturist Stephen Weller. Glyphosate resistance was almost unknown in the years before Roundup, but since then it has appeared in new species of weeds at the rate of about one a year. Applying the same herbicide to the same crop every year, with no other weed-control measures, creates a perfect laboratory for the evolution of resistance, Bauman says. “The resistant weed is out there. Just apply the herbicide, and you’ll find it.”

The first question everyone has about these glyphosate-resistant superweeds is whether they have the same resistance mechanism found in Roundup Ready seeds—that is, did the gene jump the species barrier into weeds from crops? Owen, expressing the consensus of plant biologists, says no; weeds native to the U.S. are too far apart from soybeans, corn or cotton to interbreed. (In contrast, certain plants are considered too close to their weedy relatives to run the risk of adding herbicide-resistant genes, such as creeping bentgrass, the turf of choice for golf greens.) Under the evolutionary pressure of glyphosate, weeds developed their own defenses. Resistant pigweed has the normal form of the EPSPS gene, not the altered allele engineered by Monsanto. But it has the normal gene in vastly greater numbers, from five to 160 times as many copies, which produce the enzyme in amounts that overwhelm the inhibiting effect of the herbicide.

Mystery survivor
Back in the Purdue greenhouses, Brabham’s experiment with giant ragweed demonstrates yet another kind of resistance, which appears to have also evolved independently. In susceptible weeds, the effects of glyphosate show up first in the rapidly dividing cells of the meristem. (The chemical also travels to the roots, where it may interfere with resistance to fungi; plants are notoriously hard to autopsy, but shriveled and rotted roots are often noted after spraying with glyphosate.) But when Brabham examines his specimens 18 hours after spraying, he sees something very different: the big leaves have begun to curl and brown, but the meristem is green and healthy. The plant appears to be segregating the herbicide in the leaves, which over the next week or two will die and fall off. But the plant will survive and regenerate from the meristem. “I’d love to know what’s causing that,” Weller says, “because you see the same thing in pathogen resistance. The leaf dies, but it doesn’t spread to the rest of the plant. That’s something we could really make use of, if we knew how it does it.”

It is important to remember, Weller says, that Monsanto’s Roundup Ready technology did not cause this problem by itself; the weeds evolved resistance to glyphosate on their own. But the availability of seeds for glyphosate-resistant crops enabled farmers to take the path of least resistance, which was to douse their fields with Roundup to the exclusion of other weed-control techniques and chemicals. They could have taken a lesson from medicine, which relies on a multiple-drug strategy to control fast-mutating viruses such as HIV; the odds are very much against a single organism spontaneously evolving resistance to several different chemicals at once, so ideally there are no survivors. It is fair to say that Monsanto, with a huge investment to recoup, did not exactly discourage them. “[Glyphosate resistance] could have been avoided, or at least put off for a long time, if farmers had used another herbicide in combination,” muses Glenn Nice, a Purdue extension agent who deals with farmers around the state regularly. “But farming is a business like any other.” Actually, not exactly like any other: farmers make their money at the margins—that is, after defraying expenses—and their efforts are constrained not just by cost but by the length of a day and a growing season. “An ounce of prevention is worth a pound of cure,” Nice adds, “but you still have to pay for the ounce.”

And farmers will be paying. Biotech and chemical companies are hard at work inserting genes for resistance to other herbicides into crops. Monsanto hopes to market, within the next year or two, seeds for plants resistant to an herbicide called dicamba, and Dow has developed a gene for resistance to 2,4-d. The traits will be “stacked” along with Roundup Ready genes onto a new generation of genetically engineered seeds, so that farmers can broadcast two herbicides on their fields, together or sequentially, rather than relying just on glyphosate. DuPont already sells seeds with resistance to glyphosate and another herbicide, glufosinate. That is in addition to other engineered traits bred into commercial seeds, such as the gene for Bt, a naturally occurring insecticide.

This is a prospect many agro­nomists greet warily. Dicamba and 2,4-d are older chemicals whose use has been grandfathered in under federal regulations; both are considered more toxic and persistent than glyphosate and might not easily get through the registration process if they were introduced today. Dicamba, in particular, has a tendency to volatilize after application, drift and settle on neighboring fields, where it has been known to damage other crops or wild vegetation. And there is the question, still unanswered, of how many added traits you can load onto a seed before you begin to impair the plant’s vigor and productivity. Every additional thing you ask of an organism takes energy away from what it is supposed to be doing in the first place—in this case, growing food.

The bigger question has to do with the future of agriculture and how farmers will feed a growing and increasingly affluent and urban world population. “This is a silver-bullet, industrial approach, not an agroecosystem approach,” Gurian-Sherman says. With a population of glyphosate-resistant weeds already established in many places, it is virtually certain that if dicamba and 2,4-d are used the same way, some of the same weeds will evolve resistance to them as well. Then where will we turn? There are only so many herbicide families, and chemical companies are not developing new ones, because the returns are so much better on genetic engineering of seeds. “I’m not opposed to genetic engineering in principle, but where has it gotten us?” he asks. “Billions in research have produced only two helpful traits [glyphosate resistance and Bt expression], whereas conventional techniques have yielded insect and disease resistance, drought tolerance and better crop yields at a lower cost.”

The solution, Gurian-Sherman argues, lies not with more expensive technological fixes but with the kind of crop science that would have been familiar to Gregor Mendel in the 19th century: incremental advances in yield, drought resistance and fertilizer use. “We need a fundamental shift in how we think about agriculture,” he says, “and this isn’t getting us any closer to it.”