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New era, new tools

Selection pressure and an ever-increasing list of glyphosate-resistant weeds mean we’re in a new era. Herbicide researchers are reacting by tapping the biomedical world for new tools for a new challenge

Redroot pigweed

When most people think of 1973, they think of world changing events such as the Arab oil embargo and the end of the Vietnam War. What they don’t think of is the introduction of a world-beating pesticide that not only changed the way that farmers would come to think about weeds, but also fundamentally altered the face of the globe.

This was the year that Roundup first appeared on suppliers’ shelves and in farm fields, where it created a new standard for herbicide performance, and over the next few seasons, tinkerers, dreamers and inventors in Saskatchewan, Manitoba and North Dakota perfected the first practical system to produce tillage-free annual grain crops.

The effects were enormous. The erodible dark summer fallow disappeared, conservation tillage became conventional, and spring ditches ran clear. The West’s windblown dark skies lived only in the memories of Dustbowl veterans. Glyphosate kept weeds at bay for the next 30 years, and a golden age of weed control prevailed.

But all golden ages come to an end, and we’ve seen more and more weeds become capable of quietly shaking their spring dose of glyphosate. The list of such weeds keeps growing, just like the annual list of resistant weeds compiled from all over the world. The once-mighty glyphosate has fallen to Australian rigid rye grass, American amaranth pigweed, Canadian kochia and many others. Nor do we have anything to replace it with because, after a fashion, herbicide research has also been a victim of glyphosate’s excellence.

“There’s been a real reduction in the intellectual effort going into herbicide research because of the prevalence and the tremendous success of glyphosate,” says herbicide chemist Stephen Lindell of Bayer CropScience. “Whereas, 20 years ago, there were about 40 companies involved in herbicide research, there are now perhaps a dozen.”

Lindell recalls a time when all those companies and all those chemists presented a tremendous source of inspiration. Reading each other’s patents kept the creative juices flowing. Those patents were awarded, some of them were improved and new chemistries were formulated and tested.

There are fewer patents these days, partly because there are fewer people working in the field, but there are other factors as well. The regulatory hurdles are higher. The emphasis on both public and environmental health is more important than ever, and new pesticides must conform to tougher standards than their predecessors. Further to that, some say that we’ve picked the low-hanging fruit and we’ve made the more obvious discoveries. From here on in, finding new chemistry is going to be more difficult, and getting from the lab to the field is a much rockier road.

“Now we’re a lot fewer and we can’t rely on our old sources anymore so it’s very difficult to find new chemistries,” Lindell says. “But we’re looking at new ways and there are a couple of approaches which we’re using to find new products, and we do this by targeting new modes of action.”

This is a new way of doing things that the agro-chemistry people borrowed from their colleagues in the pharmaceutical industry. At first companies looked at inventories of different chemical compounds and simply tested them on plants to see if they had herbicidal properties.

In time we’ve learned more about both the chemistry of the herbicide as well as the biochemistry of plants, so we understand how some chemical compounds can confound a plant’s inner workings. A herbicide is like a chemical monkey wrench that you throw into a plant’s metabolic gears to shut it down, and we’ve developed several different wrenches for as many different gears.

From the Grainews website: Diversify rotations to slow resistance

Glyphosate was our last great wrench, and to understand how it works you have to ease your way into the realm of the biochemist and use terms like amino acid, shikimate pathway and EPSP synthase. The first is a molecule, and everyone knows what those are, while the second is a metabolic pathway, a procedure by which a cell takes molecules, breaks them apart and then reassembles them into different molecules. The last is an enzyme, which is a molecule that starts a chemical reaction, rides it through and then pops out as the finished product moves down the line. Then the enzyme goes back and starts the reaction again, repeating this step several times before it burns out. In this way, raw materials go in, enzymes go to work and finished products come out. The cell makes proteins and the plant uses them to build tissue.

Even the name glyphosate itself is like that because it comes from glycine, an amino acid, and phosphonate, a family of chemical compounds including phosphonic acid or phosphonate salts. These terms were pulled apart and then bashed together into the name glyphosate, a molecule that pretends to be glycine and jams the shikimate pathway.

An amino acid is one of a family of about 20 compounds made up of an amine (nitrogen with two hydrogens — fertilizer) bolted to a carboxylic acid (carbon, two oxygens and a hydrogen — organic matter) and then adorned with one from a distinctive group of side chains. It’s sort of like the Mr. Potato Head toy where you have the standard potato body (the combination of the amine and carboxylic acid) with a variety of different accessories (the side chain). Since amino acids make up proteins, and proteins make tissue, biochemists will tell you that amino acids are the basic building blocks of life.

Under normal circumstances the cell takes glycine and moves it onto the shikimate workbench where it’s disassembled and the parts are recombined with other molecules. At one point the enzyme EPSP synthase drives an important part of the reaction where various fragments are put together into three different amino acids, phenylalanine, tyrosine and tryptophan.

These three are absolutely crucial to the growing plant. If you drop a molecule of glyphosate in there, the cell mistakes it for glycine but instead of breaking apart and helping to build the big three, it simply jams the pathway by binding to the EPSP synthase enzyme. And it won’t let go. The enzyme is disabled, the whole system shuts down and the plant dies.

The EPSP synthase enzyme activates what biochemists call the active site, and this is the set of “gears” that glyphosate jams. Different herbicides interfere with other sites and shut down different systems. This is called the “mode of action” and different herbicide groups are defined by their different modes of action. Glyphosate is Group 9, the EPSP synthase inhibitor. Group 4 are growth regulators such as 2,4-D which pretends to be auxin, a broadleaf growth hormone. Lindell’s team is looking at Group 27, a pigment synthesis inhibitor that goes after the HPPD enzyme.

The HPPD enzyme produces carotinoids, compounds that act like a light filter for the chloroplasts. Chloroplasts only need a narrow band within the light spectrum, so the carotinoids filter out certain wavelengths and this keeps the chloroplasts from overheating and burning out. The Group 27 HPPD inhibitors rip back the curtains exposing the chloroplasts to the sun’s full power, effectively reducing them to charcoal.

“We are hoping to use new approaches to produce or discover new compounds targeting that enzyme,” Lindell says. “Inasmuch as we’re looking for new chemistries, we believe that they will not show cross-resistance with any existing HPPD inhibitors.”

This new approach is called Fragment Based Lead Discovery. Instead of throwing a series of complex compounds at a group of plants to see what kills them, the researchers look for active sites within the plant’s metabolic pathways where they could exploit a potential weakness. Then they look for simple molecules that will bind to the site.

“Now, the thing with the fragment-based approach is that you take much smaller molecules, in fact very small molecules, because statistically the chance that you’ll find one that fits within the enzyme is much much higher,” Lindell says. “The trouble with this approach is that because it’s such a small molecule, it’s unlikely to have all of the enzyme or molecular interactions that are required to make a good inhibitor or a good herbicide.”

That’s why it’s called a lead fragment. Once we’ve found that, we can start looking at the “accessories,” the add-on parts of the molecule that will make the new herbicide potent and effective.

This really is a new way of developing pesticides, pharmaceuticals or any type of commercial biochemistry. It’s not a simpler method. In fact, it’s more complicated than the older approach, but it promises to be a more accurate way of doing things in a more complicated age. As the plants develop slightly different sites of action we can find other leads, so there is some potential to deal with evolved resistance a little faster.

“But it’s still a long, time-consuming process to discover new molecules, and we really do need to protect what we’ve got,” Lindell says. “We need to have real crop rotations with different herbicides. We need to have different modes of action, and they have to be modes of action that are active. Herbicides are a great resource, but if we lose them, then we’re really back to steel. We need to preserve them.”

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