Farmers used to worry about weeds, and then this happened–herbicides. In the 20th century chemical
companies developed thousands of herbicides. By 1984 we had 21 different modes of action for
herbicides, or 21 different ways that herbicides could kill weeds. That made weed control much
easier. Farmers could focus on maximizing yields, spending less time and money worrying about weeds,
problem solved forever, or at least until, well, we'll get to that in a minute.
Jump cut.
Among all those different herbicide options one product came to dominate the market, glyphosate,
or as it's better known. Roundup. Roundup first hit the markets in 1974. It is a broad spectrum
herbicide, meaning it kills a lot of different weeds. It works by targeting the shikimate
pathway. So it turns out that of the two common ways to pronounce this pathway. I chose the less
common one. So if you want to pronounce it the way that most people pronounce it, you might say
shikimate. I went with shikimate. tomato, tomato. I made my decision and I'm sticking with it.
That pathway is how plants and some microbes take relatively simple precursors and make the
aromatic amino acids tryptophan, phenylalanine, and tyrosine. Plants need those aromatic amino
acids to survive. Tyrosine and phenylalanine are both essential for plant metabolic pathways,
and tryptophan is the building block for the plant growth hormone auxin,
which is a pretty big deal. So if you shut down the shikimate pathway you kill the plant.
But here's the important thing. Animals do not use the shikimate pathway.
We don't produce those amino acids ourselves and instead we just eat the plants that have
already made them for us. So by targeting the shikimate pathway you're making an herbicide
that's broadly effective against all kinds of weeds, but has very low toxicity for animals.
The shikimate pathway is fairly complex. It takes seven steps to get from two simple precursors
to the substrate for those three aromatic amino acids. If you want to really dive into the organic
chemistry of the whole process we've linked to a full series on the pathway in the description.
But the short version is that there's a different enzyme to catalyze the reaction at
each of the seven steps. Seven enzymes means seven potential targets to shut down this pathway,
and that's where glyphosate comes in. Glyphosate targets five
5-enolpyruvylshikimate-3-phosphate synthase, also known as EPSP synthase, which is so much easier.
EPSP synthase is an enzyme that catalyzes one of those seven steps in the shikimate pathway.
It takes PEP and S3P and turns them into EPSP, hence the name EPSP synthase. It's an enzyme,
“-ase”, that catalyzes the synthesis of EPSP. EPSP synthase.
Glyphosate however throws a wrench in this process, almost literally. Glyphosate binds
to the enzyme where PEP would normally go and it binds with a greater affinity than PEP does
so it blocks the reaction from going forward. Blocking
this one little step shuts down the whole shikimate pathway, preventing the plant from
producing those aromatic amino acids that it needs to survive. This kills the plant.
But Monsanto, the folks who make Roundup, they weren't done yet. See glyphosate is great but
the problem is it kills everything, at least when it comes to plants. If you accidentally
spray some of your own crops with it, well it's not going to help your tomato yield for example.
So you’ve got to be pretty careful with this stuff. This is just water because I don't want
to glyphosate my own plants, but you get the idea. But if you could give your plants the
ability to survive exposure to glyphosate, well then applying it becomes a lot easier.
Enter Agrobacterium Strain CP4. This species of bacteria also uses the shikimate pathway
but its EPSP synthase doesn't really bind with glyphosate very well, making it immune to Roundup.
So Monsanto researchers took the gene for this version of EPSP synthase and put it into soybeans,
and then corn, and then canola and cotton and alfalfa and something and something.
The first Roundup ready crops were introduced in 1996, 11 years later nearly 90% of soybean acreage
in the US was planted with Roundup ready soybeans. The combination of glyphosate and Roundup ready
crops was so effective that sales of both took off, and development of new herbicides fell off
a cliff. In 1997 there were 432 new patents for herbicides. By 2009 there were only 65.
And remember how I said that there were 21 potential modes of action for herbicides
back in 1984? Well today there are 22. The most recent one was discovered in 2018.
If your crops are the only thing around that won't die from being sprayed with glyphosate
it makes the weed problem basically non-existent. You're not going to put money into research.
But that's an important if, if your crops are the only thing around the can survive
glyphosate. If the weeds are also glyphosate resistant then you're back to square one.
Roundup ready crops got their glyphosate resistant EPSP synthase from bacteria,
not plants, so it was assumed that plants would be unlikely to evolve their own resistance.
Also, evolution is a slow process right? It could take millions of years for even
a single weed species to evolve the ability to be partially resistant to
glyph… 50. There are currently more than 50 species of weeds that have evolved
glyphosate resistance. We've been using glyphosate as an herbicide for just shy of 50 years. Roundup
ready crops have been in use for just over 25 years and there are already more than 50
species of weeds that have evolved the ability to survive this broad spectrum herbicide. Sh*t.
So we've got increasing resistance to glyphosate and other herbicides that we haven't even
talked about for that matter, research into herbicides has been stagnant for decades,
and farmers are once again getting pretty worried about weeds.
This is a pain to do by hand. You're not going to do this over thousands of acres or hectares
or square kilometers. No matter what your unit of measurement is, this kind of sucks.
So the primary impact of herbicide resistance on farmers is spending more money on herbicides.
They are spraying more herbicide, or different combinations of herbicides, or planting crops
that are resistant to different herbicides other than glyphosate doing literally whatever they
can to defeat these stupid fricking weeds. And the tricky bit is you can't just come up
with a new herbicide that targets the same site on the same enzyme.
If the weeds have evolved resistance to one herbicide that targets that site it's totally
possible that a new herbicide targeting the same site will be ineffective before it ever sees the
field. That specific target in herbicide interacts with is called the site of action. Mode of action
on the other hand refers to the process that the enzyme throws a metaphorical wrench into.
Glyphosate’s mode of action is targeting the shikimate pathway.
Its site of action is EPSP synthase. Try as they might, researchers have yet to
find another site of action to inhibit the shikimate pathway. But new modes of action
would target entirely new biological pathways where weeds have never been attacked before.
Remember we have thousands of herbicides but only 22 modes of action. New modes
of action are what we really need, and in the last 38 years we've come up with one.
And that one new mode of action was something that Mitsui Chemicals was working on in 1982.
They gave up on it in 1985 because we had enough effective herbicides at that point and they just
didn't need a new one. It wasn't until the late '90s when weeds and rice paddies started evolving
resistance to the existing herbicides that Mitsui dusted off this old idea and started
working on it again. But we're not always going to have a partially developed herbicide
project just sitting on the shelf like this. So how do we come up with new modes of action?
The traditional way of doing this was to select thousands of chemicals that looked promising and
test those out on small samples of plant tissue and see what happens. If one chemical seems to do
something you take it and you tweak it a little bit and see if you can make it more effective.
You can do this thousands of times with thousands of different potential chemicals before you have
something that works. The whole process can and often does take years to decades to complete.
Another way of looking for new modes of action is to reverse that process.
First you look for a pathway or process that's essential to plant survival, something you've
never attacked before, and then you look for an enzyme within that process that you can target,
and then you try and find a molecule that interferes with just that enzyme.
Just a few years ago this would have been a needle in a haystack approach, but now we can use AI to
predict which enzymes might make good targets and then map the surface of those enzymes to
find potential binding sites. However researchers try to find new modes of action the search is on.
Farmers are spending more and more money on herbicides with less of an effect every year.
Chemical companies everywhere are jumping back into the field. The area of research,
the field, the area of research, whatever, it's a
pun–after decades of ignoring it. But whatever new modes of action they come up with,
how do we keep weeds from just evolving resistance to those after a few years?
If you want to learn more about the companies who are looking into this and how they're doing it
there's a great article in Chemical & Engineering News that inspired us to make this video,
so we'll link that in the description below. In the meantime I have more weeds to pull
because they never end, weeds never end, they're never going away, just die. It was too dark.