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.