Show #2681
DIALOGUE edit
How Weed Killers Create Antibiotic Resistant Bacteria
with guest, Dr. Ville Friman, PhD
Carl Lanore:
Today's show has been a long time in the making. It's actually something we started to discuss on this show back in 2018. It was an episode of Casual Friday. Glyphosate and other herbicides are anti-microbial in nature. The difference between an antibiotic and an anti-microbial is dose and duration of exposure. Which means that an anti-microbial can act like a weak antibiotic. We saw this happen in the weeds that glyphosate was killing. They were getting stronger. They were having to use twice as much, three times as much, five times as much.
Antibiotic resistance is a big thing in the United States. There are 2.8 million people who contract an antibiotic resistant fungus or pathogen every year; 35,000 of them will die from it. It is the leading issue in medicine today. How do we prepare for antibiotic-resistant pathogens? How do we help people save their own lives? We always thought doctors prescribing antibiotics so often must be causing the problem. Maybe that's part of it, but maybe the other part of it is what we're going to talk about today. Dr. Villa Freeman, how are you?
Dr. Ville Friman, Ph.D.:
I agree. Antibiotic resistance is a broad problem not only by antibiotic use in a clinical setting, but by antibiotics being disposed of in the environment. Lots of these antibodies are actually still in active form so even though they will definitely get diluted when they get to the environment they still remain active. They will get into our lakes, and aquatic environments as well as agricultural environments.
Carl Lanore:
A lot of these anti-microbials in agricultural environments are a result of runoff of water. What led to this research? What were you and your colleagues looking to get to the bottom of?
Dr. Ville Friman, Ph.D.:
Antibiotics have been used in animal husbandry for quite a long time to increase the yield and the growth of the animals. They've been used as a kind of growth additive. Of course, this is banned in most of the countries, but it's still happening. It's not banned everywhere. Similarly, people tend to use more amounts of heavy metals to induce meat production or growth of animals. There's one clear link. Heavy metals are also toxic for bacteria.
We are releasing lots of other chemicals to the environments. And if you think about herbicides, we are using them all the time. There's been some studies previously showing this sort of link, but I think we were the first ones to study this in natural agricultural soil systems. There’s been few lab studies focusing on the effects of herbicides on bacteria. They found similar things, but if you do something in a lab environment, aquatic culture is quite far from natural environment, soil, porous environments, heterogeneous environments. We've been the first ones to show that. I've been working with the first author, a Chinese author, for four years now. We've been mainly focused on antibiotic-resistant genes in the animal manure. Quite open people just discard that and it's not treated in any way and it gets to the environment. So its kind of just spreading around antibiotic-resistant bacteria and antibiotic-resistance genes in the environments. We've also been studying using composting to reduce the amount of antibiotic-resistant genes and antibiotic-resistant bacteria in these waste products. You can bind manure with straw or other agricultural waste products from plants, and you can ferment that into fertilizer as a compost, as a soil, which is rich in nutrients and can be used by plants. It's actually a very clever way to recycle our waste. It’s actually nutritious and contains lots of energy that can be employed by the plants for their growth. Of course, we need to take care to not be release antibiotic-resistant genes or antibiotic-resistant bacteria along with that. Because, if you think about the rumen of a cow, they do include lots of pathogenic bacteria; e-coli and other bacteria that are also harmful for us. We don't want to enrich those bacteria in the environment because it increases the risks to us.
Carl Lanore:
The recall of 2018 where e-coli was found on the romaine lettuce is the same e-coli found in the guts of ruminant animals that are being fed grain, as opposed to grass. What I predicted in that show was that e-coli could have been put on those plants by the water irrigation systems. So let's say it was there, then the application of these anti-microbials, which are herbicides, actually made the e-coli strong. Using these herbicides actually make it stronger and more resistant. Explain how herbicides work for the audience.
Dr. Ville Friman, Ph.D.:
Ekaryotes are multicellular, they’re quite different from the bacteria. The idea is that bacteria don't have the target of that herbicide, so they should be safe, but some of these targets they have are quite conserved. They can be found with bacteria or human cells or plant cells, so there could be some link there. Of course, doses have to be quite different. Antibiotics work based on the dose we use being lethal for the bacteria, but not too harmful for us. Antibiotics are also toxic for human cells, for us. We can’t take a high concentration of antibiotics. Herbicides tend to be anti-microbial and we don't know exactly how they are damaging bacterial cells but we when you expose the bacteria to herbicides for long periods of time, they do develop resistance. We found that the same mutations that help bacteria to survive antibiotics also help them to grow in the presence of herbicides. If you think about it, antibiotics are actually quite often derived from bacteria or fungi. So it is actually a result of microbial warfare; microbes competing for the space and nutrients. They're producing this toxin to kill other competitors nearby them. We can use their own weapons against them in a way if you think about antibiotics, they’ve always been in the soil so we know that we have those resistant genes. They are there because they're part of inherent competitive interactions. The herbicides are increasing the benefit of carrying these resistant genes more than would happen naturally. Antibiotic-resistant bacteria are not necessarily good at competing and growing unless there's antibiotics present in the environment
Carl Lanore:
Because the antibiotics do their job and kill everything else, but leave the terrain for them.
Dr. Ville Friman, Ph.D.:
Exactly. So herbicides are making the environment favorable for those resistant bacteria. They can survive but they have negative effects on the competition.
Carl Lanore:
It sounds to me like you've also discovered how we should be treating some of these pathogens, not necessarily scorching the earth and killing everything. Perhaps investing more science into how to create highly competitive non-harmful pathogens to compete for the same space in the body.
Dr. Ville Friman, Ph.D.:
Exactly. We need to take antibiotics at times, but the one side effect is that they are seldom specific, so they will also target our beneficial gut bacteria. There will be collateral damage. It’s okay if you don't have to take antibiotics for long periods of time but if you're suffering from some chronic infection and you need to take antibiotics repeatedly, that will cause harm via your gut microbiota, you will have some gastrointestinal problems as well. It has been shown that even short-term exposure to antibiotics can cause these issues. Our gut is quite resilient and can bounce back, but it might not bounce back exactly the same. You’re inducing these sort of negative effects with the antibiotic.If we had something that is more specific to the pathogens, that will leave the beneficial microbiota unharmed, that would be a much better treatment.
Carl Lanore:
My thought has always been to buy organic produce and vegetables as often as possible because the conventionally grown products are modified so that conventional agriculture can use more and more pesticides and not kill the plant, rather kill all the weeds around it. I have to believe that conventionally grown produce has far greater risk of carrying and implanting antibiotic-resistant pathogens into a person who consumes them, than organic, where they're not using pesticides and they're using heritage approaches to farming, to manage weeds without using anti-microbials. What do you think about that?
Dr. Ville Friman, Ph.D.:
I'm not a hundred percent sure if there's really enough data on this, but it would be a really interesting research topic to compare the benefits. Human population is expanding. Climate is changing. We're really changing the environment and are in a bad spot. We have to use all the tools we can to feed the population. I think technology is the answer there, but I think we need to do it a safe way and be aware of the risks. Organic farming might use lots of manure, which is not treated, so you might be actually introducing antibiotic-resistant bacteria in the soil along with the manure without realizing. It really comes down to relative effects. I don’t think there's enough data at the moment.
Carl Lanore:
I've done numbers of shows over the years with some of the greatest land grant universities like Washington State, University of Illinois, where they looked at whether or not the yield is increased by using the new chemical agricultural model. It's not in soybeans. You may end up with one or two bushels more organically grown soybeans, however your profits are a lot lower because you have to spend tens of thousands of dollars on these chemicals. Now we're starting to learn that maybe returning to the methods of the years before chemical agriculture may actually not only be more profitable for the farmers, but produce a healthier plant for the consumer to eat. With the understanding, as you pointed out, that if you're using manure, then the process after it's harvested has to have more steps in there to make sure that everything is washed off of the plant before it's sent out to market.
[25:28]
Carl Lanore:
Let's talk about your research itself. How was the study designed?
Dr. Ville Friman, Ph.D.:
We've been using natural systems, which are often hard to control; different temperature variations, and so on. We want to kind of take some semi natural approach where we have natural communities assembled in a very small setting in the lab. Basically it's a jar full of soil and we were applying herbicides in this soil in controlled treatments with water only, using genomic sequencing to see what is happening to the abundance of antibiotic-resistant genes and mobile genetic elements that might be moving them around in the microbial communities. We discovered we can clear increasing antibiotic-resistant genes when we apply herbicides. Then we started to do more lab-based experiments to try to understand the mechanisms; what might be driving this. We found two interesting mechanisms. First we used an approach called experimental evolution. You can start your cultures by using one bacterial species which is isogenic, then you expose that bacteria to herbicides and do that repeatedly. You're culturing the bacteria in your test, transferring the same condition and imposing selection, in this case, herbicides. You could see that slowly there are mutations accumulating, some of which are actually beneficial for the bacteria. We can run this experiment for 900 bacterial generations. We took some of those strengths that are able to resist both herbicides and antibiotics and did some sequencing to try to understand which mutations, which genetic molecules and mechanisms might explain this. We found lots of known antibiotic-resistant genes that were selected in these conditions and linked to them, making the cell membrane less permeable, so fewer antibiotics will be getting through the cell membrane and causing damage to the bacteria. There were also other things like hydrolytic enzymes that are able to break down antibiotics when they get inside the bacterial cells. Different mechanisms were found to be selected. At around 900 bacterial generations this mutation just appeared in the bacteria naturally. They were selected because they were beneficial for the bacteria and through hundreds of generations they became the most dominant bacterial genotypes in these experiments. This is the strength of testing this hypothesis. You can do a direct experiment, where you can causally show this one thing is actually leading to this outcome.
It's causal direct evidence. Another mechanism we were able to find was that antibiotics are also promoting the movement of these mobile genetic elements plasmids, a small piece of DNA that can freely move between different bacterial species. We put a few species together. One of them was carrying this antibiotic-resistant plasmid. If you expose this small model of communities to herbicides, it promotes the movements of the plasmid between different bacteria so you can track down which herbicide selection is enforcing or promoting the movement of those antibiotic-resistant genes impacting a population.
Carl Lanore:
That shows the trajectory of the evolution. This plasmid is a piece of the DNA. When it goes in, does it find a place in the DNA strand to put itself? And is that place specifically required to develop the resistance?
Dr. Ville Friman, Ph.D.:
It can coexist independently. It just needs to go inside the cell and quite often you have a high number of these plasmids. They can make copies of themselves. Sometimes they’re called conjugated plasmids, they might also have changed in a way that helps them to promote and spread between bacterial species. Basically, it's a kind of cell appendage in the cell surface that can build a bridge between two bacteria and the plasmids and then move along this bridge to the donor cell. Like genetic parasites that might have also benefits for the host.
Carl Lanore:
There's also evidence of intelligence here when you think about this, right? When the community is not capable of surviving, given the insult, whether it's an antibiotic or microbial, and there's one in there that has this plasmid it knows to share it with everybody. And everyone knows to accept it because this will help them survive. Microbes don't have a nucleus, right? They're not eukaryotes.
Dr. Ville Friman, Ph.D.:
Yeah, the chromosome is just like floating around.
Carl Lanore:
Even though these are considered pretty stupid in the hierarchy of the food chain, with fungi actually being smarter than them, they know to take that plasmid.
Dr. Ville Friman, Ph.D.:
Yes. These plasmids can act as parasites. They just want to spread around as far as they can and they don’t ask bacteria if they can come in, they just do it because they can. Bacteria have ways of discriminating against these plasmids. They can recognize the foreign DNA and try to destroy it because it's not beneficial to them. They fight against it but you have quite complex, molecular interactions. The plasmid doesn't exist alone. It always needs a host, but the host can discriminate and if they are encoding some other beneficial functions, like antibiotic-resistant genes, it’s likely that they're going to be accepted by the bacteria because there's something good going on.
[34:37]
Carl Lanore:
I want to make another prediction about cell membrane permeability being an issue. Obviously these plasmids are helping to develop resistance to the insult. I believe good agriculture and science will get together and find the way to pierce the membrane and create memory and permeability to carry the glyphosate. They’ll also look at the transfer to plasmids, that that of these actually can start to use the anti-microbials convert inside the cell. They'll target those things to make our drugs more successful and in a decade, the microbes will evolve to derail those methods because they'll get infinitely stronger and those methods won't be effective anymore.
We have to understand and have respect for evolution. Every single living thing on this planet strives for two things: survival and offspring. It will always work to survive, and it will always work to increase the trajectory of the species. Any approach by modern science to eliminate those two characteristics of a species will only create a stronger, more resilient, more robust species. These herbicides should have killed everything by now. They stay in the soil, the microbes, the pathogens, they’re just getting stronger. The weeds are getting stronger. There was an article a few years ago stating that glyphosate isn't working anymore. They're going to add dicamba because the weeds are just becoming more and more robust and they can't afford to spray more. It's evolution. Have respect for it.
Dr. Ville Friman, Ph.D.:
When you have this strong directional selection often the resistance is actually costly for the bacteria. So if you remove that antibiotic selection, the bacteria that is persistent is quite often less competitive. During this prolonged selection you're also selecting additional adaptations that are refining that resistance so you get compensates or mutations. The mutations that are giving you resistance are costly but when you have these refining compensator mutations it actually reduces the cost and increases the chances that the antibiotic-resistant bacteria can prevail regardless of the presence of antibiotics in their environment. So it's not only the appearance of the resistant mutation, but it's also all the other mutations that are helping the species of bacteria overcome those initial costs and refine the initial adaptation. That's happened throughout the history of life with all organisms.
Carl Lanore:
Did you notice any differences in the effects of one herbicide over another through the 900 generations?
Dr. Ville Friman, Ph.D.:
We didn't really compare them specifically but we have that data. Dicamba was really good at promoting the movement of these plasmids between the different bacteria. Glufosinate and glyphosate, they have different effects. They have different mechanisms they act on. It definitely needs more research and follow-up studies to answer that properly.
[41:10]
Carl Lanore:
Your research is profound and very important.
There's another aspect that's really not being discussed here. We've established that the difference between an anti-microbial and an antibiotic is the dose and the duration of exposure. That's why you have a regimen. We know that animal husbandry boasts no antibiotics used in the raising of our chickens or our cows. And the reason for that is antibiotics have proven to be very valuable for keeping animals that live in very close, unnatural quarters from sharing diseases, but more importantly, a cow on antibiotics gets fatter and bigger faster. Antibiotics improve a component of the microbiome that makes it more efficient at extracting nutrients from the food you eat while turning down energy expenditure from an evolutionary perspective.
Antibiotics are great. There’s a study that shows the growth of the average American juxtaposed against the application of antibiotics. Look at indigenous cultures in Chile and you see these little people who’ve never taken antibiotics. This particular study proposed that the exposure to antibiotics has made us bigger and fatter.
Now keep that for a second. Every time you eat a conventionally grown product that could potentially have some negligible level of glyphosate, dicamba, or some other herbicide, you're effectively eating a low non-therapeutic dose of antibiotics. We know that low levels of antibiotics cause antibiotic-resistance in the human body, but more importantly, they clearly have an effect on metabolism, as was proposed in the study. They can shift your metabolism towards becoming obese. How much of that dicamba are you eating every day and glyphosate from multiple sources, in prepared foods that don't use ingredients that were organically grown. The salad you buy when you go out to the restaurant.
We did a show seven years ago where the author of a study was asking our audience to submit to a glyphosate test. I got emails from people saying they were shocked how high the glyphosate levels were in their bodies. In Germany, they had glyphosate showing up in human breast milk. So while we're talking about plants and antibiotic-resistant infections, there's low levels of these drugs that are like weak antibiotics that people are consuming every day. When I went to Mexico a few years ago, they had an anti-microbial in the toothpaste. Is this contributing to our disease states?
Dr. Ville Friman, Ph.D.:
We do get loads of chemicals from the food we eat, and from the environment, I don’t know the relative importance of that. Regarding the growth effect with humans, I think having a more nutritious diet, healthy food available, and better healthcare probably explains the increase in size. It would be interesting to see more research on how much herbicide and chemicals our food contains, how much we're ingesting, if it’s accumulating in our body etc.
Carl Lanore:
We have a viewer question: Michael says, “what would your message be to people like my father who grows corn and soybeans for a living and obviously they’re probably GMO so I bet he uses a lot of these chemical herbicides. He's been doing it so far for 40 years in Southern Indiana.” ?
Dr. Ville Friman, Ph.D.:
There's no way we can get rid of herbicides and pesticides. We definitely need them. We should explore more the significance of herbicide use for the antibiotic-resistant genes and how they get into the food chains and food production systems. We need to use herbicides otherwise we don't have food on our table. I'm not saying that we shouldn't, rather find ways to develop these treatments, perhaps.
[49:24]
Carl Lanore:
So now we're going to change the subject. My guest today has a secret. The secret is that he is with a heavy metal band called Insomnium. That is so awesome. Where can people listen to your music? Can they find it online?
Dr. Ville Friman, Ph.D.:
They can find it online insomnium.net. I think that that's the address and, you know, Facebook, Twitter, Instagram, you know, just go put Insomnium. YouTube music videos etc.
Carl Lanore:
How long has the band been around?
Dr. Ville Friman, Ph.D.:
We started when we were teenagers. So when I was 16, I started playing guitar and we've been going for past 20 years now.
Carl Lanore:
Do you have a lot of original songs as well?
Dr. Ville Friman, Ph.D.:
Yeah. We’ve done eight albums and you know, some of the videos, there's a couple of million views and quite a good following. We toured USA quite a few times and Europe consistently.
Carl Lanore:
So now with COVID, I guess you didn't have any opportunities to play, right?
Dr. Ville Friman, Ph.D.:
No. I think the music industry is really suffering with the COVID. All performing arts. Hopefully that will bounce back at some point, but I guess it will still take time.
Carl Lanore:
Yeah. Well, keep doing science because what you're doing is going to have great impact on health. There's lots of studies that we talk about on this show and you really can't take away any actionable steps or even any valuable information other than you learn something new. But I think the research you're doing is critical because there's going to come a time where antibiotics can't save a person's life because the organism that they've contracted is resistant to everything. We can't do chemotherapy for infections so I think what you're doing is fantastic. I think that over time, your research may prove that there are better ways to deal with weeds than slathering a crop with these herbicides.
Dr. Ville Friman, Ph.D.:
We can only try. You need to have the scientific understanding on things in order to come up with new potential better solutions. We at least we have to strive for that.
Carl Lanore:
Thank you for being here at Villa. We'll see you again sometime. That was a great interview.
