November 22, 2024 • 20 mins
The Director of the Milner Centre for Evolution, Professor Turi King, talks to Professor Ed Feil about his research using genetics to understand the evolution and spread of infectious bacteria of humans and animals, as well as antimicrobial resistance, which is a major threat to global health and food security.
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(00:02):
Hello and welcome, you are listening to a podcast by the Milner Centre for Evolution, at the
University of Bath. I'm Professor Turi King, your host, and today I'm talking to Ed Feil, Professor
of Bacterial Evolution, about his research using genetics to understand the evolution and spread
of infectious bacteria of humans and animals, as well as antimicrobial resistance, which is a major
(00:24):
threat to global health and food security.So, Ed, before we get into your research
that you're doing now, how did you come to be interested in this field?
Was there something that triggered it?Well, like many evolutionary biologists,
I was originally inspired by some key books that I read in the sixth form, one being Selfish Gene
(00:44):
by Richard Dawkins that many people read. And then I kind of lucked out through my, sort of, student
days of getting to UCL, having to do genetics.I had Steve Jones as my mentor, and I lucked out
even more with my PhD at the University of Sussex, where I had two supervisors,
Prof. Brian Spratt and Prof. John Maynard Smith, who's very eminent evolutionary biologist.
(01:07):
And this project took me down the path of looking at what we would refer to as sex in bacteria. So,
bacteria don't have sex in terms of reproduction because they reproduce by binary fission,
but they do have sex in terms of moving genetic material from one individual to
another and recombining it in a single individual.So, this was what I was really interested in, and
(01:32):
the bug that I chose to work on was a bug called Neisseria gonorrhoeae, which causes gonorrhoea.
And we found that there was a lot of this, sort of, hankie panky going on in gonorrhoea genomes.
And now this is kind of accepted and mainstream that bacteria recombine and share genes all over
the place. It's one of the most intriguing aspects still about bacterial populations that they can
(01:55):
do this, and of course, it has relevance to antimicrobial resistance, but at the time
it was quite a big deal. There was still a lot of debate about how much this process happens.
So that was my PhD and subsequently in the last, I don't know, let's go back 15 years or so,
what's really been driving the nuts and bolts of what I do is the absolutely incredible advances
(02:17):
in the technology. So, you know, when I started my PhD, as I said, it would take
a year to sequence a single gene. Now we have undergraduate project students who are looking
at 20-30 complete genome sequences. You know, it would have been science fiction back in the day.
So, we have so many genome sequences now for all the really important pathogens. I mean,
(02:39):
literally tens of thousands of genome sequences for species like E. coli and Staph aureus, MRSA,
that we can really look infinitesimal detail at the micro evolutionary processes that are going
on over very short time spans. And of course, the evolution of antibiotic resistance is the sort of
stereotypical example of that sort of evolution. And it's the only sort of broad evolutionary
(03:05):
pattern that we've been really been able to observe in real time, as it's been happening,
up until Covid, which was a separate thing, because we could watch that thing evolve.
So, this is a big evolutionary change that we've been able to observe in real
time. And since the advent of all this genome sequence data, we can really pick apart exactly
the evolutionary mechanisms that’s going on.So, let's go back to this thing of bacterial sex.
(03:28):
Yeah.So, this is an interesting thing. So, you're
finding that genetic material is going from one bacterium into another bacteria, you're getting
recombination, for people who don't know what this is, what is this recombination that's going on?
Okay. So, let's go back to Neisseria gonorrhoeae. So, there are different
mechanisms by which bacterial sex can happen. Neisseria gonorrhoeae is kind of an unusual bug
(03:54):
in that it's what's called competent for transformation, constitutively competent.
So, all the while it's able to basically suck up DNA from other Neisseria gonorrhoeae cells.
Theres really clever mechanisms by which the cell can recognize DNA from its own species or related
species, and then the DNA can be incorporated into the genome of the recipient bacteria.
(04:19):
That's conceptually, I guess, the most simple sort of recombination. And this is the sort of
recombination that I was looking at in my PhD.There are other sorts of recombination which
involve phage. So, these viruses that infect bacteria can actually act as little vehicles
moving DNA around from one cell to another. And plasmids which are sort of extra chromosome,
(04:41):
little rings of DNA that sit in the cell and they can move from one cell to another. And
that's a kind of important way by which antibiotic resistance can move around.
But what we found in Neisseria was that actually transformation can bring about resistance as well.
We found these examples where a bug has acquired just a short stretch of DNA, like 500 bases,
(05:01):
from a resistant relative, and that had been incorporated into these so-called penicillin
binding proteins and that had caused resistance.It tells us something about the bacteria as well,
because in order to have access to DNA, there needs to be other different cells around in order
to acquire the DNA. So, it actually tells us a little bit something about gonorrhoea and the rate
(05:23):
of mixed infection. So, it tells us something about both the sex of the bacteria and the
sexual behaviour of the host as well. If there's mixed infections, then you're much more likely
to have this sort of recombination occurring.And that's really important because, we know,
so bacteria around us all of the time, and a lot of it doesn't do anything to us, but we do have
bacteria which is pathogenic, so it makes humans and animals ill. So, if you've got these bacteria
(05:48):
that are able to, kind of, suck up other little genes that then make them resistant to normal,
sort of, antibacterial things that we've got, or antibiotics or this kind of thing, then that's
really important to know about, I'm guessing.Absolutely, and we're still really understanding
how frequent this is. I mean, some bacteria do it much more commonly than others. But if you take an
(06:12):
environment like the human gut or the nasopharynx, which is where most Neisseria bacteria live,
it's a really crowded environment. So, they're all these bacteria that are living on mucosal surfaces
of the host, they're all sort of crowded together. And this is where you get all this sort of hanky
panky going on, of frequent gene exchange within hosts, within the guts, within our throat.
(06:33):
So, it's a very important mechanism. We can decipher the natural genetic variation from
bacteria that we are able to sample from people. But we can also do lots of quite
elegant experiments in the lab to understand the process and how frequently it happens.
So, what's the bacteria that you're working on now?
(06:53):
So right now, most of my time is spent on a bug called Klebsiella pneumoniae, which is kind of
related to E. coli, which most people would have heard of. So, it's an enteric bug, so it lives
in the gut. It's a very worrisome bug in terms of resistance. It's kind of shot to prominence
over the last, say 10-15 years, in terms of the resistance genes that it has acquired. So,
(07:17):
there aren't many antibiotics that one strain or other hasn't got resistance to at some point.
And it seems to act a little bit like flypaper, so it's really good at acquiring genes from
all over the place. And some of these resistance genes probably come from completely benign
environmental bacteria out there that people aren’t particularly bothered about, but it
(07:40):
lives out in the environment, is an ecological generalist. It lives in the guts of people,
but also lives in the guts of lots of animals. It can survive in soil and water, so it's got a lot
of opportunities for pulling in genes from all over the place. And it's causing a big problem
in hospitals all around the world, actually.So, what's the disease that it causes? So,
it's pathogenic, it's causing problems. What does it do to us?
(08:04):
So, it can cause a whole range of diseases actually, if it gets into the bloodstream,
it can cause classic sepsis, but it can also cause urinary tract infections.
If you're unlucky enough to contract a really virulent strain, then it can cause these really
nasty liver abscesses, which can be quite hard to treat and actually often fatal.
(08:25):
But up until a few years ago, we were quite reassured in a sense,
by the fact that there were distinct sets of strains in hospitals and outside of hospitals in
the community. So, the strains in hospitals tended to be the ones that were resistant to antibiotics,
but they weren't so virulent, they didn't cause these nasty liver abscesses that I talked about.
(08:45):
Then the strains outside of hospitals that are circling amongst healthy people,
they more commonly have picked up virulence genes, on a different plasmid,
which can lead to much more serious infection.What's been happening is strains have emerged
that have both the resistance plasmids and the variants plasmids. And in fact, what we found in
(09:08):
some of our data is that it's not just the case that a single strain can have the two plasmids,
it's actually slightly worse than that, that the plasmids themselves have recombined together,
so you've got a single plasmid that contains both virulence and resistance genes. And once that's
happened, then of course you can transfer, when that plasmid moves, you’re transferring
(09:29):
both virulence and resistance traits.So, this is a really worrying trend,
and it's causing a lot of problems in China and other parts of East Asia. But we are starting to
see some of these so-called convergent, virulent and resistant strains in Europe as well. So,
this is really something that we've got to keep it very carefully on.
So, Ed, I was reading about how the World Health Organization states that bacteria
(09:53):
that is resistant to antibiotics directly leads to over a million people dying each year globally
and contributes to the death of nearly 5 million more. So as more and more bacteria evolve
resistance, that number is only going to rise.So, it sounds like it's really hard to overstate
how big an issue this is, as it's going to make infections harder to treat. It's affecting animals
and plants and therefore agriculture. So, talk us through what's driving all of this?
(10:18):
Well, that's the million-dollar question in a sense. I mean, there's an obvious answer,
which is the overuse of antibiotics, which is certainly part of the problem. It's not just
the use in medicine, although in some parts of the world that needs to be seriously tightened up and
regulated, it's also the use in agriculture.So actually, part of my research agenda is
(10:41):
understanding how much of a risk those sort of environmental uses of antibiotics
pose to public health, how much sort of crosstalk there is between what's
going on in the environment and the clinic.I should say as well that the problem with
antibiotic resistance isn't just about treating infections, that's bad enough, but it's also in
the prophylactic use of antibiotics for all sorts of medical interventions. So, transplant surgery,
(11:05):
you know, you can't do without having antibiotics prophylactically to prevent infection. So,
there's a lot of procedures that would basically become impossible without them.
Of course, there's a lot more global movement than has been in the past. So,
resistance strains can move around the world very quickly. The way that we deal
(11:26):
with infection control in hospitals probably has a role in how much resistance can spread
within the clinical settings. We need more isolation wards, we need to be much better
at spotting outbreaks caused by resistant bacteria, sort of, early doors before the
genie gets out of the bottle, basically.So, there's multiple factors. There's
(11:48):
also social factors that we can sort of feed into about awareness of what antibiotic resistance is,
sort of basic facts about how antibiotics don't work for viruses, for example, they're only going
to work for bacteria. Basic levels of knowledge that mean that many people think that it’s them
that get resistant to antibiotics rather than the bacteria. So, this isn't obviously the case
(12:10):
either. So that does need to be sort of a raising of public awareness generally.
So how is your research coming to bear on all of this?
So, a couple of big projects that I've recently completed look specifically
at this question of how resistance bacteria and resistance genes, because remember, genes
themselves can move around by recombination kind of independent of the bugs themselves, so it's
(12:33):
kind of a complicated situation.So, it's understanding how resistant bacteria,
resistance genes can move around complex landscapes like farms and how the water cycle,
for example, because we know there's lots of resistant bacteria in wastewater, most of which
hopefully will get captured by wastewater treatment processes, but some will go into
(12:57):
the rivers and waterways and what happens then to the fate of those antibiotic-resistant bacteria.
Do they sort of fizzle out and get diluted out, or can they survive and maybe pass their genes on to
other bacteria? And, you know, so it's trying to unpick all these dynamics of transmission
within environmental settings, and how much of all that is feeding into the clinical problem.
(13:17):
And this all falls under an umbrella called one health, one health concept, which is a sort of
overarching framework which recognizes that, if we were just trying to deal with antibiotic
resistance by better stewardship of antibiotics in hospitals, better infection control in hospitals,
but at the same time, we're getting this constant influx from the environment,
(13:39):
then it's really sort of like trying to mop the floor with the tap wide open, you know,
so we need this whole interconnectivity of what's going on in humans, what's going on in the animals
and what's going on in the environment and how all those things are connected. So that's essentially
the big picture of what I'm trying to do.So how are you doing that?
(13:59):
Well, I'm using genomics mostly. We're now at the point where we can generate whole genome sequences
for thousands of genomes. So, we recently carried out this project in and around one
town in northern Italy called Pavia, which is a bit like an Italian Bath. It's about an hour south
of Milan. It's a similar sort of size population, big student town, lots of dairy. And we
(14:22):
essentially focused on this Klebsiella bacteria.It's a hotspot for resistance in the hospital,
as quite a lot of southern Europe is, but Italy in particular has a big problem with resistance and
Klebsiella. So, we took lots of strains from the hospitals, and we took strains from the
healthy people in the community. We took strains from the farms, there's lots of dairy farms,
(14:44):
this is where Gorgonzola comes from. And we took from the rivers, from the soil, from the plants,
from the food. And we were just trying to look at the amount of overlap from
the genome sequences to try and understand how much these different bacteria are moving around.
And the good news is, that if you were to ask the question, where does someone catch
their Klebsiella from? Then most of the time it's from another person rather than
(15:08):
from the environment or from an animal. It's different if you're working very closely with
animals. The exceptions are companion animals, so there is quite a lot of overlap between dogs,
particularly in humans, we’ve known that for a little while now, and water is a big
sort of vehicle conduit for all sorts of bugs.So, one of the things that kind of struck me
is that you are watching evolution happen, kind of like right underneath your nose,
(15:33):
as you're doing the sequencing, you get to see it kind of happen, like right there.
So how does understanding fundamental evolutionary processes, how does it help you with your work?
Yeah, it is really exciting. I mean, you can literally see evolution happened within the course
of a single infection, within a single patient.Big aspects of my research program currently is
(15:53):
looking at plasmids, actually, which are these vehicles that carry resistance genes. Quite often
they're the way in which resistance can move from one cell to another. So called horizontally rather
than vertically through the generations.And understanding the basics about plasmid
biology, how resistance plasmids seem to be compatible with some host cells but not so
(16:17):
compatible with others. There's differences in the compatibility of one plasmid and another,
in different host cells, there's all sorts of interactions going on, and this
can have direct applied consequences actually.So, if you imagine you're trying to control an
outbreak in a hospital. So traditionally you would look at the actual strain. So,
(16:37):
you say, oh this is patient Y has got strain X. So that strain X is spread on this ward, and we
can trace that outbreak. And quite often that's accurate, that's how things had happened. But
there's another possibility, which it isn't the strain that's spreading at all, it's the plasmid.
So, we can see plasmids move between strains in the gut of a single patient through, you know,
(16:58):
longitudinal sampling of a single patient. We can say, oh, that plasmids jump from, you know,
sometimes between species from a Klebsiella to an E coli, its exactly the same plasmid.
So, imagine that plasmid has resistance genes on, that's moving around between different
strains. So, the question becomes what is it we're supposed to be tracking? What is
it we're supposed to be controlling? It's not actually the strain itself, it's the plasmids.
(17:19):
So, we need to, sort of, re-engineer our whole sort of surveillance systems to actually target
specific plasmids. You know, they can hang around in sinks, they can hang around in environmental
bugs. So, we need probably a much better appreciation of the environment in general,
but the hospital environment, in particular plumbing, plumbing can be quite a major
(17:40):
source of stealthy, you know, bugs and resistance genes just hanging out for a long time, even when
there's not specific any problem in the hospital, they're there, sort of lurking in the sinks.
So, this knowledge, knowing all of this, does it then help in terms of finding new
ways to treat bacterial infections?Erm, yes. So, there's a couple of
(18:01):
alternatives. So, there’s big problem with the antibiotics pipeline, as you may know. So,
there's been very few genuinely new classes of antibiotics come to market for a long time
because it's so difficult to get them to market. And if a pharmaceutical company can, you know,
market a heart drug that people all have to take every day for the rest of their life. And, you
know, that's going to make a lot more money than spending ten years developing a new antibiotic.
(18:25):
But there are alternatives. So, there's a lot of work on using phage therapy, for example. This is
an idea that's been knocking around for decades, that you can use these phage, which are natural
viruses that infect bacteria. You can use those as therapeutic agents to actually treat bacteria. And
there's a lot of promising work being done there.Another possibility is actually the part of work
(18:46):
that I'm hoping to do in the future on fungi, is that we need a much better understanding
of the interactions that go on between different microbes in the gut, in the so-called microbiome.
There's really good evidence, for example, if we're thinking about fungal infections,
which are becoming more of a problem and they can be super resistant to all the antifungal drugs,
(19:08):
there's pretty good evidence, actually, the good bacteria, the commensal bacteria negator
on our skin can have a really strong protective effect against those fungi.
So, understanding those interactions and maybe looking to restore a healthy microbiome,
where a disturbance to the microbiome through use of antibiotics or someone
(19:29):
might be immunocompromised or whatever, everything kind of goes out of kilter. So, identifying those
commensal bacteria, the good guys that can help protect against fungal infections in particular,
I think is a really promising way forward.But in general, understanding the whole microbiome
and interactions is important for prevention of disease of all sorts. That's a nice way of
(19:52):
thinking about a possible way forward, I think.Ed thank you so much for talking with me.
This was a podcast by the Milner Centre for Evolution at the University of Bath.
I'm Turi King and thank you for listening. If you have any thoughts or comments on this
or any other episodes, please contact us via our X channel @MilnerCentre.
(20:13):
For more information about the Milner Centre for Evolution, you can visit our website.
Hello and welcome, you are listening to a podcast by the Milner Centre for Evolution, at the
University of Bath. I'm Professor Turi King, your host, and today I'm talking to Ed Feil, Professor
of Bacterial Evolution, about his research using genetics to understand the evolution and spread
of infectious bacteria of humans and animals, as well as antimicrobial resistance, which is a major
(00:24):
threat to global health and food security.So, Ed, before we get into your research
that you're doing now, how did you come to be interested in this field?
Was there something that triggered it?Well, like many evolutionary biologists,
I was originally inspired by some key books that I read in the sixth form, one being Selfish Gene
(00:44):
by Richard Dawkins that many people read. And then I kind of lucked out through my, sort of, student
days of getting to UCL, having to do genetics.I had Steve Jones as my mentor, and I lucked out
even more with my PhD at the University of Sussex, where I had two supervisors,
Prof. Brian Spratt and Prof. John Maynard Smith, who's very eminent evolutionary biologist.
(01:07):
And this project took me down the path of looking at what we would refer to as sex in bacteria. So,
bacteria don't have sex in terms of reproduction because they reproduce by binary fission,
but they do have sex in terms of moving genetic material from one individual to
another and recombining it in a single individual.So, this was what I was really interested in, and
(01:32):
the bug that I chose to work on was a bug called Neisseria gonorrhoeae, which causes gonorrhoea.
And we found that there was a lot of this, sort of, hankie panky going on in gonorrhoea genomes.
And now this is kind of accepted and mainstream that bacteria recombine and share genes all over
the place. It's one of the most intriguing aspects still about bacterial populations that they can
(01:55):
do this, and of course, it has relevance to antimicrobial resistance, but at the time
it was quite a big deal. There was still a lot of debate about how much this process happens.
So that was my PhD and subsequently in the last, I don't know, let's go back 15 years or so,
what's really been driving the nuts and bolts of what I do is the absolutely incredible advances
(02:17):
in the technology. So, you know, when I started my PhD, as I said, it would take
a year to sequence a single gene. Now we have undergraduate project students who are looking
at 20-30 complete genome sequences. You know, it would have been science fiction back in the day.
So, we have so many genome sequences now for all the really important pathogens. I mean,
(02:39):
literally tens of thousands of genome sequences for species like E. coli and Staph aureus, MRSA,
that we can really look infinitesimal detail at the micro evolutionary processes that are going
on over very short time spans. And of course, the evolution of antibiotic resistance is the sort of
stereotypical example of that sort of evolution. And it's the only sort of broad evolutionary
(03:05):
pattern that we've been really been able to observe in real time, as it's been happening,
up until Covid, which was a separate thing, because we could watch that thing evolve.
So, this is a big evolutionary change that we've been able to observe in real
time. And since the advent of all this genome sequence data, we can really pick apart exactly
the evolutionary mechanisms that’s going on.So, let's go back to this thing of bacterial sex.
(03:28):
Yeah.So, this is an interesting thing. So, you're
finding that genetic material is going from one bacterium into another bacteria, you're getting
recombination, for people who don't know what this is, what is this recombination that's going on?
Okay. So, let's go back to Neisseria gonorrhoeae. So, there are different
mechanisms by which bacterial sex can happen. Neisseria gonorrhoeae is kind of an unusual bug
(03:54):
in that it's what's called competent for transformation, constitutively competent.
So, all the while it's able to basically suck up DNA from other Neisseria gonorrhoeae cells.
Theres really clever mechanisms by which the cell can recognize DNA from its own species or related
species, and then the DNA can be incorporated into the genome of the recipient bacteria.
(04:19):
That's conceptually, I guess, the most simple sort of recombination. And this is the sort of
recombination that I was looking at in my PhD.There are other sorts of recombination which
involve phage. So, these viruses that infect bacteria can actually act as little vehicles
moving DNA around from one cell to another. And plasmids which are sort of extra chromosome,
(04:41):
little rings of DNA that sit in the cell and they can move from one cell to another. And
that's a kind of important way by which antibiotic resistance can move around.
But what we found in Neisseria was that actually transformation can bring about resistance as well.
We found these examples where a bug has acquired just a short stretch of DNA, like 500 bases,
(05:01):
from a resistant relative, and that had been incorporated into these so-called penicillin
binding proteins and that had caused resistance.It tells us something about the bacteria as well,
because in order to have access to DNA, there needs to be other different cells around in order
to acquire the DNA. So, it actually tells us a little bit something about gonorrhoea and the rate
(05:23):
of mixed infection. So, it tells us something about both the sex of the bacteria and the
sexual behaviour of the host as well. If there's mixed infections, then you're much more likely
to have this sort of recombination occurring.And that's really important because, we know,
so bacteria around us all of the time, and a lot of it doesn't do anything to us, but we do have
bacteria which is pathogenic, so it makes humans and animals ill. So, if you've got these bacteria
(05:48):
that are able to, kind of, suck up other little genes that then make them resistant to normal,
sort of, antibacterial things that we've got, or antibiotics or this kind of thing, then that's
really important to know about, I'm guessing.Absolutely, and we're still really understanding
how frequent this is. I mean, some bacteria do it much more commonly than others. But if you take an
(06:12):
environment like the human gut or the nasopharynx, which is where most Neisseria bacteria live,
it's a really crowded environment. So, they're all these bacteria that are living on mucosal surfaces
of the host, they're all sort of crowded together. And this is where you get all this sort of hanky
panky going on, of frequent gene exchange within hosts, within the guts, within our throat.
(06:33):
So, it's a very important mechanism. We can decipher the natural genetic variation from
bacteria that we are able to sample from people. But we can also do lots of quite
elegant experiments in the lab to understand the process and how frequently it happens.
So, what's the bacteria that you're working on now?
(06:53):
So right now, most of my time is spent on a bug called Klebsiella pneumoniae, which is kind of
related to E. coli, which most people would have heard of. So, it's an enteric bug, so it lives
in the gut. It's a very worrisome bug in terms of resistance. It's kind of shot to prominence
over the last, say 10-15 years, in terms of the resistance genes that it has acquired. So,
(07:17):
there aren't many antibiotics that one strain or other hasn't got resistance to at some point.
And it seems to act a little bit like flypaper, so it's really good at acquiring genes from
all over the place. And some of these resistance genes probably come from completely benign
environmental bacteria out there that people aren’t particularly bothered about, but it
(07:40):
lives out in the environment, is an ecological generalist. It lives in the guts of people,
but also lives in the guts of lots of animals. It can survive in soil and water, so it's got a lot
of opportunities for pulling in genes from all over the place. And it's causing a big problem
in hospitals all around the world, actually.So, what's the disease that it causes? So,
it's pathogenic, it's causing problems. What does it do to us?
(08:04):
So, it can cause a whole range of diseases actually, if it gets into the bloodstream,
it can cause classic sepsis, but it can also cause urinary tract infections.
If you're unlucky enough to contract a really virulent strain, then it can cause these really
nasty liver abscesses, which can be quite hard to treat and actually often fatal.
(08:25):
But up until a few years ago, we were quite reassured in a sense,
by the fact that there were distinct sets of strains in hospitals and outside of hospitals in
the community. So, the strains in hospitals tended to be the ones that were resistant to antibiotics,
but they weren't so virulent, they didn't cause these nasty liver abscesses that I talked about.
(08:45):
Then the strains outside of hospitals that are circling amongst healthy people,
they more commonly have picked up virulence genes, on a different plasmid,
which can lead to much more serious infection.What's been happening is strains have emerged
that have both the resistance plasmids and the variants plasmids. And in fact, what we found in
(09:08):
some of our data is that it's not just the case that a single strain can have the two plasmids,
it's actually slightly worse than that, that the plasmids themselves have recombined together,
so you've got a single plasmid that contains both virulence and resistance genes. And once that's
happened, then of course you can transfer, when that plasmid moves, you’re transferring
(09:29):
both virulence and resistance traits.So, this is a really worrying trend,
and it's causing a lot of problems in China and other parts of East Asia. But we are starting to
see some of these so-called convergent, virulent and resistant strains in Europe as well. So,
this is really something that we've got to keep it very carefully on.
So, Ed, I was reading about how the World Health Organization states that bacteria
(09:53):
that is resistant to antibiotics directly leads to over a million people dying each year globally
and contributes to the death of nearly 5 million more. So as more and more bacteria evolve
resistance, that number is only going to rise.So, it sounds like it's really hard to overstate
how big an issue this is, as it's going to make infections harder to treat. It's affecting animals
and plants and therefore agriculture. So, talk us through what's driving all of this?
(10:18):
Well, that's the million-dollar question in a sense. I mean, there's an obvious answer,
which is the overuse of antibiotics, which is certainly part of the problem. It's not just
the use in medicine, although in some parts of the world that needs to be seriously tightened up and
regulated, it's also the use in agriculture.So actually, part of my research agenda is
(10:41):
understanding how much of a risk those sort of environmental uses of antibiotics
pose to public health, how much sort of crosstalk there is between what's
going on in the environment and the clinic.I should say as well that the problem with
antibiotic resistance isn't just about treating infections, that's bad enough, but it's also in
the prophylactic use of antibiotics for all sorts of medical interventions. So, transplant surgery,
(11:05):
you know, you can't do without having antibiotics prophylactically to prevent infection. So,
there's a lot of procedures that would basically become impossible without them.
Of course, there's a lot more global movement than has been in the past. So,
resistance strains can move around the world very quickly. The way that we deal
(11:26):
with infection control in hospitals probably has a role in how much resistance can spread
within the clinical settings. We need more isolation wards, we need to be much better
at spotting outbreaks caused by resistant bacteria, sort of, early doors before the
genie gets out of the bottle, basically.So, there's multiple factors. There's
(11:48):
also social factors that we can sort of feed into about awareness of what antibiotic resistance is,
sort of basic facts about how antibiotics don't work for viruses, for example, they're only going
to work for bacteria. Basic levels of knowledge that mean that many people think that it’s them
that get resistant to antibiotics rather than the bacteria. So, this isn't obviously the case
(12:10):
either. So that does need to be sort of a raising of public awareness generally.
So how is your research coming to bear on all of this?
So, a couple of big projects that I've recently completed look specifically
at this question of how resistance bacteria and resistance genes, because remember, genes
themselves can move around by recombination kind of independent of the bugs themselves, so it's
(12:33):
kind of a complicated situation.So, it's understanding how resistant bacteria,
resistance genes can move around complex landscapes like farms and how the water cycle,
for example, because we know there's lots of resistant bacteria in wastewater, most of which
hopefully will get captured by wastewater treatment processes, but some will go into
(12:57):
the rivers and waterways and what happens then to the fate of those antibiotic-resistant bacteria.
Do they sort of fizzle out and get diluted out, or can they survive and maybe pass their genes on to
other bacteria? And, you know, so it's trying to unpick all these dynamics of transmission
within environmental settings, and how much of all that is feeding into the clinical problem.
(13:17):
And this all falls under an umbrella called one health, one health concept, which is a sort of
overarching framework which recognizes that, if we were just trying to deal with antibiotic
resistance by better stewardship of antibiotics in hospitals, better infection control in hospitals,
but at the same time, we're getting this constant influx from the environment,
(13:39):
then it's really sort of like trying to mop the floor with the tap wide open, you know,
so we need this whole interconnectivity of what's going on in humans, what's going on in the animals
and what's going on in the environment and how all those things are connected. So that's essentially
the big picture of what I'm trying to do.So how are you doing that?
(13:59):
Well, I'm using genomics mostly. We're now at the point where we can generate whole genome sequences
for thousands of genomes. So, we recently carried out this project in and around one
town in northern Italy called Pavia, which is a bit like an Italian Bath. It's about an hour south
of Milan. It's a similar sort of size population, big student town, lots of dairy. And we
(14:22):
essentially focused on this Klebsiella bacteria.It's a hotspot for resistance in the hospital,
as quite a lot of southern Europe is, but Italy in particular has a big problem with resistance and
Klebsiella. So, we took lots of strains from the hospitals, and we took strains from the
healthy people in the community. We took strains from the farms, there's lots of dairy farms,
(14:44):
this is where Gorgonzola comes from. And we took from the rivers, from the soil, from the plants,
from the food. And we were just trying to look at the amount of overlap from
the genome sequences to try and understand how much these different bacteria are moving around.
And the good news is, that if you were to ask the question, where does someone catch
their Klebsiella from? Then most of the time it's from another person rather than
(15:08):
from the environment or from an animal. It's different if you're working very closely with
animals. The exceptions are companion animals, so there is quite a lot of overlap between dogs,
particularly in humans, we’ve known that for a little while now, and water is a big
sort of vehicle conduit for all sorts of bugs.So, one of the things that kind of struck me
is that you are watching evolution happen, kind of like right underneath your nose,
(15:33):
as you're doing the sequencing, you get to see it kind of happen, like right there.
So how does understanding fundamental evolutionary processes, how does it help you with your work?
Yeah, it is really exciting. I mean, you can literally see evolution happened within the course
of a single infection, within a single patient.Big aspects of my research program currently is
(15:53):
looking at plasmids, actually, which are these vehicles that carry resistance genes. Quite often
they're the way in which resistance can move from one cell to another. So called horizontally rather
than vertically through the generations.And understanding the basics about plasmid
biology, how resistance plasmids seem to be compatible with some host cells but not so
(16:17):
compatible with others. There's differences in the compatibility of one plasmid and another,
in different host cells, there's all sorts of interactions going on, and this
can have direct applied consequences actually.So, if you imagine you're trying to control an
outbreak in a hospital. So traditionally you would look at the actual strain. So,
(16:37):
you say, oh this is patient Y has got strain X. So that strain X is spread on this ward, and we
can trace that outbreak. And quite often that's accurate, that's how things had happened. But
there's another possibility, which it isn't the strain that's spreading at all, it's the plasmid.
So, we can see plasmids move between strains in the gut of a single patient through, you know,
(16:58):
longitudinal sampling of a single patient. We can say, oh, that plasmids jump from, you know,
sometimes between species from a Klebsiella to an E coli, its exactly the same plasmid.
So, imagine that plasmid has resistance genes on, that's moving around between different
strains. So, the question becomes what is it we're supposed to be tracking? What is
it we're supposed to be controlling? It's not actually the strain itself, it's the plasmids.
(17:19):
So, we need to, sort of, re-engineer our whole sort of surveillance systems to actually target
specific plasmids. You know, they can hang around in sinks, they can hang around in environmental
bugs. So, we need probably a much better appreciation of the environment in general,
but the hospital environment, in particular plumbing, plumbing can be quite a major
(17:40):
source of stealthy, you know, bugs and resistance genes just hanging out for a long time, even when
there's not specific any problem in the hospital, they're there, sort of lurking in the sinks.
So, this knowledge, knowing all of this, does it then help in terms of finding new
ways to treat bacterial infections?Erm, yes. So, there's a couple of
(18:01):
alternatives. So, there’s big problem with the antibiotics pipeline, as you may know. So,
there's been very few genuinely new classes of antibiotics come to market for a long time
because it's so difficult to get them to market. And if a pharmaceutical company can, you know,
market a heart drug that people all have to take every day for the rest of their life. And, you
know, that's going to make a lot more money than spending ten years developing a new antibiotic.
(18:25):
But there are alternatives. So, there's a lot of work on using phage therapy, for example. This is
an idea that's been knocking around for decades, that you can use these phage, which are natural
viruses that infect bacteria. You can use those as therapeutic agents to actually treat bacteria. And
there's a lot of promising work being done there.Another possibility is actually the part of work
(18:46):
that I'm hoping to do in the future on fungi, is that we need a much better understanding
of the interactions that go on between different microbes in the gut, in the so-called microbiome.
There's really good evidence, for example, if we're thinking about fungal infections,
which are becoming more of a problem and they can be super resistant to all the antifungal drugs,
(19:08):
there's pretty good evidence, actually, the good bacteria, the commensal bacteria negator
on our skin can have a really strong protective effect against those fungi.
So, understanding those interactions and maybe looking to restore a healthy microbiome,
where a disturbance to the microbiome through use of antibiotics or someone
(19:29):
might be immunocompromised or whatever, everything kind of goes out of kilter. So, identifying those
commensal bacteria, the good guys that can help protect against fungal infections in particular,
I think is a really promising way forward.But in general, understanding the whole microbiome
and interactions is important for prevention of disease of all sorts. That's a nice way of
(19:52):
thinking about a possible way forward, I think.Ed thank you so much for talking with me.
This was a podcast by the Milner Centre for Evolution at the University of Bath.
I'm Turi King and thank you for listening. If you have any thoughts or comments on this
or any other episodes, please contact us via our X channel @MilnerCentre.
(20:13):
For more information about the Milner Centre for Evolution, you can visit our website.
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