The Director of the Milner Centre for Evolution, Professor Turi King, talks to Associate Professor Stephanie Lo about her research into Pneumococcal diseases, the formulation of more effective vaccines and the impact those vaccines can have on reducing our reliance on antibiotics.
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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 Stephanie Lo,
senior lecturer at the Milner Centre for Evolution. Stephanie has been conducting
groundbreaking research into the bacteria which causes pneumococcal diseases such
(00:23):
as septicaemia, meningitis, and pneumonia.Pneumococcal diseases are some of the biggest
killers of children in low- and middle-income countries, and Stephanie is using that knowledge
to help develop better vaccines to protect against disease. But first, Stephanie,
tell me about how you came to be in this field, you started your academic career in Hong Kong?
(00:47):
Actually, I grew up in Macao. None of my parents went to university, and I'm the
first family member went to university.In the university it's eye opening. I'm
curious about everything, I ask a lot of questions, and I particularly like
microbiology, and it's also my forte. So, after my undergraduate study, I pursue a PhD in medical
(01:09):
microbiology in the University of Hong Kong.So, what were you looking at for your PhD?
So, in my PhD, I look at antimicrobial resistance spread between humans and animals. And one of the
hypotheses is that the antimicrobial resistance is coming from the food animals. So, something
that we eat that contains antimicrobial resistant bacteria can go into our gut.
(01:34):
So, tell me about antimicrobial resistance. What is it for people who don't know?
So antibiotic is a very important discovery that allows us to cure bacterial infections. However,
over time, the bacteria can mutate or acquire genes that can convert resistant
to the antibiotics. And if it becomes resistant, which means the antibiotic
(01:59):
treatment will not be effective in human.So, this is actually really important,
it’s something which is becoming a really big issue now isn't it?
YesAntimicrobial resistance. So, what were you
looking at for your PhD then. You're looking at this transfer between, sort of, animals and humans
in terms of bacterial resistance to antibiotics?So, in the beginning we thought that it might
(02:22):
be some E. coli strains or other bacteria strains that transmit from food animals to
humans or vice versa. But when we look at the DNA fingerprint of the bacteria, we found that it's
not that easy because the DNA fingerprints are different between human and animal.
And then we started to look at the antimicrobial resistance genes that are in common and found
(02:47):
that actually it's not the bacterial strains that are in common between humans and animals,
but just a part of the DNA called plasmid, that is shared between humans and animals.
So, tell me, so what are plasmids?So, plasmid is living in the bacterial cell,
but it is independent in the chromosome. So, they can replicate itself, and the plasmid can also do
(03:12):
horizontal gene transfer. What does it mean is that the plasmid can go from one bacterial host
to another bacterial host, and therefore the DNA fingerprint is different when we first look into
the bacterial strains between humans and animals.So that's really interesting. So, it's not
a particular bacterial strain that you're worried about, it's the fact that there's
(03:34):
these like little genes that confer resistance to antibiotics, and it can move between bacteria.
So how do you go about examining that? How do you look at how these genes are moving
across? Are you sequencing, kind of, plasmids in all these different types of bacteria and
(03:54):
looking for bits that are in common?Yes, that's actually one of the first
turning points in my career. So, at that time there’s an emerging technology called Next
Generation Sequencing, that can sequence a large number of bacterial sequences at low cost. So,
I was the first one in the department to use this technology to sequence a bunch of bacterial
(04:18):
strains carrying that plasmid. And it helped us to understand that plasmids are not just prevalent in
Hong Kong, but also in Southeast Asia region.Wow. Okay. So that must have been quite a
step change because as soon as you get Next Generation Sequencing, you can do sequencing
of lots of different things.So, you're looking at fruit,
you're looking at animals, you're looking at humans in Southeast Asia. Are you going
(04:41):
any kind of wider than that, or was that your PhD? It was kind of like that sort of area.
Yeah. So, this PhD study equipped me with the expertise in bioinformatics, and I think this Next
Generation Sequencing creates such a large dataset that will eventually benefit the global health.
So, after that, I started to look at opportunities that I can expand my
(05:04):
research. And I found that there was a global pneumococcal sequencing project established
by Professor Stephen Bentley, in Cambridge, at the Sanger Institute. And I applied for the job,
and I'm very lucky that I got it and got into this global pneumococcal sequencing project.
Its abbreviation is called GPS project. It’s not a navigation system, but more
(05:25):
like a navigation for us to use whole genome sequencing to guide us to better global health.
So, you have been involved with and have actually led the global pneumococcal
sequencing project. Now that's funded by the Bill and Melinda Gates Foundation. And
it's at the super prestigious Wellcome Sanger Institute. What's the goal of that project?
(05:51):
Okay. This project started in 2011 when Next Generation Sequencing could be used
to sequence bacterial genomes. At that time, we don't know if it has any implications to guide
vaccine or we can generate any solutions to global health issues. It is a proof-of-concept project.
(06:12):
So, in the beginning, we aim to sequence 20,000 pneumococcal genomes and see how it
can inform the impact of the vaccine on the pneumococcal population.
So, one of the aims is to understand how the pneumococcal population can evolve to evade
the vaccine. And ten years later, we finally have some answers. We found that some strains
(06:36):
are more prone to evade the vaccine, and those are very problematic because they undergo more
horizontal gene transfer, which means that they can acquire a diversity of vaccine antigens and
also antimicrobial resistance. So, it makes them very difficult to prevent and difficult to treat.
And because of some of the findings in our project, we successfully
(07:00):
guided the next generation pneumococcal conjugate vaccine by including a very invasive serotype into
the vaccine formulation.So, what's pneumococcal
bacteria and why are we worried about it?Yeah, it has been with us for centuries.
So pneumococcal bacteria is one of the major bacterial killers for young children, especially
(07:22):
in low- and middle-income countries. With the help of Gavi, pneumococcal conjugate vaccine
started to introduce in more and more countries, especially in low- and middle-income countries.
So, the GPS project is focused on generating data to understand the impact of the pneumococcal
conjugate vaccine in low- and middle-income countries. So this was basically a question
(07:45):
around, you don't know what these various pneumococcal bacteria genomes look like,
but if you can sequence loads of them from around the world, you can look for differences,
and that can basically help you in terms of designing new vaccines.
Yes. With the GPS project, this is our first time to understand the genetic diversity of just
(08:07):
a single bacterial species. And we found that there's a vast diversity of these species, and
it is so vast that we can delineate into almost a thousand different lineages across the world.
And not all of the lineages can evade the vaccine. And we found that some of the
lineages are really old and wise and well prepared, that they can express a lot of
(08:33):
different vaccine antigens. And in that case, if you whack some of them and the other can emerge
and expand after the vaccine introduction.So let's talk about how vaccines work then.
So normally what a vaccine is doing is it gives somebody a little tiny bit of the
(08:54):
bacterial sequence, something that's not going to make them, sort of, really ill, but enough
so that the body goes right, that is what this bacteria looks like. And next time I see this,
I want my immune system to attack it. But what you're really interested in is how are the
bacteria evolving, which means that the sequence changes, so you have to change that vaccine. And
(09:17):
that's sort of what you're looking at isn't it?So, the pneumococcal conjugate vaccine is
targeting the codes around the pneumococcal cell. It is actually basically a polysaccharide capsule,
so it's some sugar. So, the vaccine targets those sugar sequences,
however the sugar sequences could be very diverse, and if you use a set of antisera to profile them,
(09:42):
they can be type into different serotypes.So presumably it's useful to know what the
different serotypes are so that you can help develop,
is it slightly different vaccines for each one?So, we know the serotypes for 80 years now,
and we know that some of the serotypes can cause more disease. So, the pneumococcal
(10:03):
conjugate vaccine is based on this information to include different serotypes into the vaccine.
So, for now it's up to 25 serotypes could be conjugate in the vaccine. However, in the entire
species there are known 105 different serotypes, and I think there will be many more. So that's
(10:25):
impossible for us to put all the serotypes into one vaccine, so we have to think smart
and the GPS project allows us to, not just use the antisera to type the pneumococcal strains,
we could also use the DNA fingerprint to type them into different lineages. And we found
that some of the lineages, they could express a lot of different serotypes, which means they
(10:50):
are a moving target for our current vaccine.So, we are thinking that in my future research,
I'm really prompted to understand if there is any other target, for example, conserved
surface protein in those super lineages that can express multiple serotypes, could be a target.
In that case, we will have due target in the vaccine to fight this evolutionary arms race.
(11:16):
So, you've said it just there, it's like being in an arms race, because you have a vaccine that
works, and then the bacteria evolves and you're looking for other ways to attack it as well. So,
does it feel like you're in this constant race as you're doing this?
Yeah, absolutely. So now the pneumococcal conjugate vaccine has been introduced in
many countries. And for example, in the UK, we found that 3 to 4 years after being used,
(11:42):
a vaccine, we have reached the maximum benefit of the vaccine. The pneumococcal disease
become plateaued and no longer further reduced. And if we don't do anything,
the strains not targeted by the vaccine will start to increase and it will compromise the benefit.
So, my future research really wants to focus on if we can develop a vaccine that is to have
(12:07):
a due target. In that case, we can extend the cycle of renewal of the vaccine formulation.
So, Stephanie, you now run your own group here at the Milner Centre for Evolution,
which looks to improve vaccine design and reduce antimicrobial resistance. So,
talk me through what you're working on now.So, I'm working on improving the vaccine design
(12:29):
so it will extend the cycle of the renewal of the vaccine formulation. But in my current research,
we also found that the use of vaccine can reduce antimicrobial resistance. And the way to reduce
it is because when you deploy the vaccine in the country, it will reduce the infectious
disease. So therefore, you will reduce the use of antibiotics. So less antibiotic selective
(12:54):
pressure means less antibiotic resistance.So, what's the ultimate goal of your research.
So I always kind of think what would it be if you get to retirement and you look back
on your career, what would you feel most proud of if you could say, I did that,
what would you like to do by the time you retire?So, my research goal is always thinking about
(13:17):
reduced child deaths across the globe. But one thing I think is very effective is
developing a vaccine against infectious disease, especially in low- and middle-income countries.
And the other thing that I'm working on is to empower low- and middle-income country
researchers to build up their national surveillance systems. So that they can
(13:38):
better understand the disease burden in their country and what preventative measures should
be implemented to reduce infectious disease cases.Stephanie, 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
(14:02):
or any other episodes, please contact us via our X channel @MilnerCentre.
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 Stephanie Lo,
senior lecturer at the Milner Centre for Evolution. Stephanie has been conducting
groundbreaking research into the bacteria which causes pneumococcal diseases such
(00:23):
as septicaemia, meningitis, and pneumonia.Pneumococcal diseases are some of the biggest
killers of children in low- and middle-income countries, and Stephanie is using that knowledge
to help develop better vaccines to protect against disease. But first, Stephanie,
tell me about how you came to be in this field, you started your academic career in Hong Kong?
(00:47):
Actually, I grew up in Macao. None of my parents went to university, and I'm the
first family member went to university.In the university it's eye opening. I'm
curious about everything, I ask a lot of questions, and I particularly like
microbiology, and it's also my forte. So, after my undergraduate study, I pursue a PhD in medical
(01:09):
microbiology in the University of Hong Kong.So, what were you looking at for your PhD?
So, in my PhD, I look at antimicrobial resistance spread between humans and animals. And one of the
hypotheses is that the antimicrobial resistance is coming from the food animals. So, something
that we eat that contains antimicrobial resistant bacteria can go into our gut.
(01:34):
So, tell me about antimicrobial resistance. What is it for people who don't know?
So antibiotic is a very important discovery that allows us to cure bacterial infections. However,
over time, the bacteria can mutate or acquire genes that can convert resistant
to the antibiotics. And if it becomes resistant, which means the antibiotic
(01:59):
treatment will not be effective in human.So, this is actually really important,
it’s something which is becoming a really big issue now isn't it?
YesAntimicrobial resistance. So, what were you
looking at for your PhD then. You're looking at this transfer between, sort of, animals and humans
in terms of bacterial resistance to antibiotics?So, in the beginning we thought that it might
(02:22):
be some E. coli strains or other bacteria strains that transmit from food animals to
humans or vice versa. But when we look at the DNA fingerprint of the bacteria, we found that it's
not that easy because the DNA fingerprints are different between human and animal.
And then we started to look at the antimicrobial resistance genes that are in common and found
(02:47):
that actually it's not the bacterial strains that are in common between humans and animals,
but just a part of the DNA called plasmid, that is shared between humans and animals.
So, tell me, so what are plasmids?So, plasmid is living in the bacterial cell,
but it is independent in the chromosome. So, they can replicate itself, and the plasmid can also do
(03:12):
horizontal gene transfer. What does it mean is that the plasmid can go from one bacterial host
to another bacterial host, and therefore the DNA fingerprint is different when we first look into
the bacterial strains between humans and animals.So that's really interesting. So, it's not
a particular bacterial strain that you're worried about, it's the fact that there's
(03:34):
these like little genes that confer resistance to antibiotics, and it can move between bacteria.
So how do you go about examining that? How do you look at how these genes are moving
across? Are you sequencing, kind of, plasmids in all these different types of bacteria and
(03:54):
looking for bits that are in common?Yes, that's actually one of the first
turning points in my career. So, at that time there’s an emerging technology called Next
Generation Sequencing, that can sequence a large number of bacterial sequences at low cost. So,
I was the first one in the department to use this technology to sequence a bunch of bacterial
(04:18):
strains carrying that plasmid. And it helped us to understand that plasmids are not just prevalent in
Hong Kong, but also in Southeast Asia region.Wow. Okay. So that must have been quite a
step change because as soon as you get Next Generation Sequencing, you can do sequencing
of lots of different things.So, you're looking at fruit,
you're looking at animals, you're looking at humans in Southeast Asia. Are you going
(04:41):
any kind of wider than that, or was that your PhD? It was kind of like that sort of area.
Yeah. So, this PhD study equipped me with the expertise in bioinformatics, and I think this Next
Generation Sequencing creates such a large dataset that will eventually benefit the global health.
So, after that, I started to look at opportunities that I can expand my
(05:04):
research. And I found that there was a global pneumococcal sequencing project established
by Professor Stephen Bentley, in Cambridge, at the Sanger Institute. And I applied for the job,
and I'm very lucky that I got it and got into this global pneumococcal sequencing project.
Its abbreviation is called GPS project. It’s not a navigation system, but more
(05:25):
like a navigation for us to use whole genome sequencing to guide us to better global health.
So, you have been involved with and have actually led the global pneumococcal
sequencing project. Now that's funded by the Bill and Melinda Gates Foundation. And
it's at the super prestigious Wellcome Sanger Institute. What's the goal of that project?
(05:51):
Okay. This project started in 2011 when Next Generation Sequencing could be used
to sequence bacterial genomes. At that time, we don't know if it has any implications to guide
vaccine or we can generate any solutions to global health issues. It is a proof-of-concept project.
(06:12):
So, in the beginning, we aim to sequence 20,000 pneumococcal genomes and see how it
can inform the impact of the vaccine on the pneumococcal population.
So, one of the aims is to understand how the pneumococcal population can evolve to evade
the vaccine. And ten years later, we finally have some answers. We found that some strains
(06:36):
are more prone to evade the vaccine, and those are very problematic because they undergo more
horizontal gene transfer, which means that they can acquire a diversity of vaccine antigens and
also antimicrobial resistance. So, it makes them very difficult to prevent and difficult to treat.
And because of some of the findings in our project, we successfully
(07:00):
guided the next generation pneumococcal conjugate vaccine by including a very invasive serotype into
the vaccine formulation.So, what's pneumococcal
bacteria and why are we worried about it?Yeah, it has been with us for centuries.
So pneumococcal bacteria is one of the major bacterial killers for young children, especially
(07:22):
in low- and middle-income countries. With the help of Gavi, pneumococcal conjugate vaccine
started to introduce in more and more countries, especially in low- and middle-income countries.
So, the GPS project is focused on generating data to understand the impact of the pneumococcal
conjugate vaccine in low- and middle-income countries. So this was basically a question
(07:45):
around, you don't know what these various pneumococcal bacteria genomes look like,
but if you can sequence loads of them from around the world, you can look for differences,
and that can basically help you in terms of designing new vaccines.
Yes. With the GPS project, this is our first time to understand the genetic diversity of just
(08:07):
a single bacterial species. And we found that there's a vast diversity of these species, and
it is so vast that we can delineate into almost a thousand different lineages across the world.
And not all of the lineages can evade the vaccine. And we found that some of the
lineages are really old and wise and well prepared, that they can express a lot of
(08:33):
different vaccine antigens. And in that case, if you whack some of them and the other can emerge
and expand after the vaccine introduction.So let's talk about how vaccines work then.
So normally what a vaccine is doing is it gives somebody a little tiny bit of the
(08:54):
bacterial sequence, something that's not going to make them, sort of, really ill, but enough
so that the body goes right, that is what this bacteria looks like. And next time I see this,
I want my immune system to attack it. But what you're really interested in is how are the
bacteria evolving, which means that the sequence changes, so you have to change that vaccine. And
(09:17):
that's sort of what you're looking at isn't it?So, the pneumococcal conjugate vaccine is
targeting the codes around the pneumococcal cell. It is actually basically a polysaccharide capsule,
so it's some sugar. So, the vaccine targets those sugar sequences,
however the sugar sequences could be very diverse, and if you use a set of antisera to profile them,
(09:42):
they can be type into different serotypes.So presumably it's useful to know what the
different serotypes are so that you can help develop,
is it slightly different vaccines for each one?So, we know the serotypes for 80 years now,
and we know that some of the serotypes can cause more disease. So, the pneumococcal
(10:03):
conjugate vaccine is based on this information to include different serotypes into the vaccine.
So, for now it's up to 25 serotypes could be conjugate in the vaccine. However, in the entire
species there are known 105 different serotypes, and I think there will be many more. So that's
(10:25):
impossible for us to put all the serotypes into one vaccine, so we have to think smart
and the GPS project allows us to, not just use the antisera to type the pneumococcal strains,
we could also use the DNA fingerprint to type them into different lineages. And we found
that some of the lineages, they could express a lot of different serotypes, which means they
(10:50):
are a moving target for our current vaccine.So, we are thinking that in my future research,
I'm really prompted to understand if there is any other target, for example, conserved
surface protein in those super lineages that can express multiple serotypes, could be a target.
In that case, we will have due target in the vaccine to fight this evolutionary arms race.
(11:16):
So, you've said it just there, it's like being in an arms race, because you have a vaccine that
works, and then the bacteria evolves and you're looking for other ways to attack it as well. So,
does it feel like you're in this constant race as you're doing this?
Yeah, absolutely. So now the pneumococcal conjugate vaccine has been introduced in
many countries. And for example, in the UK, we found that 3 to 4 years after being used,
(11:42):
a vaccine, we have reached the maximum benefit of the vaccine. The pneumococcal disease
become plateaued and no longer further reduced. And if we don't do anything,
the strains not targeted by the vaccine will start to increase and it will compromise the benefit.
So, my future research really wants to focus on if we can develop a vaccine that is to have
(12:07):
a due target. In that case, we can extend the cycle of renewal of the vaccine formulation.
So, Stephanie, you now run your own group here at the Milner Centre for Evolution,
which looks to improve vaccine design and reduce antimicrobial resistance. So,
talk me through what you're working on now.So, I'm working on improving the vaccine design
(12:29):
so it will extend the cycle of the renewal of the vaccine formulation. But in my current research,
we also found that the use of vaccine can reduce antimicrobial resistance. And the way to reduce
it is because when you deploy the vaccine in the country, it will reduce the infectious
disease. So therefore, you will reduce the use of antibiotics. So less antibiotic selective
(12:54):
pressure means less antibiotic resistance.So, what's the ultimate goal of your research.
So I always kind of think what would it be if you get to retirement and you look back
on your career, what would you feel most proud of if you could say, I did that,
what would you like to do by the time you retire?So, my research goal is always thinking about
(13:17):
reduced child deaths across the globe. But one thing I think is very effective is
developing a vaccine against infectious disease, especially in low- and middle-income countries.
And the other thing that I'm working on is to empower low- and middle-income country
researchers to build up their national surveillance systems. So that they can
(13:38):
better understand the disease burden in their country and what preventative measures should
be implemented to reduce infectious disease cases.Stephanie, 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
(14:02):
or any other episodes, please contact us via our X channel @MilnerCentre.
For more information about the Milner Centre for Evolution, you can visit our website.
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