September 9, 2024 • 21 mins
Our gastrointestinal system contains more than 70% of the body’s immune cells and can house more microbial cells than there are human cells in our entire body. Unravelling all that complexity is more important than ever, with conditions affecting the gut, such as Crohn’s and ulcerative colitis, on the rise. In today’s episode, we speak to Dr Kylie James who is taking a genetic deep dive – using single cell genomics – to develop more personalised approaches to preventing and treating inflammatory bowel disease.
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Episode Transcript
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Dr Viviane Richter (00:01):
It's often underappreciated, but our gastrointestinal system is fascinating. It
has its own brain. It can house more microbial cells
than there are human cells in our entire body. And
did you know that more than 70% of the body's
immune cells are found in our gut? Unravelling all that
complexity is more important than ever, with conditions affecting the gut,
(00:24):
such as Crohn's and ulcerative colitis on the rise. In
today's episode, we speak to a researcher who is taking
a genetic deep dive, using single-cell genomics to develop more
personalised approaches to preventing and treating inflammatory bowel disease. You're
listening to Medical Minds. The podcast that takes you inside
(00:45):
the labs at the Garvan Institute of Medical Research. I'm
your host, Dr Viviane Richter. And with me here is Dr Kylie James,
leader of the Gut Immunogenomics Group at Garvan. Welcome, Kylie.
Dr Kylie James (00:59):
Hi, Viv. Thank you. It's so good to be here.
Dr Viviane Richter (01:01):
Kylie, let's talk about the gut, which happens to be
one of my favourite topics.
What do we know about the gut and how it works?
Dr Kylie James (01:09):
Well, Viv, what we know about the gut has changed
a lot over the course of centuries. We used to
recognise that it was an organ that was involved in
digestion and absorption of nutrients. But actually, now we recognise
it's much more complicated than that and has many roles
in our health. So some cool facts about what we've
learned about the gut is we actually recognise that it
(01:32):
had a microbiome all the way back in the 1680s,
there was a researcher called Antonie van Leeuwenhoek, who looked at his
own stool under a microscope and saw that there were
little creatures in it, which he called animalcules, which is
Latin for 'little animals'. And then fast forward to the 1900s,
a researcher called Metchnikoff, who is actually regarded as the
(01:54):
grandfather of innate immunity. He was the first person to
propose this idea that the bacteria in our gut, some
of them could actually be good and beneficial for our health.
And it was a balance between the good and the
bad bacteria that could determine whether we have disease. And
then we come forward even more recently to the 1980s,
when two Australian researchers called Marshall and Warren, they actually
(02:19):
were the first to show that stomach ulcers were not
the product of stress and anxiety and spicy food, which
was the common knowledge even in the 1980s, but were actually
the product of a H pylori infection, a bacterial infection.
And actually the way that Barry Marshall showed this was
by drinking a culture of bacteria and then showing that
(02:41):
he got stomach ulcers, which was crazy. That was just
in the 1980s. But really, what has driven our appreciation
of the complexity of the gut even further is the
invention of sequencing technologies. So about in the early 2000s,
we have now been able to take a biopsy, a
piece of the gut and determine all the different bacteria
(03:05):
in that gut tissue and at the same time, all
the different cell types in that tissue and look at
how they are associated with each other. So from even
40 years ago having to drink bacteria to show the
role of bacteria -
Dr Viviane Richter (03:20):
That wouldn't be allowed anymore these days!
Dr Kylie James (03:22):
No! To now being able to catalogue all the different types
of bacteria cells in the gut. We've really come a
long way, and it's an exciting time to be a
researcher in gut biology.
Dr Viviane Richter (03:32):
Kylie there's no doubt that we have a much greater
awareness now of what's happening in the gut. But why
are diseases affecting the gut on the rise?
Dr Kylie James (03:43):
These diseases, which covers inflammatory bowel disease and also irritable
bowel syndrome and a whole range of other conditions, are
increasing in Australia and actually there's 100,000 Australians currently living
with IBD. Why are they increasing? Well? There's a whole
range of risk factors that affects someone's likelihood of getting
(04:05):
these diseases. And some of the environmental factors include the
changes in our diet in developed countries. So, for instance,
we are now eating more processed red meats, more saturated fats,
and we also have much lower intake of complex carbohydrates
and fresh fruit and vegetables. And these are really important
for fostering a healthy gut and a healthy microbiome. Other
(04:29):
environmental factors include additives to our foods like emulsifiers, which
happen to be in, like so many processed foods and
also exposure to pesticides and chemicals which also affect our microbiome.
An important point here, though, is although we might live
in the same environment, it doesn't mean we have the
(04:51):
same risk of developing IBD because another major factor is
in our genes. We all have small variabilities in our
genetic code that make us unique. But they also change
our susceptibility to developing diseases, including inflammatory bowel disease. What
we are really trying to understand is in people who
(05:13):
have these risk factors, how that impacts their cells and
their microbiome to go on and develop inflammatory bowel disease.
Dr Viviane Richter (05:20):
And that's obviously your specific area of research. I understand
you're looking at the individual cells within the gut. Can
you take us there what is actually happening in the
gut at that level of the individual cell?
Dr Kylie James (05:36):
Yes, Viv, If I can paint a picture of the gut,
it would have these great kind of protrusions, which are called villi.
And lining those villi are these little cuboidal-shaped cells called epithelial cells.
And those epithelial cells are the cells that are tasked
with absorbing nutrients, and some of them also secrete mucus,
so it forms this nice, cushy layer on the surface
(05:58):
of the gut, which kind of also forms a barrier
for the microbiome. But other epithelial cells are also involved in
sensing the environment, sensing things that signals that come through
the gut and feeding this through to the enteric nervous
system and then underneath that epithelial layer you have even
more different types of cells, including our immune cells. And
(06:18):
so some of those cells are tasked with defending against
potentially pathogenic microbes. And then another side of the immune
system is tasked with dampening down that response, so providing
tolerance to kind of make it a nice symbiotic environment.
And then there are cells that are involved in or
(06:38):
create the vessels, the blood vessels and the lymph vessels,
and they're called endothelial cells. There are also structural cells
called stromal cells that have many other roles as well.
So I'm oversimplifying this. The list just goes on. And actually,
in some of my earlier work, we catalogued the different
types of cells, and there was 133 different cell types
(06:59):
and states that we found in the gut. And actually,
one thing that's interesting is that they change depending on
their environment. So we've actually seen that even within the colon.
So this is the large bowel. We've seen differences in
the response of immune cells from the left side of
the colon versus the right side of the colon. And
(07:19):
this is dependent on changing microbiome because they're interacting with
the microbiome all the time and we we can see
that the microbiome actually changes across the length of the
gut as well. And and that's kind of, I guess,
to be expected, because the microbiome is eating our food
and and responding to the levels of oxygen and water
in in our gut. And of course, that changes from
(07:42):
from the top of the gut to the lower gut
as well, so we can see the whole way along
the gut. All these features are changing, and I think
that's that's really interesting. And that's something that we're trying
to understand, particularly in the context of disease.
Dr Viviane Richter (07:56):
Sounds like a really complex environment to study. And your
focus is specifically on immune cells.
Dr Kylie James (08:04):
Yes, so we have a particular interest in immune cells
because they have quite an important role to play in
diseases such as inflammatory bowel disease. So they are a
key cell in driving inflammation, but actually we analyse all
the different cells. So one of the technologies that we
use is called single-cell RNA sequencing, and this is a
(08:26):
technology that allows us to be quite unbiased in our
approach to analysing cells. So it means from one biopsy from a patient,
for instance, we can then release all the cells from
that and analyse all of them at the same time.
So we don't have to be picky about which cell
we analyse, but we can look at them all, and
we can see how they're all interacting. And they're all
(08:48):
contributing to that disease.
Dr Viviane Richter (08:50):
Kylie, what has your research shown you?
Dr Kylie James (08:53):
Well, inflammatory bowel disease is actually a spectrum of disorders,
and there's a great degree of variability in terms of
a patient's experience of inflammatory bowel disease, but also their
response to treatments. So without understanding the basis of this variability,
there's a lot of guesswork in terms of the clinical treatments.
So the moment a patient might come in and they
(09:15):
might be bounced between drug classes until one is found
that works for them, and all this time they are
experiencing quite debilitating symptoms. So what my research is trying
to do is to understand how the cells and the
microbiome of the colon drive this variability in terms of
IBD subtypes and also response to treatments One of the
(09:36):
most exciting findings that we've made from this work is
actually a new role for a cell type called mast cells,
and these cells have previously been associated with allergies, so
that's what they are most known for. But they actually
have a really important role to play in inflammation, including
inflammatory bowel disease. So we found in both of these
two patient cohorts that we've been studying, that there is
(09:57):
this really active mast cell phenotype in the gut of these patients,
and we've actually found a drug that can turn this
inflammatory mast cell phenotype off. And it's presenting a really exciting new
direction now for possible new ways that we could treat
inflammatory bowel disease in these patients.
Dr Viviane Richter (10:17):
Why have you chosen to use single-cell genomics to look
at this problem?
Dr Kylie James (10:22):
So single-cell technology is really powerful. There's a whole bunch
of cell types that are contributing to the onset of
disease and its progression, so single-cell RNA sequencing allows us
to look at all of the cells, which gives us
a much more comprehensive understanding of the disease.
So we never know where the data is going to
(10:42):
take us. We can collaborate with scientists that have expertise
in different areas. We can collaborate with scientists at Garvan
that have expertise in immunology and also in cancer biology
and even outside of the Garvan. We collaborate with microbiologists
at UNSW, so single-cell technology opens up the opportunity to
(11:05):
be quite collaborative in how we do our research. And
another key aspect of our research is access to clinical samples.
So we are very lucky at Garvan to be next
to St Vincent's Hospital, and we collaborate so closely with
gastroenterologists there who treat patients with inflammatory bowel disease. Then
(11:27):
we receive from the clinician little biopsies from these patients,
which we use for our research. We can have the
benefit of the research expertise, but also the clinical expertise
and patient groups. And it means that our research can
have direct line to the actual patients that have these diseases.
So it's the perfect situation to be doing research into
(11:51):
inflammatory bowel disease.
Dr Viviane Richter (11:53):
So, Kylie, what does a future appointment with a gastroenterologist
look like? With these sorts of new tools and measures
being introduced into clinical practice?
Dr Kylie James (12:03):
Well, so at the moment, someone with IBD is subjected
to routine colonoscopies to manage their disease, to to check
if it's progressed. But in the future, wouldn't it be
great if someone came into their their clinician's office? And
they did a simple blood test or a test of
their stool? And that told the clinician, right, this patient
(12:23):
has this kind of disease? We can know that it's
going to progress this way, and this treatment is best
suited for that patient. So that's kind of what we're
hoping for. So it wouldn't be to run the whole,
you know, the whole single-cell RNA sequencing on every patient.
We wouldn't need to do that because we already know
from our current research that these features mean this to
(12:46):
this patient.
Dr Viviane Richter (12:47):
So you mentioned genes are involved in inflammatory bowel disease?
Can someone look at my genes and figure out whether
I'm likely to get it?
Dr Kylie James (12:56):
There have been genetic tests or analysis done on inflammatory
bowel disease and also colorectal cancer, and there are risk
variants that are associated with IBD. There are 200. So
we don't really know whether they are causative, these genetic variations,
because inflammatory bowel disease is a complex disease there's many
(13:17):
other features. It's not as simple as saying yes, it's
one gene like cystic fibrosis. You know it's a particular
gene mutation. It's not as easy. It's not as simple
for IBD, so there's no genetic test that you can
do for inflammatory bowel disease. It does tend to run
in families, so you at greater risk if your mum
or your dad have it. But there's a lot of
(13:38):
work to do also in the genetic space to understand
the role that genes have to play because ultimately it's
the genes that affect your biology, your cells, which determines
whether you go on to get inflammatory bowel disease.
Dr Viviane Richter (13:52):
I'm so glad we've talked about the genetics, but I'd
love to also know a little bit more about the
environmental factors. Kylie. for those of us who aren't experts,
what can we do to improve our gut health?
Dr Kylie James (14:05):
There are a few things, and most of them are
are changes to our lifestyle. So, for instance, if you
have a more healthy, active lifestyle, you reduce your risk also,
if you change your diet, so if you reduce your
intake of processed red meats and increase dietary fibre which
is something that continually comes up as being key. Then
(14:28):
you'll also reduce your risk of getting inflammatory bowel disease
and actually, dietary fibre is really interesting because it is
food for our microbiome. So there are bacteria good bacteria
in our gut that use dietary fibre and ferment it
and digest it and produce short chain fatty acids in
particular one called butyrate, which is the preferred energy source
(14:50):
for our epithelial cells. So remember, these are the cells
that line the gut. We actually need to feed and
help our microbiome. You don't have to necessarily run out
and buy Metamucil and start drinking this all the time.
What you can do is just make different choices. So
choose brown rice instead of white rice or brown whole
(15:10):
grain bread instead of white bread. We're looking for complex
carbohydrates that are that we can't digest, but our microbiome can.
Another thing that could be really beneficial are fermented foods.
So I'm talking about sauerkraut or kombucha, which is really
fashionable at the moment. So a lot of these bacteria
actually don't make it through to our gut. They they
(15:31):
kind of die in our stomach. But some do it
fosters a diverse microbiome. So what we're aiming for is
diversity in our microbiome.
Dr Viviane Richter (15:40):
Kylie, how did you come to be doing this work
at Garvan?
Dr Kylie James (15:43):
When I was a child, I wanted to be an entomologist, actually.
So I really wanted to be Henry Walter Bates, who
was a naturalist and explored the Amazon. That's who I
wanted to be when I was 10. So it's not
surprising that I ended up as a scientist. I did
a science degree at university. I then did a an
(16:04):
honours degree, an honours year, and my topic was actually parasitology.
And then I did a PhD in a malaria lab. So
malaria is also caused by a parasite called plasmodium. But
at that point, I then looked more on the host side.
So the immune response to infection. And that was my
(16:24):
kind of introduction, that the immune system was super cool
and super complex. And then I was very fortunate to
be offered a postdoctoral position in the UK at the
Wellcome Sanger Institute, and this was at earliest time of
single-cell RNA sequencing technology. So my supervisor over in the
UK her name was Sarah Teichmann, she started this thing
(16:47):
called the Human Cell Atlas, which is an international effort
to use single-cell technologies to map all the different cell
types in the human body. And so I came in
into her office when I started in her lab and
she asked, Kylie, well, what do you want to work on?
And I said, I just want to work on the
immune system. One of my collaborators is like, well, why
don't you work on the gut? There's a really active
(17:10):
immune system in the gut, and we actually don't know
much about how it changes along the gastrointestinal tract. So
my postdoctoral training was about mapping all the different cell
types in the gut. And actually, we're using my findings
from my post doc training as a reference now to
compare to inflammatory bowel disease.
Dr Viviane Richter (17:33):
In your research what's the next question you're hoping to answer?
Dr Kylie James (17:37):
So, Viv, we've actually just started working on a clinical trial,
which is looking at whether FMT, which is faecal microbiome transplantation,
is effective against colitis, which is a side effect of
people getting immune checkpoint inhibitor treatment for their cancer. A
lot of people who have treatment against cancer actually develop colitis,
(17:57):
which is similar to inflammatory bowel disease as an adverse effect.
And one of the possible treatments is actually to replenish
their microbiome by transferring processed faecal microbiome, and so what we
are doing there is to look at how this changes
the intestinal cells and how those cells change over the
(18:18):
process of the treatment because it's a longitudinal. So we
look at them at the start of their treatment when
they have active colitis and then later on in their treatment,
to see how that affects their colitis. And some people
respond and some people don't. So we also want to
know what's the difference there. Can we predict who's going
to benefit from this treatment? So I'm really excited to
(18:40):
see whether we can actually change the microbiome to have
an effect on colitis. So this really fits in with
the general theme of my research, which is to understand
the cellular and the microbial basis of disease so that
we can get patients onto treatments that work for them sooner.
Dr Viviane Richter (18:59):
Kylie, before we let you get back to the lab,
it's time for the Fast Five. Are you ready?
Dr Kylie James (19:06):
Bring it on.
Dr Viviane Richter (19:06):
What was your first job?
Dr Kylie James (19:08):
When I was 14 I was a checkout chick at Bilo.
Do you remember Bilo? Back in the day? That was
my first job. And I have so much respect for
checkout people because of my time as a checkout chick.
Dr Viviane Richter (19:21):
Do you have a favourite quote?
Dr Kylie James (19:23):
I do. I actually have a sticky note beside my desk,
which has a quote that I find really motivational. It's:
Do or do not. There is no try. by Master Yoda.
Dr Viviane Richter (19:34):
So how's that informed your research work?
Dr Kylie James (19:37):
There are many periods in my in my day where I'm procrastinating,
not doing the difficult tasks. And I look to that
quote and I just get on and do it.
Dr Viviane Richter (19:48):
Do you have any secret skills?
Dr Kylie James (19:50):
I'm quite good at at drawing with pastels. And it's
something that I do to unwind. Well, I used to
do it when I had more time, but I'm not
bad at that.
Dr Viviane Richter (19:58):
Who's the most famous person you've met?
Dr Kylie James (20:00):
I had afternoon tea in the gardens of Buckingham Palace.
Dr Viviane Richter (20:05):
No.
Dr Kylie James (20:05):
Yes. I didn't meet the queen. She was in another
marquee with mixing with guests more distinguished than I was.
But I did meet her cousin, Prince Richard, Duke of Gloucester.
Is he famous? I'm not sure it's all relative right?
Dr Viviane Richter (20:19):
Who inspires you the most?
Dr Kylie James (20:21):
The person who inspires me the most is my postdoctoral supervisor,
I think Sarah Teichmann. She is super successful in her
career in in research, but she always acts with really
a high amount of integrity. And she's super collaborative, and
she also has raised a family at the same time.
So I kind of look to her for motivation and
(20:42):
and just how to juggle everything and be and still
be successful.
Dr Viviane Richter (20:46):
I think you're certainly on the road to success yourself there.
Dr Kylie James, thank you so much for joining us
on Medical Minds.
Dr Kylie James (20:55):
Thank you so much for having me, Viv. It's been a real
pleasure speaking with you.
Dr Viviane Richter (20:58):
If you'd like to know more about Kylie's research or
donate to the work we do at Garvan, head to garvan.org.au.
And if you've enjoyed this podcast, please leave a review
and share with other podcast lovers. I'm Dr Viviane Richter.
Thanks for listening.
This podcast was recorded on the traditional Country of the
(21:20):
Gadigal people of the Eora nation. We recognise their continuing
connection to land, waters and community. We pay our respects
to Aboriginal and Torres Strait Islander cultures and Elders past,
present and emerging.
It's often underappreciated, but our gastrointestinal system is fascinating. It
has its own brain. It can house more microbial cells
than there are human cells in our entire body. And
did you know that more than 70% of the body's
immune cells are found in our gut? Unravelling all that
complexity is more important than ever, with conditions affecting the gut,
(00:24):
such as Crohn's and ulcerative colitis on the rise. In
today's episode, we speak to a researcher who is taking
a genetic deep dive, using single-cell genomics to develop more
personalised approaches to preventing and treating inflammatory bowel disease. You're
listening to Medical Minds. The podcast that takes you inside
(00:45):
the labs at the Garvan Institute of Medical Research. I'm
your host, Dr Viviane Richter. And with me here is Dr Kylie James,
leader of the Gut Immunogenomics Group at Garvan. Welcome, Kylie.
Dr Kylie James (00:59):
Hi, Viv. Thank you. It's so good to be here.
Dr Viviane Richter (01:01):
Kylie, let's talk about the gut, which happens to be
one of my favourite topics.
What do we know about the gut and how it works?
Dr Kylie James (01:09):
Well, Viv, what we know about the gut has changed
a lot over the course of centuries. We used to
recognise that it was an organ that was involved in
digestion and absorption of nutrients. But actually, now we recognise
it's much more complicated than that and has many roles
in our health. So some cool facts about what we've
learned about the gut is we actually recognise that it
(01:32):
had a microbiome all the way back in the 1680s,
there was a researcher called Antonie van Leeuwenhoek, who looked at his
own stool under a microscope and saw that there were
little creatures in it, which he called animalcules, which is
Latin for 'little animals'. And then fast forward to the 1900s,
a researcher called Metchnikoff, who is actually regarded as the
(01:54):
grandfather of innate immunity. He was the first person to
propose this idea that the bacteria in our gut, some
of them could actually be good and beneficial for our health.
And it was a balance between the good and the
bad bacteria that could determine whether we have disease. And
then we come forward even more recently to the 1980s,
when two Australian researchers called Marshall and Warren, they actually
(02:19):
were the first to show that stomach ulcers were not
the product of stress and anxiety and spicy food, which
was the common knowledge even in the 1980s, but were actually
the product of a H pylori infection, a bacterial infection.
And actually the way that Barry Marshall showed this was
by drinking a culture of bacteria and then showing that
(02:41):
he got stomach ulcers, which was crazy. That was just
in the 1980s. But really, what has driven our appreciation
of the complexity of the gut even further is the
invention of sequencing technologies. So about in the early 2000s,
we have now been able to take a biopsy, a
piece of the gut and determine all the different bacteria
(03:05):
in that gut tissue and at the same time, all
the different cell types in that tissue and look at
how they are associated with each other. So from even
40 years ago having to drink bacteria to show the
role of bacteria -
Dr Viviane Richter (03:20):
That wouldn't be allowed anymore these days!
Dr Kylie James (03:22):
No! To now being able to catalogue all the different types
of bacteria cells in the gut. We've really come a
long way, and it's an exciting time to be a
researcher in gut biology.
Dr Viviane Richter (03:32):
Kylie there's no doubt that we have a much greater
awareness now of what's happening in the gut. But why
are diseases affecting the gut on the rise?
Dr Kylie James (03:43):
These diseases, which covers inflammatory bowel disease and also irritable
bowel syndrome and a whole range of other conditions, are
increasing in Australia and actually there's 100,000 Australians currently living
with IBD. Why are they increasing? Well? There's a whole
range of risk factors that affects someone's likelihood of getting
(04:05):
these diseases. And some of the environmental factors include the
changes in our diet in developed countries. So, for instance,
we are now eating more processed red meats, more saturated fats,
and we also have much lower intake of complex carbohydrates
and fresh fruit and vegetables. And these are really important
for fostering a healthy gut and a healthy microbiome. Other
(04:29):
environmental factors include additives to our foods like emulsifiers, which
happen to be in, like so many processed foods and
also exposure to pesticides and chemicals which also affect our microbiome.
An important point here, though, is although we might live
in the same environment, it doesn't mean we have the
(04:51):
same risk of developing IBD because another major factor is
in our genes. We all have small variabilities in our
genetic code that make us unique. But they also change
our susceptibility to developing diseases, including inflammatory bowel disease. What
we are really trying to understand is in people who
(05:13):
have these risk factors, how that impacts their cells and
their microbiome to go on and develop inflammatory bowel disease.
Dr Viviane Richter (05:20):
And that's obviously your specific area of research. I understand
you're looking at the individual cells within the gut. Can
you take us there what is actually happening in the
gut at that level of the individual cell?
Dr Kylie James (05:36):
Yes, Viv, If I can paint a picture of the gut,
it would have these great kind of protrusions, which are called villi.
And lining those villi are these little cuboidal-shaped cells called epithelial cells.
And those epithelial cells are the cells that are tasked
with absorbing nutrients, and some of them also secrete mucus,
so it forms this nice, cushy layer on the surface
(05:58):
of the gut, which kind of also forms a barrier
for the microbiome. But other epithelial cells are also involved in
sensing the environment, sensing things that signals that come through
the gut and feeding this through to the enteric nervous
system and then underneath that epithelial layer you have even
more different types of cells, including our immune cells. And
(06:18):
so some of those cells are tasked with defending against
potentially pathogenic microbes. And then another side of the immune
system is tasked with dampening down that response, so providing
tolerance to kind of make it a nice symbiotic environment.
And then there are cells that are involved in or
(06:38):
create the vessels, the blood vessels and the lymph vessels,
and they're called endothelial cells. There are also structural cells
called stromal cells that have many other roles as well.
So I'm oversimplifying this. The list just goes on. And actually,
in some of my earlier work, we catalogued the different
types of cells, and there was 133 different cell types
(06:59):
and states that we found in the gut. And actually,
one thing that's interesting is that they change depending on
their environment. So we've actually seen that even within the colon.
So this is the large bowel. We've seen differences in
the response of immune cells from the left side of
the colon versus the right side of the colon. And
(07:19):
this is dependent on changing microbiome because they're interacting with
the microbiome all the time and we we can see
that the microbiome actually changes across the length of the
gut as well. And and that's kind of, I guess,
to be expected, because the microbiome is eating our food
and and responding to the levels of oxygen and water
in in our gut. And of course, that changes from
(07:42):
from the top of the gut to the lower gut
as well, so we can see the whole way along
the gut. All these features are changing, and I think
that's that's really interesting. And that's something that we're trying
to understand, particularly in the context of disease.
Dr Viviane Richter (07:56):
Sounds like a really complex environment to study. And your
focus is specifically on immune cells.
Dr Kylie James (08:04):
Yes, so we have a particular interest in immune cells
because they have quite an important role to play in
diseases such as inflammatory bowel disease. So they are a
key cell in driving inflammation, but actually we analyse all
the different cells. So one of the technologies that we
use is called single-cell RNA sequencing, and this is a
(08:26):
technology that allows us to be quite unbiased in our
approach to analysing cells. So it means from one biopsy from a patient,
for instance, we can then release all the cells from
that and analyse all of them at the same time.
So we don't have to be picky about which cell
we analyse, but we can look at them all, and
we can see how they're all interacting. And they're all
(08:48):
contributing to that disease.
Dr Viviane Richter (08:50):
Kylie, what has your research shown you?
Dr Kylie James (08:53):
Well, inflammatory bowel disease is actually a spectrum of disorders,
and there's a great degree of variability in terms of
a patient's experience of inflammatory bowel disease, but also their
response to treatments. So without understanding the basis of this variability,
there's a lot of guesswork in terms of the clinical treatments.
So the moment a patient might come in and they
(09:15):
might be bounced between drug classes until one is found
that works for them, and all this time they are
experiencing quite debilitating symptoms. So what my research is trying
to do is to understand how the cells and the
microbiome of the colon drive this variability in terms of
IBD subtypes and also response to treatments One of the
(09:36):
most exciting findings that we've made from this work is
actually a new role for a cell type called mast cells,
and these cells have previously been associated with allergies, so
that's what they are most known for. But they actually
have a really important role to play in inflammation, including
inflammatory bowel disease. So we found in both of these
two patient cohorts that we've been studying, that there is
(09:57):
this really active mast cell phenotype in the gut of these patients,
and we've actually found a drug that can turn this
inflammatory mast cell phenotype off. And it's presenting a really exciting new
direction now for possible new ways that we could treat
inflammatory bowel disease in these patients.
Dr Viviane Richter (10:17):
Why have you chosen to use single-cell genomics to look
at this problem?
Dr Kylie James (10:22):
So single-cell technology is really powerful. There's a whole bunch
of cell types that are contributing to the onset of
disease and its progression, so single-cell RNA sequencing allows us
to look at all of the cells, which gives us
a much more comprehensive understanding of the disease.
So we never know where the data is going to
(10:42):
take us. We can collaborate with scientists that have expertise
in different areas. We can collaborate with scientists at Garvan
that have expertise in immunology and also in cancer biology
and even outside of the Garvan. We collaborate with microbiologists
at UNSW, so single-cell technology opens up the opportunity to
(11:05):
be quite collaborative in how we do our research. And
another key aspect of our research is access to clinical samples.
So we are very lucky at Garvan to be next
to St Vincent's Hospital, and we collaborate so closely with
gastroenterologists there who treat patients with inflammatory bowel disease. Then
(11:27):
we receive from the clinician little biopsies from these patients,
which we use for our research. We can have the
benefit of the research expertise, but also the clinical expertise
and patient groups. And it means that our research can
have direct line to the actual patients that have these diseases.
So it's the perfect situation to be doing research into
(11:51):
inflammatory bowel disease.
Dr Viviane Richter (11:53):
So, Kylie, what does a future appointment with a gastroenterologist
look like? With these sorts of new tools and measures
being introduced into clinical practice?
Dr Kylie James (12:03):
Well, so at the moment, someone with IBD is subjected
to routine colonoscopies to manage their disease, to to check
if it's progressed. But in the future, wouldn't it be
great if someone came into their their clinician's office? And
they did a simple blood test or a test of
their stool? And that told the clinician, right, this patient
(12:23):
has this kind of disease? We can know that it's
going to progress this way, and this treatment is best
suited for that patient. So that's kind of what we're
hoping for. So it wouldn't be to run the whole,
you know, the whole single-cell RNA sequencing on every patient.
We wouldn't need to do that because we already know
from our current research that these features mean this to
(12:46):
this patient.
Dr Viviane Richter (12:47):
So you mentioned genes are involved in inflammatory bowel disease?
Can someone look at my genes and figure out whether
I'm likely to get it?
Dr Kylie James (12:56):
There have been genetic tests or analysis done on inflammatory
bowel disease and also colorectal cancer, and there are risk
variants that are associated with IBD. There are 200. So
we don't really know whether they are causative, these genetic variations,
because inflammatory bowel disease is a complex disease there's many
(13:17):
other features. It's not as simple as saying yes, it's
one gene like cystic fibrosis. You know it's a particular
gene mutation. It's not as easy. It's not as simple
for IBD, so there's no genetic test that you can
do for inflammatory bowel disease. It does tend to run
in families, so you at greater risk if your mum
or your dad have it. But there's a lot of
(13:38):
work to do also in the genetic space to understand
the role that genes have to play because ultimately it's
the genes that affect your biology, your cells, which determines
whether you go on to get inflammatory bowel disease.
Dr Viviane Richter (13:52):
I'm so glad we've talked about the genetics, but I'd
love to also know a little bit more about the
environmental factors. Kylie. for those of us who aren't experts,
what can we do to improve our gut health?
Dr Kylie James (14:05):
There are a few things, and most of them are
are changes to our lifestyle. So, for instance, if you
have a more healthy, active lifestyle, you reduce your risk also,
if you change your diet, so if you reduce your
intake of processed red meats and increase dietary fibre which
is something that continually comes up as being key. Then
(14:28):
you'll also reduce your risk of getting inflammatory bowel disease
and actually, dietary fibre is really interesting because it is
food for our microbiome. So there are bacteria good bacteria
in our gut that use dietary fibre and ferment it
and digest it and produce short chain fatty acids in
particular one called butyrate, which is the preferred energy source
(14:50):
for our epithelial cells. So remember, these are the cells
that line the gut. We actually need to feed and
help our microbiome. You don't have to necessarily run out
and buy Metamucil and start drinking this all the time.
What you can do is just make different choices. So
choose brown rice instead of white rice or brown whole
(15:10):
grain bread instead of white bread. We're looking for complex
carbohydrates that are that we can't digest, but our microbiome can.
Another thing that could be really beneficial are fermented foods.
So I'm talking about sauerkraut or kombucha, which is really
fashionable at the moment. So a lot of these bacteria
actually don't make it through to our gut. They they
(15:31):
kind of die in our stomach. But some do it
fosters a diverse microbiome. So what we're aiming for is
diversity in our microbiome.
Dr Viviane Richter (15:40):
Kylie, how did you come to be doing this work
at Garvan?
Dr Kylie James (15:43):
When I was a child, I wanted to be an entomologist, actually.
So I really wanted to be Henry Walter Bates, who
was a naturalist and explored the Amazon. That's who I
wanted to be when I was 10. So it's not
surprising that I ended up as a scientist. I did
a science degree at university. I then did a an
(16:04):
honours degree, an honours year, and my topic was actually parasitology.
And then I did a PhD in a malaria lab. So
malaria is also caused by a parasite called plasmodium. But
at that point, I then looked more on the host side.
So the immune response to infection. And that was my
(16:24):
kind of introduction, that the immune system was super cool
and super complex. And then I was very fortunate to
be offered a postdoctoral position in the UK at the
Wellcome Sanger Institute, and this was at earliest time of
single-cell RNA sequencing technology. So my supervisor over in the
UK her name was Sarah Teichmann, she started this thing
(16:47):
called the Human Cell Atlas, which is an international effort
to use single-cell technologies to map all the different cell
types in the human body. And so I came in
into her office when I started in her lab and
she asked, Kylie, well, what do you want to work on?
And I said, I just want to work on the
immune system. One of my collaborators is like, well, why
don't you work on the gut? There's a really active
(17:10):
immune system in the gut, and we actually don't know
much about how it changes along the gastrointestinal tract. So
my postdoctoral training was about mapping all the different cell
types in the gut. And actually, we're using my findings
from my post doc training as a reference now to
compare to inflammatory bowel disease.
Dr Viviane Richter (17:33):
In your research what's the next question you're hoping to answer?
Dr Kylie James (17:37):
So, Viv, we've actually just started working on a clinical trial,
which is looking at whether FMT, which is faecal microbiome transplantation,
is effective against colitis, which is a side effect of
people getting immune checkpoint inhibitor treatment for their cancer. A
lot of people who have treatment against cancer actually develop colitis,
(17:57):
which is similar to inflammatory bowel disease as an adverse effect.
And one of the possible treatments is actually to replenish
their microbiome by transferring processed faecal microbiome, and so what we
are doing there is to look at how this changes
the intestinal cells and how those cells change over the
(18:18):
process of the treatment because it's a longitudinal. So we
look at them at the start of their treatment when
they have active colitis and then later on in their treatment,
to see how that affects their colitis. And some people
respond and some people don't. So we also want to
know what's the difference there. Can we predict who's going
to benefit from this treatment? So I'm really excited to
(18:40):
see whether we can actually change the microbiome to have
an effect on colitis. So this really fits in with
the general theme of my research, which is to understand
the cellular and the microbial basis of disease so that
we can get patients onto treatments that work for them sooner.
Dr Viviane Richter (18:59):
Kylie, before we let you get back to the lab,
it's time for the Fast Five. Are you ready?
Dr Kylie James (19:06):
Bring it on.
Dr Viviane Richter (19:06):
What was your first job?
Dr Kylie James (19:08):
When I was 14 I was a checkout chick at Bilo.
Do you remember Bilo? Back in the day? That was
my first job. And I have so much respect for
checkout people because of my time as a checkout chick.
Dr Viviane Richter (19:21):
Do you have a favourite quote?
Dr Kylie James (19:23):
I do. I actually have a sticky note beside my desk,
which has a quote that I find really motivational. It's:
Do or do not. There is no try. by Master Yoda.
Dr Viviane Richter (19:34):
So how's that informed your research work?
Dr Kylie James (19:37):
There are many periods in my in my day where I'm procrastinating,
not doing the difficult tasks. And I look to that
quote and I just get on and do it.
Dr Viviane Richter (19:48):
Do you have any secret skills?
Dr Kylie James (19:50):
I'm quite good at at drawing with pastels. And it's
something that I do to unwind. Well, I used to
do it when I had more time, but I'm not
bad at that.
Dr Viviane Richter (19:58):
Who's the most famous person you've met?
Dr Kylie James (20:00):
I had afternoon tea in the gardens of Buckingham Palace.
Dr Viviane Richter (20:05):
No.
Dr Kylie James (20:05):
Yes. I didn't meet the queen. She was in another
marquee with mixing with guests more distinguished than I was.
But I did meet her cousin, Prince Richard, Duke of Gloucester.
Is he famous? I'm not sure it's all relative right?
Dr Viviane Richter (20:19):
Who inspires you the most?
Dr Kylie James (20:21):
The person who inspires me the most is my postdoctoral supervisor,
I think Sarah Teichmann. She is super successful in her
career in in research, but she always acts with really
a high amount of integrity. And she's super collaborative, and
she also has raised a family at the same time.
So I kind of look to her for motivation and
(20:42):
and just how to juggle everything and be and still
be successful.
Dr Viviane Richter (20:46):
I think you're certainly on the road to success yourself there.
Dr Kylie James, thank you so much for joining us
on Medical Minds.
Dr Kylie James (20:55):
Thank you so much for having me, Viv. It's been a real
pleasure speaking with you.
Dr Viviane Richter (20:58):
If you'd like to know more about Kylie's research or
donate to the work we do at Garvan, head to garvan.org.au.
And if you've enjoyed this podcast, please leave a review
and share with other podcast lovers. I'm Dr Viviane Richter.
Thanks for listening.
This podcast was recorded on the traditional Country of the
(21:20):
Gadigal people of the Eora nation. We recognise their continuing
connection to land, waters and community. We pay our respects
to Aboriginal and Torres Strait Islander cultures and Elders past,
present and emerging.
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