October 15, 2023 • 24 mins
APDS is a rare inherited immune condition that has been reported in less than 300 people worldwide. So how could studying it help improve outcomes for the millions of people who live with autoimmune disease? Today, we meet A/Prof Elissa Deenick, a researcher who is taking a deep dive into the genetics of immune cells to make sure no patient gets left behind.
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Episode Transcript
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Dr Viviane Richter (00:02):
APDS is an inherited immue condition that is rare. Since it
was discovered 10 years ago, it has been reported in
less than 300 people worldwide. So how could studying a
disease that only affects a few hundred help improve the
outcomes for millions of people who live with autoimmune disease?
Today we meet a researcher who is diving deep into
(00:24):
the genetics of immune cells to make sure no patient
gets left behind. You're listening to Medical Minds
takes you inside the labs at the Garvan Institute of
Medical Research. I'm your host, Dr Viviane Richter. And with
me here is Associate Professor Elissa Deenick, head of the Lymphocyte
Signalling and Activation Lab. Welcome, Elissa.
Associate Professor Elissa Deenick (00:48):
Thank you, Viv. It's great to be here.
Dr Viviane Richter (00:50):
Before we launch into finding out about APDS, this rare
disease that you and your team are working on, Elissa,
can you tell us about your journey studying the immune system?
Where did it all start?
Associate Professor Elissa Deenick (01:01):
Even as a kid, I was really interested in science
and how things worked. My dad was a science teacher,
so that might have impacted me. And then when I
was in year 10 I went off on a a
science summer school, and that summer school had a lot
of stuff about human biology, how the human body worked.
And I just became fascinated with how complex the human
(01:22):
body was and how interesting it was to study. So
I decided that when I finished school, I was gonna
do a medical science degree, which is what I did.
And then kind of at the end of second year,
I was looking for a research project that would give
me some research experience in a lab, and I kind
of by chance ended up in an immunology lab. But I
loved it. I loved how complex the immune system was,
(01:44):
but how important it was. And then when I came
to doing my honours, I decided I wanted to continue
in that. And it was really my supervisor at the
time who was just so excited about science and understanding
the way that the immune system worked together to protect
us against disease. That really made me choose that project
and go down that path.
Dr Viviane Richter (02:06):
That's brilliant. What was the project you were working on
at the time?
Associate Professor Elissa Deenick (02:10):
Actually, I think the title of my thesis was "Quantitative
Analysis of Lymphocyte Proliferation and Differentiation", which does not sound
very exciting. But it was really interesting because there's this
whole problem in immunology about, you know, if I get
an infection, I've got these immune cells that need to
fight it off. But in order to do that, you
(02:30):
need enough of them to fight it off. So that's
the proliferation where the cells divide, so you get enough of
them to fight it off and the differentiation, which is
where the immune cells need to get appropriate function so
that they can get rid of that infection. So really,
it was about understanding how lymphocytes – one of our immune
cells – do that, also understanding that it's not a black
(02:51):
and white thing. It's quantitative, so there are ranges of
scales of how activated you can be and what path
you go down.
Dr Viviane Richter (03:00):
Elissa, your research is looking at a rare condition called APDS.
Can you tell us about that?
Associate Professor Elissa Deenick (03:07):
Yeah, so APDS stands for activated PI3 kinase-delta syndrome. That's
a long name, but really, it's just describing the protein
that's affected in these patients. So this is a rare
condition that was described first about 10 years ago, and
it's caused by a genetic change in the gene that
encodes for this protein. And these patients have a range
(03:31):
of clinical manifestations. The most common one is that they
have these recurrent respiratory infections, so particularly with bacteria. But
they also have problems dealing with some viruses, like EBV,
which is the virus that causes glandular fever. They really
have trouble dealing with that, and they also have problems
with vaccine responses. Vaccine responses are to do with producing
(03:55):
antibodies that protect us against infection. They also produce antibodies
that attack their own cells, though so autoimmunity. It's a
really interesting problem where they've got deficient immunity in some areas,
but then overreactive immunity in other areas.
Dr Viviane Richter (04:12):
What's the difference between these rare immune conditions, such as
APDS and more common autoimmune conditions such as rheumatoid arthritis
or MS?
Associate Professor Elissa Deenick (04:22):
So APDS is what we refer to as an inborn
era of immunity, and these are conditions and there's now
over 400 of them that are caused by changes in
a single gene, so each one is a different single gene.
But APDS, for example, is caused by a change in
(04:43):
the gene that encodes for PI3 kinase. And these changes
have a big impact on the immune system. So they
cause immunodeficiency so susceptibility to infection it could be autoimmunity.
It could be increased rates of allergy. In contrast, in
diseases like rheumatoid arthritis, there's not a single gene change
(05:05):
that's happened that's driving disease. There's probably a complex interaction
of many different genes working together. Environmental factors. These all
work together to drive the disease.
Dr Viviane Richter (05:18):
How did you first come to study APDS?
Associate Professor Elissa Deenick (05:21):
Just over 10 years ago, I was working at the
Garvan and I was working with one of our other
Garvan researchers, Stu Tangye, and collaborators at NIH, which is
the National Institutes of Health in the US, the biggest
centre for research reached out and said, we've got this
cohort of patients, this group of patients and we think
we've found the genetic cause. Can you help us link
(05:44):
what we think is the gene involved to the problems
with the cells? So we did some work in our
lab to look at the cells of those patients and
to show that those cells were defective and make that
link to prove that this was a genetic cause of disease.
Dr Viviane Richter (06:02):
Through your work, what have you learned about this disease?
Associate Professor Elissa Deenick (06:04):
Yeah, so we've done a lot of work trying to
understand which immune cells are impacted by these genetic changes
and how that then leads to the symptoms that the
patients get. So we've looked at the T and B cells,
which work together to make antibodies, and we've shown that
there's defects in both the CD4 T cells and the
(06:26):
B cells, which means that they can't work together well
to make effective antibodies. But we've also been able to
show that the B cells react, funnily so they react
poorly to these foreign things. But when it's something like
what we call a self antigen, so part of our
own body, the B cells, which normally should be turned
(06:47):
off when they see something that cells instead get activated
and start making antibodies against that thing. So then these patients,
their B cells, get inappropriately activated, and they start making
antibodies against platelets or red blood cells, and that leads
to then problems with clotting or problems with oxygen transport.
(07:08):
For those patients. They then need treatments to suppress their
immune system and try and bring them under control again.
So it's this often this cycle of flares of disease
and then treatment and then being OK for a while
and then needing to come back.
Dr Viviane Richter (07:22):
And these patients would be on lifelong treatment paths, I would assume.
Associate Professor Elissa Deenick (07:27):
Yeah, and certainly before we had identified the genetic cause,
many of these patients just didn't know what was wrong
with them. They had these recurrent infections, or they had
these cytopenias. Their blood cells are being destroyed, and they
didn't know why their doctors didn't know why. And so
it's very difficult if you don't know what's driving disease
(07:49):
to treat appropriately. You end up just dealing with the
symptoms as they come up, rather than being able to
hit what's driving that disease and hopefully prevent ever getting
to that point.
Dr Viviane Richter (08:00):
And what has that discovery meant for APDS patients?
Associate Professor Elissa Deenick (08:04):
Well, first, it's meant that these patients can get a diagnosis,
so that meant that then clinicians all around the world
looked at patients they might have been seeing and went
I think that patient may also have that same genetic cause.
And so then they were able to test patients and
then give them a diagnosis.
Dr Viviane Richter (08:25):
So what did that mean for patient outcomes?
Associate Professor Elissa Deenick (08:28):
Well, one of the good things for patients with APDS
was that there were already some drugs on the market
that targeted the pathways that were dysregulated in these patients.
So that's meant that clinicians could use those drugs to
start treating these patients. And really, there's been some really
good outcomes in terms of seeing their disease improve.
Dr Viviane Richter (08:51):
That must be quite rewarding to know that you're helping
all these patients in this way.
Associate Professor Elissa Deenick (08:55):
Yeah, it is. I mean, science in the lab, you
can sometimes feel quite distant from what's going on in
the clinic. So it's really good to see these outcomes
and see real life changes for people. A lot of
lab work can be quite repetitive late nights stuck in
lab doing your experiments. But to see that at the
(09:17):
end of all that work, there are real changes for people.
People who didn't used to have a diagnosis now have one.
People who didn't have good treatments are now healthier. I mean,
I don't think you could ask for anything more really.
Dr Viviane Richter (09:31):
Elissa, What does research into such rare immune conditions mean
for patients with autoimmune disease more broadly?
Associate Professor Elissa Deenick (09:39):
It's really helpful, actually, for us to understand these other
autoimmune conditions. As discussed at the beginning of this conversation,
the immune system is really complex, and there are lots
of moving parts that work together to lead to an
immune response. And so then it can be really difficult
to know what's driving that response so we might see
(09:59):
the damage at the end. But what started that response?
So take lupus as an example of an autoimmune disease.
In lupus patients, they get a whole lot of antibodies
that target bits of the cell, like DNA, and that
causes damage that you see in lupus
problems in your kidney. And so we've grouped all these
(10:20):
lupus patients together because they have these symptoms at the end,
the symptoms of lupus. But lupus is almost certainly not
of one disease. It's probably a group of different diseases
where the initial starting problem that drove those B cells
to make those damaging antibodies and that caused the immune
system to go wrong is different. But the question is
(10:43):
in those patients, how do we get to the heart
of what's driving their disease? Because, really, we want to
treat the drivers of their disease, not the symptoms at
the end. We want to get in at the start
and make sure we stop them. So these APDS patients,
they show us that this protein PI3 kinase can be
a really important driver, and so that allows us to
(11:04):
then go back to other autoimmune diseases like lupus and say,
do some of these patients have similar drivers? Do they
also have dysregulation of this protein, this pathway that might
be driving disease? And if so, maybe we can use
similar drugs that we're using for the APDS patients to treat
those lupus patients. And that's true, not just of APDS,
(11:25):
but there's a lot of other what we call inborn
errors of immunity. So genetic causes that also result in autoimmunity.
And if we can use those to study what are the
really important genes and proteins in immune cells that control
whether we make good protective response or a bad destructive response,
(11:45):
can we then apply that to these other, more common
autoimmune diseases like lupus or multiple sclerosis and be able
to better treat those patients.
Dr Viviane Richter (11:56):
Will this approach help you identify patients who are more
or less likely to benefit from a specific treatment?
Associate Professor Elissa Deenick (12:04):
Yeah, so I guess the aim of what I do
and actually what the Precision Immunology Program at Garvan is
aiming to do is to really match treatment to specific patients.
A lot of our treatments currently for autoimmune diseases are not
very specific. That kind of generally suppress the immune system
(12:25):
rather than targeting the specific driver of disease. And that
has consequences. One
a high risk that you'll then suppress it too much
and you'll get infections. But also it's not always effective
for every patient. So really, what we hope to do
is to develop ways, develop tests or what we sometimes
(12:49):
call in science biomarkers that allow us to identify which
patient may have a particular driver of disease and then
match it with a drug that targets that driver. And
the hope would be that if we do that, we
will be able to inhibit disease more specifically and hopefully
have less impact on the protective functions of the immune system.
Dr Viviane Richter (13:11):
What is making this work possible now?
Associate Professor Elissa Deenick (13:14):
I think there's been several changes that have really transformed
the study of human immunology in particular in terms of
these genetic causes of disease. I think our ability with
increased sequencing technology. So our ability to sequence all the
genes in an individual has allowed us now to identify
(13:35):
these changes in genes that these patients have, and so
then link those with disease and dysfunction of the immune system.
Dr Viviane Richter (13:44):
Do you feel autoimmune disease will be treated completely differently
in future?
Associate Professor Elissa Deenick (13:49):
Yeah, I think we'll see in the next decade or
so a real transformation in the way that we treat
autoimmune disease. Already there are new drugs coming onto the
market we call biologics that are more targeted approaches. And
as we develop ways of identifying which patients will be
treated best with those and develop even targeted therapies, I
(14:09):
think we will be able to track their response to
those treatments so we can optimise that treatment going forward
and make sure that we are suppressing disease while not
suppressing protective functions of the immune system as well as
much as possible.
Dr Viviane Richter (14:25):
Elissa, I heard that you've launched a research program in
collaboration with St Vincent's Hospital Sydney, to look at this
exactly to look at how we can better support patients
with these rare immune conditions.
Associate Professor Elissa Deenick (14:38):
As I said earlier, the number of conditions that we've
now identified – these genetic conditions that cause immune dysfunction –
has expanded greatly. But the problem with that is that
we actually are only just starting to do these kind
of personalised treatments for these patients, and we don't actually
know what all the outcomes are for those patients and
(14:59):
necessarily what the best treatment is. So what we're hoping
to do is to track these patients over time and
look at how these personalised treatments change their outcomes, change
their disease, change their quality of life. That's what the
clinicians at St Vincent's are doing. But what we're doing
in the lab is actually then working with them to
(15:21):
look for new ways of monitoring the immune health of
these patients. But the problem with trying to tailor treatment
is that at the moment, actually, we don't have really
good measures of immune health. So if I want to
track a patient and say is this treatment working. If
I don't actually know what a healthy immune system looks like,
(15:42):
how do I know if that treatment's been really effective?
So really, we need better ways of kind of looking
in greater detail about how the immune system has changed and
which particular components are missing, so that we can have
a much more detailed measure of immune health and really
be able to detect and then, as we treat them,
(16:05):
be able to see, are we restoring those defects, or
are we suppressing the cells that are really driving the autoimmunity?
But we'll only be able to do that well, if
we have better measures of immune health.
Dr Viviane Richter (16:19):
Are you hoping that this will give clinicians more options
on how to treat patients with these rare immune conditions?
Associate Professor Elissa Deenick (16:25):
Yeah, that's what we're hoping and not only give them
more options but help them to be able to decide
which is the best option for their patients. One of
the problems is that we don't know what the long
term outcomes for many of those patients are, because these
conditions have only been diagnosed relatively recently, so clinicians don't
(16:47):
have the information they need to know how best to
treat these patients. Can I use some of these targeted drugs?
And will that give long term protection and outcomes for
these patients? Or is it better to consider a bone
marrow transplant for these patients? Because if a bone marrow
(17:08):
transplant works, that can be curative, a bone marrow transplant
being where you wipe out your own immune system and
now you get someone else's bone marrow and your immune
system redevelops from that bone marrow. So you've replaced your
old defective immune system now with a new immune system.
But the problem with that is that bone marrow transplant
(17:29):
is risky. It's a wiping out your immune system, and
then you are waiting for the new one to redevelop,
and that makes you very susceptible to infection. And also
there's problems where bone marrow can react against you, so
you really need to have that data about what's the
best treatment. And so that's why we're working with St
Vincent's to track these patients to track their outcomes, to
(17:51):
track their immune health, track their responses to different treatments
so that we can provide the information that's required to
make these choices so that we can see how we
can get the best outcomes for these patients, both in
terms of their immune health, but also in terms of
quality of life.
Dr Viviane Richter (18:10):
Elissa, you're translating your research to autoimmune disease patients more broadly,
to patients with lupus for instance, how might that work?
Associate Professor Elissa Deenick (18:21):
So currently, if you're diagnosed with upus, you'll probably go
to your specialist and they'll prescribe you kind of whatever
the standard of care is firstline treatments. For some people
that will work really well. Their disease will go into remission,
and that's great. For other people they might go into remission,
but then they relapse. A specialist might try another drug
(18:45):
and see if that works. And then there's this change
in treatment looking for the thing that works. And so
there's this process of kind of looking for the best
treatment that will really work for a patient, and some
patients may go through that for years. What we're really
hoping will be the case in the future is that
(19:06):
when you are first diagnosed with lupus, that we'll be
able to do tests on your immune system, and we'll
be able to say, from the get go, actually, we
think this is the best treatment for you. So you
patients won't have to go through those stages of trying
different things to see what works, but we'll be able to
(19:26):
go straight to the best treatment.
Dr Viviane Richter (19:28):
So, Elissa, what's the big picture on all of this?
You're learning about how all these different components of the
immune system are working. How does it all hang together?
Associate Professor Elissa Deenick (19:39):
Yeah, well, a really important thing is not just that
we generate lots of data, but that we understand what
the big questions we're asking are and how the data
can answer those questions. So many different immune cells, they're
receiving kind of inputs from all over the place, the environment, microbiome.
And by that we mean the bacteria that might be
(20:01):
in our gut or in our skin. The things we
eat the you know, the things we do, they're all
impacting on our immune system. And how do we really
tease that out? And we want to make sure that
we're not just generating more and more data, but really
using that data to understand what's going on. And it's
not just us who are generating data. There are you know,
(20:23):
labs around the world who are also generating data. So
how can we make the best use of that data?
How can we integrate that data to really answer those
questions about how the immune system functions? Thankfully, I think
there's a lot of new technology coming on board in
terms of AI and machine learning, things that I don't really
understand but which are really allowing us to integrate these
(20:45):
data sets well. And we need that combination of people
like me who are immunologists and really into the biology
and data scientists who can really help us to interrogate
that data well, to ask the questions we want to and
start asking, can we see these interactions happening between different
immune cells, and we can really start to intervene.
Dr Viviane Richter (21:09):
Before we let you get back to the lab. Elissa,
it's time for the Fast Five where we find out
a little more about you. Are you ready?
Associate Professor Elissa Deenick (21:18):
I'm ready.
Dr Viviane Richter (21:19):
What do you do in your downtime?
Associate Professor Elissa Deenick (21:20):
I love playing sport. I'll play almost any sport at
the moment. AFL Nines, a bit of ice hockey and
a bit of golf
Dr Viviane Richter (21:26):
And which sport are you the best at?
Associate Professor Elissa Deenick (21:28):
I'd probably say ice hockey. I played that for the longest.
I did actually during my PhD win the national championships,
and I was actually the second string goalie. So I
actually saw hardly any ice time. But I still have
the medal to prove it.
Dr Viviane Richter (21:43):
Do you have any secret skills Elissa.
Associate Professor Elissa Deenick (21:46):
I used to say limbo when I was younger, actually,
but I think I've lost my flexibility.
Dr Viviane Richter (21:52):
Do you have a pet peeve?
Associate Professor Elissa Deenick (21:53):
Badly organised queues and it's always at airports like why
it's not that hard to efficiently run a queuing system.
You know, the worst was you have a queue and
then they open up a new queue. But they send
the people from the back of the line to the
front of the new queue. I'm like, meanwhile, the people
have been waiting in the line for ages.
Dr Viviane Richter (22:15):
What's been your favourite holiday?
Associate Professor Elissa Deenick (22:17):
I think it would definitely have to be when I was
living in Canada, working in a lab there, I got
into white water canoeing, So I went on this trip
where we flew in on a seaplane landed on a
lake in the middle of the Canadian wilderness. And he
dropped me off with my canoe in the middle of
(22:37):
the lake. And then we paddled for the next five
days through the wilderness, back to civiliation. It was amazing.
Dr Viviane Richter (22:45):
What motivates you to come to work every day?
Associate Professor Elissa Deenick (22:47):
I think it's just such a privilege to have a
job where you can turn up and you can both
have that intellectual stimulation of I just discovered something that
no one else in the world knows, but also knowing
that that discovery is actually potentially gonna really help people
(23:09):
and improve their health. I mean, I don't think you
could ask for much more in a job.
Dr Viviane Richter (23:13):
Associate Professor Elissa Deenick. Thank you so much for joining
us on Medical Minds.
Associate Professor Elissa Deenick (23:18):
Thanks for having me. I've loved it.
Dr Viviane Richter (23:20):
If you'd like to know more about Elissa's research or
the work we do at Garvan, head over 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
(23:43):
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.
APDS is an inherited immue condition that is rare. Since it
was discovered 10 years ago, it has been reported in
less than 300 people worldwide. So how could studying a
disease that only affects a few hundred help improve the
outcomes for millions of people who live with autoimmune disease?
Today we meet a researcher who is diving deep into
(00:24):
the genetics of immune cells to make sure no patient
gets left behind. You're listening to Medical Minds
takes you inside the labs at the Garvan Institute of
Medical Research. I'm your host, Dr Viviane Richter. And with
me here is Associate Professor Elissa Deenick, head of the Lymphocyte
Signalling and Activation Lab. Welcome, Elissa.
Associate Professor Elissa Deenick (00:48):
Thank you, Viv. It's great to be here.
Dr Viviane Richter (00:50):
Before we launch into finding out about APDS, this rare
disease that you and your team are working on, Elissa,
can you tell us about your journey studying the immune system?
Where did it all start?
Associate Professor Elissa Deenick (01:01):
Even as a kid, I was really interested in science
and how things worked. My dad was a science teacher,
so that might have impacted me. And then when I
was in year 10 I went off on a a
science summer school, and that summer school had a lot
of stuff about human biology, how the human body worked.
And I just became fascinated with how complex the human
(01:22):
body was and how interesting it was to study. So
I decided that when I finished school, I was gonna
do a medical science degree, which is what I did.
And then kind of at the end of second year,
I was looking for a research project that would give
me some research experience in a lab, and I kind
of by chance ended up in an immunology lab. But I
loved it. I loved how complex the immune system was,
(01:44):
but how important it was. And then when I came
to doing my honours, I decided I wanted to continue
in that. And it was really my supervisor at the
time who was just so excited about science and understanding
the way that the immune system worked together to protect
us against disease. That really made me choose that project
and go down that path.
Dr Viviane Richter (02:06):
That's brilliant. What was the project you were working on
at the time?
Associate Professor Elissa Deenick (02:10):
Actually, I think the title of my thesis was "Quantitative
Analysis of Lymphocyte Proliferation and Differentiation", which does not sound
very exciting. But it was really interesting because there's this
whole problem in immunology about, you know, if I get
an infection, I've got these immune cells that need to
fight it off. But in order to do that, you
(02:30):
need enough of them to fight it off. So that's
the proliferation where the cells divide, so you get enough of
them to fight it off and the differentiation, which is
where the immune cells need to get appropriate function so
that they can get rid of that infection. So really,
it was about understanding how lymphocytes – one of our immune
cells – do that, also understanding that it's not a black
(02:51):
and white thing. It's quantitative, so there are ranges of
scales of how activated you can be and what path
you go down.
Dr Viviane Richter (03:00):
Elissa, your research is looking at a rare condition called APDS.
Can you tell us about that?
Associate Professor Elissa Deenick (03:07):
Yeah, so APDS stands for activated PI3 kinase-delta syndrome. That's
a long name, but really, it's just describing the protein
that's affected in these patients. So this is a rare
condition that was described first about 10 years ago, and
it's caused by a genetic change in the gene that
encodes for this protein. And these patients have a range
(03:31):
of clinical manifestations. The most common one is that they
have these recurrent respiratory infections, so particularly with bacteria. But
they also have problems dealing with some viruses, like EBV,
which is the virus that causes glandular fever. They really
have trouble dealing with that, and they also have problems
with vaccine responses. Vaccine responses are to do with producing
(03:55):
antibodies that protect us against infection. They also produce antibodies
that attack their own cells, though so autoimmunity. It's a
really interesting problem where they've got deficient immunity in some areas,
but then overreactive immunity in other areas.
Dr Viviane Richter (04:12):
What's the difference between these rare immune conditions, such as
APDS and more common autoimmune conditions such as rheumatoid arthritis
or MS?
Associate Professor Elissa Deenick (04:22):
So APDS is what we refer to as an inborn
era of immunity, and these are conditions and there's now
over 400 of them that are caused by changes in
a single gene, so each one is a different single gene.
But APDS, for example, is caused by a change in
(04:43):
the gene that encodes for PI3 kinase. And these changes
have a big impact on the immune system. So they
cause immunodeficiency so susceptibility to infection it could be autoimmunity.
It could be increased rates of allergy. In contrast, in
diseases like rheumatoid arthritis, there's not a single gene change
(05:05):
that's happened that's driving disease. There's probably a complex interaction
of many different genes working together. Environmental factors. These all
work together to drive the disease.
Dr Viviane Richter (05:18):
How did you first come to study APDS?
Associate Professor Elissa Deenick (05:21):
Just over 10 years ago, I was working at the
Garvan and I was working with one of our other
Garvan researchers, Stu Tangye, and collaborators at NIH, which is
the National Institutes of Health in the US, the biggest
centre for research reached out and said, we've got this
cohort of patients, this group of patients and we think
we've found the genetic cause. Can you help us link
(05:44):
what we think is the gene involved to the problems
with the cells? So we did some work in our
lab to look at the cells of those patients and
to show that those cells were defective and make that
link to prove that this was a genetic cause of disease.
Dr Viviane Richter (06:02):
Through your work, what have you learned about this disease?
Associate Professor Elissa Deenick (06:04):
Yeah, so we've done a lot of work trying to
understand which immune cells are impacted by these genetic changes
and how that then leads to the symptoms that the
patients get. So we've looked at the T and B cells,
which work together to make antibodies, and we've shown that
there's defects in both the CD4 T cells and the
(06:26):
B cells, which means that they can't work together well
to make effective antibodies. But we've also been able to
show that the B cells react, funnily so they react
poorly to these foreign things. But when it's something like
what we call a self antigen, so part of our
own body, the B cells, which normally should be turned
(06:47):
off when they see something that cells instead get activated
and start making antibodies against that thing. So then these patients,
their B cells, get inappropriately activated, and they start making
antibodies against platelets or red blood cells, and that leads
to then problems with clotting or problems with oxygen transport.
(07:08):
For those patients. They then need treatments to suppress their
immune system and try and bring them under control again.
So it's this often this cycle of flares of disease
and then treatment and then being OK for a while
and then needing to come back.
Dr Viviane Richter (07:22):
And these patients would be on lifelong treatment paths, I would assume.
Associate Professor Elissa Deenick (07:27):
Yeah, and certainly before we had identified the genetic cause,
many of these patients just didn't know what was wrong
with them. They had these recurrent infections, or they had
these cytopenias. Their blood cells are being destroyed, and they
didn't know why their doctors didn't know why. And so
it's very difficult if you don't know what's driving disease
(07:49):
to treat appropriately. You end up just dealing with the
symptoms as they come up, rather than being able to
hit what's driving that disease and hopefully prevent ever getting
to that point.
Dr Viviane Richter (08:00):
And what has that discovery meant for APDS patients?
Associate Professor Elissa Deenick (08:04):
Well, first, it's meant that these patients can get a diagnosis,
so that meant that then clinicians all around the world
looked at patients they might have been seeing and went
I think that patient may also have that same genetic cause.
And so then they were able to test patients and
then give them a diagnosis.
Dr Viviane Richter (08:25):
So what did that mean for patient outcomes?
Associate Professor Elissa Deenick (08:28):
Well, one of the good things for patients with APDS
was that there were already some drugs on the market
that targeted the pathways that were dysregulated in these patients.
So that's meant that clinicians could use those drugs to
start treating these patients. And really, there's been some really
good outcomes in terms of seeing their disease improve.
Dr Viviane Richter (08:51):
That must be quite rewarding to know that you're helping
all these patients in this way.
Associate Professor Elissa Deenick (08:55):
Yeah, it is. I mean, science in the lab, you
can sometimes feel quite distant from what's going on in
the clinic. So it's really good to see these outcomes
and see real life changes for people. A lot of
lab work can be quite repetitive late nights stuck in
lab doing your experiments. But to see that at the
(09:17):
end of all that work, there are real changes for people.
People who didn't used to have a diagnosis now have one.
People who didn't have good treatments are now healthier. I mean,
I don't think you could ask for anything more really.
Dr Viviane Richter (09:31):
Elissa, What does research into such rare immune conditions mean
for patients with autoimmune disease more broadly?
Associate Professor Elissa Deenick (09:39):
It's really helpful, actually, for us to understand these other
autoimmune conditions. As discussed at the beginning of this conversation,
the immune system is really complex, and there are lots
of moving parts that work together to lead to an
immune response. And so then it can be really difficult
to know what's driving that response so we might see
(09:59):
the damage at the end. But what started that response?
So take lupus as an example of an autoimmune disease.
In lupus patients, they get a whole lot of antibodies
that target bits of the cell, like DNA, and that
causes damage that you see in lupus
problems in your kidney. And so we've grouped all these
(10:20):
lupus patients together because they have these symptoms at the end,
the symptoms of lupus. But lupus is almost certainly not
of one disease. It's probably a group of different diseases
where the initial starting problem that drove those B cells
to make those damaging antibodies and that caused the immune
system to go wrong is different. But the question is
(10:43):
in those patients, how do we get to the heart
of what's driving their disease? Because, really, we want to
treat the drivers of their disease, not the symptoms at
the end. We want to get in at the start
and make sure we stop them. So these APDS patients,
they show us that this protein PI3 kinase can be
a really important driver, and so that allows us to
(11:04):
then go back to other autoimmune diseases like lupus and say,
do some of these patients have similar drivers? Do they
also have dysregulation of this protein, this pathway that might
be driving disease? And if so, maybe we can use
similar drugs that we're using for the APDS patients to treat
those lupus patients. And that's true, not just of APDS,
(11:25):
but there's a lot of other what we call inborn
errors of immunity. So genetic causes that also result in autoimmunity.
And if we can use those to study what are the
really important genes and proteins in immune cells that control
whether we make good protective response or a bad destructive response,
(11:45):
can we then apply that to these other, more common
autoimmune diseases like lupus or multiple sclerosis and be able
to better treat those patients.
Dr Viviane Richter (11:56):
Will this approach help you identify patients who are more
or less likely to benefit from a specific treatment?
Associate Professor Elissa Deenick (12:04):
Yeah, so I guess the aim of what I do
and actually what the Precision Immunology Program at Garvan is
aiming to do is to really match treatment to specific patients.
A lot of our treatments currently for autoimmune diseases are not
very specific. That kind of generally suppress the immune system
(12:25):
rather than targeting the specific driver of disease. And that
has consequences. One
a high risk that you'll then suppress it too much
and you'll get infections. But also it's not always effective
for every patient. So really, what we hope to do
is to develop ways, develop tests or what we sometimes
(12:49):
call in science biomarkers that allow us to identify which
patient may have a particular driver of disease and then
match it with a drug that targets that driver. And
the hope would be that if we do that, we
will be able to inhibit disease more specifically and hopefully
have less impact on the protective functions of the immune system.
Dr Viviane Richter (13:11):
What is making this work possible now?
Associate Professor Elissa Deenick (13:14):
I think there's been several changes that have really transformed
the study of human immunology in particular in terms of
these genetic causes of disease. I think our ability with
increased sequencing technology. So our ability to sequence all the
genes in an individual has allowed us now to identify
(13:35):
these changes in genes that these patients have, and so
then link those with disease and dysfunction of the immune system.
Dr Viviane Richter (13:44):
Do you feel autoimmune disease will be treated completely differently
in future?
Associate Professor Elissa Deenick (13:49):
Yeah, I think we'll see in the next decade or
so a real transformation in the way that we treat
autoimmune disease. Already there are new drugs coming onto the
market we call biologics that are more targeted approaches. And
as we develop ways of identifying which patients will be
treated best with those and develop even targeted therapies, I
(14:09):
think we will be able to track their response to
those treatments so we can optimise that treatment going forward
and make sure that we are suppressing disease while not
suppressing protective functions of the immune system as well as
much as possible.
Dr Viviane Richter (14:25):
Elissa, I heard that you've launched a research program in
collaboration with St Vincent's Hospital Sydney, to look at this
exactly to look at how we can better support patients
with these rare immune conditions.
Associate Professor Elissa Deenick (14:38):
As I said earlier, the number of conditions that we've
now identified – these genetic conditions that cause immune dysfunction –
has expanded greatly. But the problem with that is that
we actually are only just starting to do these kind
of personalised treatments for these patients, and we don't actually
know what all the outcomes are for those patients and
(14:59):
necessarily what the best treatment is. So what we're hoping
to do is to track these patients over time and
look at how these personalised treatments change their outcomes, change
their disease, change their quality of life. That's what the
clinicians at St Vincent's are doing. But what we're doing
in the lab is actually then working with them to
(15:21):
look for new ways of monitoring the immune health of
these patients. But the problem with trying to tailor treatment
is that at the moment, actually, we don't have really
good measures of immune health. So if I want to
track a patient and say is this treatment working. If
I don't actually know what a healthy immune system looks like,
(15:42):
how do I know if that treatment's been really effective?
So really, we need better ways of kind of looking
in greater detail about how the immune system has changed and
which particular components are missing, so that we can have
a much more detailed measure of immune health and really
be able to detect and then, as we treat them,
(16:05):
be able to see, are we restoring those defects, or
are we suppressing the cells that are really driving the autoimmunity?
But we'll only be able to do that well, if
we have better measures of immune health.
Dr Viviane Richter (16:19):
Are you hoping that this will give clinicians more options
on how to treat patients with these rare immune conditions?
Associate Professor Elissa Deenick (16:25):
Yeah, that's what we're hoping and not only give them
more options but help them to be able to decide
which is the best option for their patients. One of
the problems is that we don't know what the long
term outcomes for many of those patients are, because these
conditions have only been diagnosed relatively recently, so clinicians don't
(16:47):
have the information they need to know how best to
treat these patients. Can I use some of these targeted drugs?
And will that give long term protection and outcomes for
these patients? Or is it better to consider a bone
marrow transplant for these patients? Because if a bone marrow
(17:08):
transplant works, that can be curative, a bone marrow transplant
being where you wipe out your own immune system and
now you get someone else's bone marrow and your immune
system redevelops from that bone marrow. So you've replaced your
old defective immune system now with a new immune system.
But the problem with that is that bone marrow transplant
(17:29):
is risky. It's a wiping out your immune system, and
then you are waiting for the new one to redevelop,
and that makes you very susceptible to infection. And also
there's problems where bone marrow can react against you, so
you really need to have that data about what's the
best treatment. And so that's why we're working with St
Vincent's to track these patients to track their outcomes, to
(17:51):
track their immune health, track their responses to different treatments
so that we can provide the information that's required to
make these choices so that we can see how we
can get the best outcomes for these patients, both in
terms of their immune health, but also in terms of
quality of life.
Dr Viviane Richter (18:10):
Elissa, you're translating your research to autoimmune disease patients more broadly,
to patients with lupus for instance, how might that work?
Associate Professor Elissa Deenick (18:21):
So currently, if you're diagnosed with upus, you'll probably go
to your specialist and they'll prescribe you kind of whatever
the standard of care is firstline treatments. For some people
that will work really well. Their disease will go into remission,
and that's great. For other people they might go into remission,
but then they relapse. A specialist might try another drug
(18:45):
and see if that works. And then there's this change
in treatment looking for the thing that works. And so
there's this process of kind of looking for the best
treatment that will really work for a patient, and some
patients may go through that for years. What we're really
hoping will be the case in the future is that
(19:06):
when you are first diagnosed with lupus, that we'll be
able to do tests on your immune system, and we'll
be able to say, from the get go, actually, we
think this is the best treatment for you. So you
patients won't have to go through those stages of trying
different things to see what works, but we'll be able to
(19:26):
go straight to the best treatment.
Dr Viviane Richter (19:28):
So, Elissa, what's the big picture on all of this?
You're learning about how all these different components of the
immune system are working. How does it all hang together?
Associate Professor Elissa Deenick (19:39):
Yeah, well, a really important thing is not just that
we generate lots of data, but that we understand what
the big questions we're asking are and how the data
can answer those questions. So many different immune cells, they're
receiving kind of inputs from all over the place, the environment, microbiome.
And by that we mean the bacteria that might be
(20:01):
in our gut or in our skin. The things we
eat the you know, the things we do, they're all
impacting on our immune system. And how do we really
tease that out? And we want to make sure that
we're not just generating more and more data, but really
using that data to understand what's going on. And it's
not just us who are generating data. There are you know,
(20:23):
labs around the world who are also generating data. So
how can we make the best use of that data?
How can we integrate that data to really answer those
questions about how the immune system functions? Thankfully, I think
there's a lot of new technology coming on board in
terms of AI and machine learning, things that I don't really
understand but which are really allowing us to integrate these
(20:45):
data sets well. And we need that combination of people
like me who are immunologists and really into the biology
and data scientists who can really help us to interrogate
that data well, to ask the questions we want to and
start asking, can we see these interactions happening between different
immune cells, and we can really start to intervene.
Dr Viviane Richter (21:09):
Before we let you get back to the lab. Elissa,
it's time for the Fast Five where we find out
a little more about you. Are you ready?
Associate Professor Elissa Deenick (21:18):
I'm ready.
Dr Viviane Richter (21:19):
What do you do in your downtime?
Associate Professor Elissa Deenick (21:20):
I love playing sport. I'll play almost any sport at
the moment. AFL Nines, a bit of ice hockey and
a bit of golf
Dr Viviane Richter (21:26):
And which sport are you the best at?
Associate Professor Elissa Deenick (21:28):
I'd probably say ice hockey. I played that for the longest.
I did actually during my PhD win the national championships,
and I was actually the second string goalie. So I
actually saw hardly any ice time. But I still have
the medal to prove it.
Dr Viviane Richter (21:43):
Do you have any secret skills Elissa.
Associate Professor Elissa Deenick (21:46):
I used to say limbo when I was younger, actually,
but I think I've lost my flexibility.
Dr Viviane Richter (21:52):
Do you have a pet peeve?
Associate Professor Elissa Deenick (21:53):
Badly organised queues and it's always at airports like why
it's not that hard to efficiently run a queuing system.
You know, the worst was you have a queue and
then they open up a new queue. But they send
the people from the back of the line to the
front of the new queue. I'm like, meanwhile, the people
have been waiting in the line for ages.
Dr Viviane Richter (22:15):
What's been your favourite holiday?
Associate Professor Elissa Deenick (22:17):
I think it would definitely have to be when I was
living in Canada, working in a lab there, I got
into white water canoeing, So I went on this trip
where we flew in on a seaplane landed on a
lake in the middle of the Canadian wilderness. And he
dropped me off with my canoe in the middle of
(22:37):
the lake. And then we paddled for the next five
days through the wilderness, back to civiliation. It was amazing.
Dr Viviane Richter (22:45):
What motivates you to come to work every day?
Associate Professor Elissa Deenick (22:47):
I think it's just such a privilege to have a
job where you can turn up and you can both
have that intellectual stimulation of I just discovered something that
no one else in the world knows, but also knowing
that that discovery is actually potentially gonna really help people
(23:09):
and improve their health. I mean, I don't think you
could ask for much more in a job.
Dr Viviane Richter (23:13):
Associate Professor Elissa Deenick. Thank you so much for joining
us on Medical Minds.
Associate Professor Elissa Deenick (23:18):
Thanks for having me. I've loved it.
Dr Viviane Richter (23:20):
If you'd like to know more about Elissa's research or
the work we do at Garvan, head over 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
(23:43):
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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