October 2, 2023 • 24 mins
Inside your blood stream, billions of immune cells are working hard to protect you – from bacteria, viruses, fungi, toxins – anything that could disturb your body's delicate balance. But how does this immune protection work? Today, we meet Professor Stuart Tangye, a scientific detective who is working to solve the immune system puzzle.
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Episode Transcript
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Dr Viviane Richter (00:00):
In your downtime, you might feel that your body is
not doing much. You might be sitting down having a
cup of tea, driving or taking a bus. But inside
your bloodstream, billions of immune cells are working hard to
protect you from bacteria, viruses, fungi, toxins anything that could
disturb your body's delicate balance. Sounds exhausting. But how does
(00:24):
this immune protection work? Today we meet a scientific detective
who is helping to answer that question. You're listening to
medical minds, the podcast that takes you inside the labs
at the Garvan Institute of Medical Research. I'm your host,
Dr Viviane Richter. And with me here is Professor Stuart Tangye,
head of the Immunology and Immunodeficiency Lab at Garvan. Welcome, Stu.
Prof Stuart Tangye (00:48):
Hi Viv. Great to be here.
Dr Viviane Richter (00:50):
Stuart, I think most of us have a general idea.
But for those who don't know, what is immunology?
Prof Stuart Tangye (00:56):
Immunology is the study of our immune system, and that's
one of the body's systems. But unlike our heart or
our nervous system, the immune system is everywhere, and I
was at my daughter's school recently talking to the kids
about science, and I said to them, what is the immune system?
And I was thrilled to know that they realised that
it was everywhere. And the reason that is is because
(01:19):
it's a force field that we have to develop and
strengthen over time to protect us against infection, no matter
how we're going to come across that infection.
Dr Viviane Richter (01:29):
Stu, what inspired you for a career in immunology?
Prof Stuart Tangye (01:32):
When I was young, I always liked puzzles. In fact,
I actually wanted to be a police officer, a detective,
because I wanted to solve things like crimes. But those
were the days when you had to be a particular height,
to be a into the police force, and I was
never going to be tall enough to be a policeman.
I also really liked forensic science, and that was sort
of coming to age then. But it's nothing like what
(01:53):
we know it is now. So there wasn't really a
university course to do forensic science. So I did a
degree called Bachelor of Biomedical Science, and I was learning
about biochemistry and microbiology. But then we started learning about
immunology from a young professor who had just started at
the university, and he just had this buzz and this
(02:14):
excitement to his lectures and what was riveting was you'd
ask the lecturer questions and he would say
And it's not that he didn't know it's that we,
as a field didn't know, whereas you sort of felt, we
knew everything that we were gonna learn about biochemistry and microbiology,
which obviously isn't true. But the way immunology was taught,
it was dynamic. It was fresh, it was vibrant. And
it was unknown, much more than any other scientific subject
(02:37):
that I was being taught when I was at university.
Dr Viviane Richter (02:40):
So it was an exciting time for immunology.
Prof Stuart Tangye (02:42):
It was a terrifically exciting time. This was the late
eighties early nineties, so access to scientific journals was not
like what it is today. I remember I would go
to the medical library at Sydney University because the uni
I was at didn't have a medical library, and you'd
wait for months for journal subscriptions to arrive. And you'd
just be there feverishly poring over journal table of contents
(03:05):
to see what's new. But the reality is that it
wasn't that new. It was published six months ago. That
was the way science was communicated 30 years ago. It's
not like a click of a button now where you
can download a science article or there's press releases about science.
You had to really dig in the library to find
out what it was. And that was also exciting because
it added to the whole mystery of how do you
(03:25):
find out stuff? You've got to really look for it
and dig for it, and it takes me back to again,
when I was a kid, I just wanted to find
bits and pieces, put them together, solve a problem and
tell a story.
Dr Viviane Richter (03:35):
Sounds like that took real commitment.
Prof Stuart Tangye (03:38):
It was. It was fun. It didn't feel like it
was a chore, though, and I think that's what I've
been really lucky about. I've been fortunate to work in
a career which is almost a hobby. You know, I'm
very passionate about science. I love many aspects of my job.
I'm blessed that this is my career. It's not without challenges, obviously,
but it was fun to and probably nerdy to sit
(03:58):
in a library and read science articles or stand over
a photocopier and again photocopy your articles, seeing it come
out and think this is gonna be really interesting and exciting.
Dr Viviane Richter (04:08):
Today we have immediate access to so much information. How
has that changed science?
Prof Stuart Tangye (04:14):
I think for researchers in Australia, that's made a huge
difference because these days everything is online, which is terrific
and immediate. So you can be on top of the
literature straight away. I don't have to wait for weeks
to months for those journals to come in. The other
transformation in my mind is the nature of my work
(04:35):
has always been very collaborative. But a while ago you'd
have to literally send letters or faxes to people talking
to them about
But now research is global and almost in real time.
Despite time differences, you send emails. My best collaborators are
actually overseas. We meet, we chat, we zoom, we skype,
(04:56):
we catch up all the time and we do experiments
together in real time. So we're solving these puzzles that
I find really interesting and challenging together at the same
time with a shared goal of solving a problem without
having to feel like you're always playing catch-up because something
similar was published six months ago.
Dr Viviane Richter (05:16):
Stu, I heard the first project you worked on in
a research lab was using a bee toxin. Is that right?
Prof Stuart Tangye (05:22):
That's absolutely right, Viv. For my Honours project, I was working
on what's called an immunotoxin, and what that is was
using an antibody, a monoclonal antibody, to target a particular cancer.
In this case, it was targeting a myeloma, and the
antibody itself was the vehicle by which to deliver a toxin.
(05:44):
And the toxin we used was a protein called melatin,
which is the toxin from the European honeybee. So what
we were doing, we were binding melatin to this antibody
and using that as a silver bullet to try to
kill cancer cells. And that's really interesting, because these days
the biggest development in treating human diseases has been the
(06:05):
application of immunotherapy for various types of cancers. And we
are now seeing these fantastic outcomes in patients who have
had otherwise very life-threatening, if not fatal, malignancies having a
new lease on life because we've been able to target
the immune system and improve the way the immune system
behaves by immunotherapies and ramping up the immune system. And
(06:26):
it's sort of interesting to reflect on my Honours year
where we were sort of doing something at a very,
very low level. But that was the principle of using
aspects of the immune system to target malignancies.
Dr Viviane Richter (06:36):
So what is immunotherapy? How does that actually work?
Prof Stuart Tangye (06:40):
This is another aspect that I find amazing about immunology.
Not only is immunology itself a discipline and a study
of the immune system, but the immune system itself makes
a whole lot of tools, uh, that protect us. And
one of these tools is called antibodies. Now, we use
antibodies to treat many diseases, and one of these, of course,
(07:00):
is different types of cancer. So these monoclonal antibodies are
given to patients, and what they do is they target
particular immune cells, and they basically turn them on so
that they can become very effective at recognising and killing
cancer cells, whereas before that, they were sort of held
in a bit of a dormant state. So the immunotherapy
is really ramping up the functionality of the immune system
(07:22):
to really clear out cancer cells.
Dr Viviane Richter (07:24):
So you started your research career in Australia, and after that,
I heard you went in search for the California dream.
Tell us about that.
Prof Stuart Tangye (07:33):
That's right, Viv. I grew up with my family in
the southern suburbs of Sydney. Spent a lot of time
on the coast. I was in the surf club and
things like this, so I really love the beaches. My
parents were very much into the Beach Boys and that
sort of west coast sound. So I was quite drawn
to California as a kid and as a young person.
But then, during my PhD, there was some terrific science
(07:55):
being done at a place called the DNAX Research Institute
of Molecular and Cell Biology, which is in Northern California.
I really wanted to go and work there, so I
got in touch with one of the heads of the
lab there. So luckily, he offered me a postdoc research position there.
So I went and joined his lab, and it was
the dream. I was living in California. I was spending
weekends out and about around the area there, which is
(08:17):
just a spectacular part of the world, the whole Pacific Northwest.
And then during the week and many weekends, I'd be
working at this institute, which was just a hub of activity.
Some of the biggest discoveries in immunology came out of
this place in the eighties and the nineties, and it
was frankly overwhelming. I was relatively young, I worked in
(08:38):
a small university department, and now I was sort of
dropped in the middle of all the action. And I
remember my, supervisor telling me not in a threatening way,
basically saying
up to you. There's no experiment that can't be done.
There's no service we can't provide you. There's no opportunity
that you can't take. So it was really up to
me to make the best of this situation, which was
(09:01):
terrifying but also incredibly inspiring, because I knew if I
was going to do anything. Now is my time. Because
basically I had unfettered access to smart people, technology projects, science,
and it was fantastic.
Dr Viviane Richter (09:15):
What project did you end up sinking your teeth into?
Prof Stuart Tangye (09:19):
I was drawn to human immunology, and a lot of
research was being done in mouse models of immunology, but
this was an opportunity to work in a human immunology department.
So there was a discovery of the cause of a
very rare genetic disease and that finding serendipitously actually informed
a project that I was working on significantly at the time.
(09:39):
So through collaboration with a colleague in Boston, I started
working on patients with this particular rare genetic disease, which
is called XLP. And the problem with this disease is
that the affected individuals – who are only boys, it's an
X-linked disease, so it only presents in males – they're healthy
until they get exposed to a virus called Epstein Barr virus,
(10:01):
which is actually incredibly common. It causes glandular fever, and
it's actually very hard to avoid. So these kids are
healthy until they get exposed to EBV, and then that
sort of sets off a ticking time bomb. They develop
dreadful disease. Their immune system can't handle the viral infection,
and they can have really severe, even fatal outcomes.
Dr Viviane Richter (10:19):
Stu, when we're talking about these rare genetic conditions, what
is rare, how many kids are actually affected by them?
Prof Stuart Tangye (10:26):
So for XLP that has an incidence of about one
in 500,000 to 1 in a million males because it
only affects boys, so that's very rare in Australia. There
might be one or two dozen cases, however, when it
comes to genetic immune diseases, there's over 500 genes have
been found that can cause these types of conditions. So
whilst one of those is obviously very rare, when you
(10:49):
combine all of those 500 genetic diseases, they're not as
rare as you think. In fact, they're more likely to affect, say,
one in 5000 or one in 10,000 individuals.
Dr Viviane Richter (10:58):
And even though these conditions might individually be quite rare,
the effect on the individual patient is extremely profound, right?
Prof Stuart Tangye (11:07):
That's right. If these conditions can be really severe, they
typically present very early in life, often within the first
12 months of life. And it's typically things like recurrent
ongoing refractory infections, bacterial infections, viral infections so kids are
often in and out of hospital. It's the sort of
situation where GPs will say, I've never seen this case before,
(11:28):
so that's the sort of presentation that they have.
Dr Viviane Richter (11:31):
Stu, tell us about the CIRCA program that you started.
Prof Stuart Tangye (11:35):
So we started the Clinical Immunogenomics Research Consortium of Australasia, CIRCA,
back in 2015. We got together and realised there was
an opportunity here to crowdsource expertise, so we brought together
scientists like myself clinicians across many of the hospitals in
initially in Sydney but now across Australia, geneticists and other
(11:56):
research groups who could sort of work together as a
collective as a collaborative unit to really try to solve
some of these really challenging cases from a diagnostic perspective.
But then also, hopefully, have those findings translate to ways
where we could give specific or better treatments for these
kids or families. There's no doubt that the work we've
(12:20):
done in CIRCA has changed lives. We've diagnosed many patients
who up until we set up CIRCA were undiagnosed. So
we've been able to inform families of exactly what disease
they have. That's also led to immediate plans for treatment.
If we know what the genetic cause of a disease is,
we often know what the best treatment is. These may
(12:40):
be very intensive treatments, like a bone marrow transplant, which
is itself not trivial, but we know that if you've
got this disease, you have to have a bone marrow transplant.
Other cases we've been able to diagnose additional members in
the family, and that's obviously been very important for themselves,
but also possibly family planning perspectives and we've also been
able to advise clinicians that they might consider trying alternative treatments,
(13:06):
which are more specific for the symptoms that are arising
because we're actually treating the genetic cause rather than just
treating the symptoms.
Dr Viviane Richter (13:14):
And how does it feel to have these impacts on
patient lives?
Prof Stuart Tangye (13:18):
It is pretty amazing. And whilst I don't actually see
the patients themselves or I'm not there when the information
about the outcomes is shared, it is pretty gratifying to
know that the research program that my lab has been
running and the research consortia that we've set up is
having a positive effect. And fundamentally, that's why we do
medical research. I did have the good fortune a few
(13:40):
years ago of meeting a young man who we had
diagnosed years before, and he was only eight or nine
at that time. But now he was 10 years older
and he'd had a bone marrow transplant. He was healthy.
He was in school. He was about to start university
and just knowing that if we hadn't had those understandings
at the time, his career or life trajectory would have
(14:02):
been very, very different.
Dr Viviane Richter (14:03):
So what does this research into these rare immune diseases.
What does that mean for the rest of us?
Prof Stuart Tangye (14:09):
So each of us has a unique immune system. Most
of us are healthy and fine, but then occasionally we'll
be struck down quite severely with some infection. COVID-19 really
brought this out in the fact that SARS-CoV-2 was a
virus that humans had never been exposed to before. And
suddenly people from all walks of life all ages were
(14:31):
being infected. And we realised that whilst it was clear
that there was a particular demographic being affected by SARS-CoV-2
so clearly, the elderly, men were more likely to get
really sick. There were other cases of people who were
otherwise healthy, who were suddenly presenting with severe and in
some cases fatal COVID-19. And that gave us the opportunity,
(14:52):
through this very large international global collective called the COVID Human Genetic Effort,
to really start studying the general population and why the
incidence and impact of SARS-CoV-2 infection could be really severe
in otherwise healthy individuals, and that actually led to a
whole lot of fascinating discoveries about what the immune system
(15:13):
needs to protect us against SARS-CoV-2 and other viruses and
how that could inform some treatments. And that has led to,
I think, some of the biggest understandings of the basic
issues around host-pathogen interaction. So how the human interacts with
SARS-CoV-2 and it's informed treatments for people who have severe COVID-19.
Dr Viviane Richter (15:33):
So how do these discoveries of the immune system how
do they lead to treatments? What's the process there?
Prof Stuart Tangye (15:40):
In the context of SARS-CoV-2 a lot of it was empirical.
There was an observation, and one of them, for example,
was that there's a chemical made by the immune system
called type I interferon. And it was found early on
that if you had a defect that prevented your immune
systems from making type I interferon or that they couldn't
respond to it very well, you often had very severe COVID-19. So, luckily,
(16:05):
type I interferon is actually a drug. It's been used to
treat other viral infections and some malignancies. So people started
using type I interferon and in some cases it was
successful so that that was one example. Translating discoveries from
immunological research into treatments is a fascinating field, and again,
this comes back to something I said before. The immune
(16:26):
system isn't just this defence force against pathogens. It can
be really harnessed and leveraged because of the components of it.
So it's possible to make monoclonal antibodies to improve cancer,
we can use monoclonal antibodies as treatments for inflammatory diseases.
We can put back molecules that are missing. The classic
(16:48):
example is diabetes. You don't have enough insulin. You treat
it with insulin. There are other immune diseases where a
part of your immune system is missing. And that can
be replaced. Understanding how the immune system works is also
really relevant for precision medicine. From the genetic aspect of
immune diseases – which is what I work in – understanding The
(17:09):
genetic cause of a disease really opens up opportunities for therapies.
So there's a disease that I work on, which is
called activated PI3 kinase delta syndrome or APDS for short and the genetic
cause there is an enzyme having too much activity, and this
was a very well studied enzyme well before it was
known to cause this human disease, because it's really fundamental
(17:29):
for many aspects of cell biology. So fortuitously, this enzyme
has been targeted to treat other diseases, particularly B cell malignancies.
There are several pharmaceutical companies who have developed specific inhibitors
for this enzyme, and that's now being used to treat
these rare patients with APDS. And there's many examples like
(17:50):
that where you actually treat the genetic cause rather than
treating the symptoms. So instead of doing general immunosuppression, for example,
with steroids, which can have a lot of off target effects,
you can just target the pathway that's the root cause
of the disease and hopefully just modulate that specifically rather
than non-specifically targeting a whole lot of immune pathways that
(18:10):
can then have their own complications.
Dr Viviane Richter (18:13):
Stu, you've spent much of your research career at the
Garvan Institute. Can you tell us why it's such a
powerhouse for immunology research?
Prof Stuart Tangye (18:21):
So immunology has always been a hugely successful discipline of
medical research across Australia, and that's been the case probably
since the sixties, because of some pioneers back in the day.
And that's still the case today. So we're very lucky
that there's been a really great collection of individuals and colleagues,
collaborators who have come to Garvan over the last 20
(18:42):
years to work in the immunology space. Garvan immunology has
changed a lot since I've been there, but the constant
has been the collegiality, the collaborations, the brains trust, that
critical mass that you need to have a really creative, innovative,
dynamic research environment that can be done with your colleagues
or in your own lab. But knowing that you're contributing
(19:03):
to something bigger than the individual parts, Garvan has always been
at the forefront of medical research across Australia and internationally,
and the immunology research that's being there is certainly world class.
There's terrific scientists, terrific leaders, but for me, working in
the genomic space, Garvan really is a powerhouse in genomic technologies,
(19:25):
adopting new techniques to study the genome, where we can
combine bioinformatics and genomic biology with what I do, which
is cellular immunology. And it comes together to try to
solve these puzzles that I've always been intrigued about since
I was a kid into how things work, why things
work and why don't they work when things go wrong
and how can we fix it? And then if we
(19:46):
can take that information and then transfer it to the
clinic and see the application of research for improving treatments
or outcomes for a patient, that's just gold.
Dr Viviane Richter (19:57):
Stu, or those listening today, what can we do in
our everyday life to help our immune system out?
Prof Stuart Tangye (20:02):
Well, being an immunologist, I am a huge advocate for vaccination.
So I strongly encourage people to get vaccinated to get
their kids vaccinated, to be up-to-date with their vaccine boosters.
And I think we just need to look back. A
couple of 100 years ago, life expectancy was much shorter
than what it is today. It was, you know, 30
40 50 years of age. If we were having this conversation,
(20:23):
then there's a very good chance that I may not
be alive because there were so many infectious diseases. But
these days, with the ongoing development of vaccines, many of
those infectious diseases are now preventable.
Dr Viviane Richter (20:36):
Stu, when you're thinking back at the boy who wanted
to be a detective, do you think we'll ever completely
solve the puzzle of the immune system?
Prof Stuart Tangye (20:45):
I'd really like to think we will. However, COVID has shown
us that as much as we know, there's a hell
of a lot that we don't. For me, there's just
these stark observations. We could be vaccinated against, say, smallpox,
and you just need one dose of a smallpox vaccine
and you're protected for life. SARS-CoV-2 showed us though, you
(21:07):
can be continually exposed, you can be vaccinated, but we're
still getting sick. The way your immune system responds to
one pathogen can be very different and defective to the way
it responds to another one. COVID has just made that stark.
We know a lot. There's no doubt about it. We
know so much more now than we did even when
I started 30 years ago, but that's a stark reminder
(21:29):
that we don't know everything. The mystery will continue. Hopefully,
we will get resolution around a lot of it. But
there's always gonna be unknowns. And the beauty of research
in one way is that as many questions as it answers,
it often throws up new questions. And for people like
me who love the unknown or those puzzles, it keeps
us going, and it's rewarding because you're solving one problem.
(21:51):
But you're opening a door to another set of questions
which you didn't know was there, and that's the door
you go through next.
Dr Viviane Richter (21:59):
OK, Stu. So this is the part of the podcast
where we get to find out all sorts of things
about you. It's called the Fast Five. Are you up
for it?
Prof Stuart Tangye (22:08):
Sure I am.
Dr Viviane Richter (22:09):
What do you do in your down time?
Prof Stuart Tangye (22:10):
I have, I have three kids aged nearly 12, 14
and 16, so I don't have a lot of down time,
but I spend a lot of my non work time
with my kids.
Dr Viviane Richter (22:19):
Favourite movie?
Prof Stuart Tangye (22:21):
Well, my favourite movie is Flying High. Uh, and that
almost ended my relationship with my current wife.
Dr Viviane Richter (22:29):
You have to tell us why.
Prof Stuart Tangye (22:30):
Well, when we were dating initially, I thought I'd impress
her by saying, oh, let's watch my favourite movie. Let's
just say she didn't think it was the best movie
ever made.
Dr Viviane Richter (22:43):
You're still together. You got over it.
Prof Stuart Tangye (22:45):
Oh, we're still very much together. But she still hasn't seen
all of Flying High.
Dr Viviane Richter (22:50):
Stu, do you have any secret skills?
Prof Stuart Tangye (22:52):
Well, I don't know if you call it a skill,
but when I was a kid, I always wanted to
learn how to play guitar. But one of my sons
started learning guitar himself a number of years ago, so
I thought, why not? So I started learning guitar about
six years ago.
Dr Viviane Richter (23:07):
What do you like to rip out on your guitar?
Prof Stuart Tangye (23:09):
I don't mind playing a few Cure songs, or I really
quite like Neil Young's Rocking in the Free World.
Dr Viviane Richter (23:15):
If you could be a movie character, who would you be?
Prof Stuart Tangye (23:17):
I certainly do like Indiana Jones... some of those characters
from the early Star Wars movies, so I think something
like that would be pretty cool. I think Indiana Jones
would be pretty hard to beat. Or James Bond.
Dr Viviane Richter (23:29):
What's the first concert you ever went to?
Prof Stuart Tangye (23:31):
Midnight Oil in 1993 at the Sydney Entertainment Centre. But
my mum reminds me that she took me to see
Johnny Farnham years before that when I was a kid.
But for some reason, I don't remember that one.
Dr Viviane Richter (23:43):
Love that. Professor Stuart Tangye. Thank you so much for
joining us on Medical Minds.
Prof Stuart Tangye (23:49):
It's been an absolute pleasure, Viv. Thanks very much.
Dr Viviane Richter (23:52):
If you'd like to know more about Professor Stuart Tangye'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
(24:13):
Gadigal people of the Eora nation. We recognise their continuing
connection to land, waters and community. We pay our respect
to Aboriginal and Torres Strait Islander cultures and Elders past,
present and emerging.
In your downtime, you might feel that your body is
not doing much. You might be sitting down having a
cup of tea, driving or taking a bus. But inside
your bloodstream, billions of immune cells are working hard to
protect you from bacteria, viruses, fungi, toxins anything that could
disturb your body's delicate balance. Sounds exhausting. But how does
(00:24):
this immune protection work? Today we meet a scientific detective
who is helping to answer that question. You're listening to
medical minds, the podcast that takes you inside the labs
at the Garvan Institute of Medical Research. I'm your host,
Dr Viviane Richter. And with me here is Professor Stuart Tangye,
head of the Immunology and Immunodeficiency Lab at Garvan. Welcome, Stu.
Prof Stuart Tangye (00:48):
Hi Viv. Great to be here.
Dr Viviane Richter (00:50):
Stuart, I think most of us have a general idea.
But for those who don't know, what is immunology?
Prof Stuart Tangye (00:56):
Immunology is the study of our immune system, and that's
one of the body's systems. But unlike our heart or
our nervous system, the immune system is everywhere, and I
was at my daughter's school recently talking to the kids
about science, and I said to them, what is the immune system?
And I was thrilled to know that they realised that
it was everywhere. And the reason that is is because
(01:19):
it's a force field that we have to develop and
strengthen over time to protect us against infection, no matter
how we're going to come across that infection.
Dr Viviane Richter (01:29):
Stu, what inspired you for a career in immunology?
Prof Stuart Tangye (01:32):
When I was young, I always liked puzzles. In fact,
I actually wanted to be a police officer, a detective,
because I wanted to solve things like crimes. But those
were the days when you had to be a particular height,
to be a into the police force, and I was
never going to be tall enough to be a policeman.
I also really liked forensic science, and that was sort
of coming to age then. But it's nothing like what
(01:53):
we know it is now. So there wasn't really a
university course to do forensic science. So I did a
degree called Bachelor of Biomedical Science, and I was learning
about biochemistry and microbiology. But then we started learning about
immunology from a young professor who had just started at
the university, and he just had this buzz and this
(02:14):
excitement to his lectures and what was riveting was you'd
ask the lecturer questions and he would say
And it's not that he didn't know it's that we,
as a field didn't know, whereas you sort of felt, we
knew everything that we were gonna learn about biochemistry and microbiology,
which obviously isn't true. But the way immunology was taught,
it was dynamic. It was fresh, it was vibrant. And
it was unknown, much more than any other scientific subject
(02:37):
that I was being taught when I was at university.
Dr Viviane Richter (02:40):
So it was an exciting time for immunology.
Prof Stuart Tangye (02:42):
It was a terrifically exciting time. This was the late
eighties early nineties, so access to scientific journals was not
like what it is today. I remember I would go
to the medical library at Sydney University because the uni
I was at didn't have a medical library, and you'd
wait for months for journal subscriptions to arrive. And you'd
just be there feverishly poring over journal table of contents
(03:05):
to see what's new. But the reality is that it
wasn't that new. It was published six months ago. That
was the way science was communicated 30 years ago. It's
not like a click of a button now where you
can download a science article or there's press releases about science.
You had to really dig in the library to find
out what it was. And that was also exciting because
it added to the whole mystery of how do you
(03:25):
find out stuff? You've got to really look for it
and dig for it, and it takes me back to again,
when I was a kid, I just wanted to find
bits and pieces, put them together, solve a problem and
tell a story.
Dr Viviane Richter (03:35):
Sounds like that took real commitment.
Prof Stuart Tangye (03:38):
It was. It was fun. It didn't feel like it
was a chore, though, and I think that's what I've
been really lucky about. I've been fortunate to work in
a career which is almost a hobby. You know, I'm
very passionate about science. I love many aspects of my job.
I'm blessed that this is my career. It's not without challenges, obviously,
but it was fun to and probably nerdy to sit
(03:58):
in a library and read science articles or stand over
a photocopier and again photocopy your articles, seeing it come
out and think this is gonna be really interesting and exciting.
Dr Viviane Richter (04:08):
Today we have immediate access to so much information. How
has that changed science?
Prof Stuart Tangye (04:14):
I think for researchers in Australia, that's made a huge
difference because these days everything is online, which is terrific
and immediate. So you can be on top of the
literature straight away. I don't have to wait for weeks
to months for those journals to come in. The other
transformation in my mind is the nature of my work
(04:35):
has always been very collaborative. But a while ago you'd
have to literally send letters or faxes to people talking
to them about
But now research is global and almost in real time.
Despite time differences, you send emails. My best collaborators are
actually overseas. We meet, we chat, we zoom, we skype,
(04:56):
we catch up all the time and we do experiments
together in real time. So we're solving these puzzles that
I find really interesting and challenging together at the same
time with a shared goal of solving a problem without
having to feel like you're always playing catch-up because something
similar was published six months ago.
Dr Viviane Richter (05:16):
Stu, I heard the first project you worked on in
a research lab was using a bee toxin. Is that right?
Prof Stuart Tangye (05:22):
That's absolutely right, Viv. For my Honours project, I was working
on what's called an immunotoxin, and what that is was
using an antibody, a monoclonal antibody, to target a particular cancer.
In this case, it was targeting a myeloma, and the
antibody itself was the vehicle by which to deliver a toxin.
(05:44):
And the toxin we used was a protein called melatin,
which is the toxin from the European honeybee. So what
we were doing, we were binding melatin to this antibody
and using that as a silver bullet to try to
kill cancer cells. And that's really interesting, because these days
the biggest development in treating human diseases has been the
(06:05):
application of immunotherapy for various types of cancers. And we
are now seeing these fantastic outcomes in patients who have
had otherwise very life-threatening, if not fatal, malignancies having a
new lease on life because we've been able to target
the immune system and improve the way the immune system
behaves by immunotherapies and ramping up the immune system. And
(06:26):
it's sort of interesting to reflect on my Honours year
where we were sort of doing something at a very,
very low level. But that was the principle of using
aspects of the immune system to target malignancies.
Dr Viviane Richter (06:36):
So what is immunotherapy? How does that actually work?
Prof Stuart Tangye (06:40):
This is another aspect that I find amazing about immunology.
Not only is immunology itself a discipline and a study
of the immune system, but the immune system itself makes
a whole lot of tools, uh, that protect us. And
one of these tools is called antibodies. Now, we use
antibodies to treat many diseases, and one of these, of course,
(07:00):
is different types of cancer. So these monoclonal antibodies are
given to patients, and what they do is they target
particular immune cells, and they basically turn them on so
that they can become very effective at recognising and killing
cancer cells, whereas before that, they were sort of held
in a bit of a dormant state. So the immunotherapy
is really ramping up the functionality of the immune system
(07:22):
to really clear out cancer cells.
Dr Viviane Richter (07:24):
So you started your research career in Australia, and after that,
I heard you went in search for the California dream.
Tell us about that.
Prof Stuart Tangye (07:33):
That's right, Viv. I grew up with my family in
the southern suburbs of Sydney. Spent a lot of time
on the coast. I was in the surf club and
things like this, so I really love the beaches. My
parents were very much into the Beach Boys and that
sort of west coast sound. So I was quite drawn
to California as a kid and as a young person.
But then, during my PhD, there was some terrific science
(07:55):
being done at a place called the DNAX Research Institute
of Molecular and Cell Biology, which is in Northern California.
I really wanted to go and work there, so I
got in touch with one of the heads of the
lab there. So luckily, he offered me a postdoc research position there.
So I went and joined his lab, and it was
the dream. I was living in California. I was spending
weekends out and about around the area there, which is
(08:17):
just a spectacular part of the world, the whole Pacific Northwest.
And then during the week and many weekends, I'd be
working at this institute, which was just a hub of activity.
Some of the biggest discoveries in immunology came out of
this place in the eighties and the nineties, and it
was frankly overwhelming. I was relatively young, I worked in
(08:38):
a small university department, and now I was sort of
dropped in the middle of all the action. And I
remember my, supervisor telling me not in a threatening way,
basically saying
up to you. There's no experiment that can't be done.
There's no service we can't provide you. There's no opportunity
that you can't take. So it was really up to
me to make the best of this situation, which was
(09:01):
terrifying but also incredibly inspiring, because I knew if I
was going to do anything. Now is my time. Because
basically I had unfettered access to smart people, technology projects, science,
and it was fantastic.
Dr Viviane Richter (09:15):
What project did you end up sinking your teeth into?
Prof Stuart Tangye (09:19):
I was drawn to human immunology, and a lot of
research was being done in mouse models of immunology, but
this was an opportunity to work in a human immunology department.
So there was a discovery of the cause of a
very rare genetic disease and that finding serendipitously actually informed
a project that I was working on significantly at the time.
(09:39):
So through collaboration with a colleague in Boston, I started
working on patients with this particular rare genetic disease, which
is called XLP. And the problem with this disease is
that the affected individuals – who are only boys, it's an
X-linked disease, so it only presents in males – they're healthy
until they get exposed to a virus called Epstein Barr virus,
(10:01):
which is actually incredibly common. It causes glandular fever, and
it's actually very hard to avoid. So these kids are
healthy until they get exposed to EBV, and then that
sort of sets off a ticking time bomb. They develop
dreadful disease. Their immune system can't handle the viral infection,
and they can have really severe, even fatal outcomes.
Dr Viviane Richter (10:19):
Stu, when we're talking about these rare genetic conditions, what
is rare, how many kids are actually affected by them?
Prof Stuart Tangye (10:26):
So for XLP that has an incidence of about one
in 500,000 to 1 in a million males because it
only affects boys, so that's very rare in Australia. There
might be one or two dozen cases, however, when it
comes to genetic immune diseases, there's over 500 genes have
been found that can cause these types of conditions. So
whilst one of those is obviously very rare, when you
(10:49):
combine all of those 500 genetic diseases, they're not as
rare as you think. In fact, they're more likely to affect, say,
one in 5000 or one in 10,000 individuals.
Dr Viviane Richter (10:58):
And even though these conditions might individually be quite rare,
the effect on the individual patient is extremely profound, right?
Prof Stuart Tangye (11:07):
That's right. If these conditions can be really severe, they
typically present very early in life, often within the first
12 months of life. And it's typically things like recurrent
ongoing refractory infections, bacterial infections, viral infections so kids are
often in and out of hospital. It's the sort of
situation where GPs will say, I've never seen this case before,
(11:28):
so that's the sort of presentation that they have.
Dr Viviane Richter (11:31):
Stu, tell us about the CIRCA program that you started.
Prof Stuart Tangye (11:35):
So we started the Clinical Immunogenomics Research Consortium of Australasia, CIRCA,
back in 2015. We got together and realised there was
an opportunity here to crowdsource expertise, so we brought together
scientists like myself clinicians across many of the hospitals in
initially in Sydney but now across Australia, geneticists and other
(11:56):
research groups who could sort of work together as a
collective as a collaborative unit to really try to solve
some of these really challenging cases from a diagnostic perspective.
But then also, hopefully, have those findings translate to ways
where we could give specific or better treatments for these
kids or families. There's no doubt that the work we've
(12:20):
done in CIRCA has changed lives. We've diagnosed many patients
who up until we set up CIRCA were undiagnosed. So
we've been able to inform families of exactly what disease
they have. That's also led to immediate plans for treatment.
If we know what the genetic cause of a disease is,
we often know what the best treatment is. These may
(12:40):
be very intensive treatments, like a bone marrow transplant, which
is itself not trivial, but we know that if you've
got this disease, you have to have a bone marrow transplant.
Other cases we've been able to diagnose additional members in
the family, and that's obviously been very important for themselves,
but also possibly family planning perspectives and we've also been
able to advise clinicians that they might consider trying alternative treatments,
(13:06):
which are more specific for the symptoms that are arising
because we're actually treating the genetic cause rather than just
treating the symptoms.
Dr Viviane Richter (13:14):
And how does it feel to have these impacts on
patient lives?
Prof Stuart Tangye (13:18):
It is pretty amazing. And whilst I don't actually see
the patients themselves or I'm not there when the information
about the outcomes is shared, it is pretty gratifying to
know that the research program that my lab has been
running and the research consortia that we've set up is
having a positive effect. And fundamentally, that's why we do
medical research. I did have the good fortune a few
(13:40):
years ago of meeting a young man who we had
diagnosed years before, and he was only eight or nine
at that time. But now he was 10 years older
and he'd had a bone marrow transplant. He was healthy.
He was in school. He was about to start university
and just knowing that if we hadn't had those understandings
at the time, his career or life trajectory would have
(14:02):
been very, very different.
Dr Viviane Richter (14:03):
So what does this research into these rare immune diseases.
What does that mean for the rest of us?
Prof Stuart Tangye (14:09):
So each of us has a unique immune system. Most
of us are healthy and fine, but then occasionally we'll
be struck down quite severely with some infection. COVID-19 really
brought this out in the fact that SARS-CoV-2 was a
virus that humans had never been exposed to before. And
suddenly people from all walks of life all ages were
(14:31):
being infected. And we realised that whilst it was clear
that there was a particular demographic being affected by SARS-CoV-2
so clearly, the elderly, men were more likely to get
really sick. There were other cases of people who were
otherwise healthy, who were suddenly presenting with severe and in
some cases fatal COVID-19. And that gave us the opportunity,
(14:52):
through this very large international global collective called the COVID Human Genetic Effort,
to really start studying the general population and why the
incidence and impact of SARS-CoV-2 infection could be really severe
in otherwise healthy individuals, and that actually led to a
whole lot of fascinating discoveries about what the immune system
(15:13):
needs to protect us against SARS-CoV-2 and other viruses and
how that could inform some treatments. And that has led to,
I think, some of the biggest understandings of the basic
issues around host-pathogen interaction. So how the human interacts with
SARS-CoV-2 and it's informed treatments for people who have severe COVID-19.
Dr Viviane Richter (15:33):
So how do these discoveries of the immune system how
do they lead to treatments? What's the process there?
Prof Stuart Tangye (15:40):
In the context of SARS-CoV-2 a lot of it was empirical.
There was an observation, and one of them, for example,
was that there's a chemical made by the immune system
called type I interferon. And it was found early on
that if you had a defect that prevented your immune
systems from making type I interferon or that they couldn't
respond to it very well, you often had very severe COVID-19. So, luckily,
(16:05):
type I interferon is actually a drug. It's been used to
treat other viral infections and some malignancies. So people started
using type I interferon and in some cases it was
successful so that that was one example. Translating discoveries from
immunological research into treatments is a fascinating field, and again,
this comes back to something I said before. The immune
(16:26):
system isn't just this defence force against pathogens. It can
be really harnessed and leveraged because of the components of it.
So it's possible to make monoclonal antibodies to improve cancer,
we can use monoclonal antibodies as treatments for inflammatory diseases.
We can put back molecules that are missing. The classic
(16:48):
example is diabetes. You don't have enough insulin. You treat
it with insulin. There are other immune diseases where a
part of your immune system is missing. And that can
be replaced. Understanding how the immune system works is also
really relevant for precision medicine. From the genetic aspect of
immune diseases – which is what I work in – understanding The
(17:09):
genetic cause of a disease really opens up opportunities for therapies.
So there's a disease that I work on, which is
called activated PI3 kinase delta syndrome or APDS for short and the genetic
cause there is an enzyme having too much activity, and this
was a very well studied enzyme well before it was
known to cause this human disease, because it's really fundamental
(17:29):
for many aspects of cell biology. So fortuitously, this enzyme
has been targeted to treat other diseases, particularly B cell malignancies.
There are several pharmaceutical companies who have developed specific inhibitors
for this enzyme, and that's now being used to treat
these rare patients with APDS. And there's many examples like
(17:50):
that where you actually treat the genetic cause rather than
treating the symptoms. So instead of doing general immunosuppression, for example,
with steroids, which can have a lot of off target effects,
you can just target the pathway that's the root cause
of the disease and hopefully just modulate that specifically rather
than non-specifically targeting a whole lot of immune pathways that
(18:10):
can then have their own complications.
Dr Viviane Richter (18:13):
Stu, you've spent much of your research career at the
Garvan Institute. Can you tell us why it's such a
powerhouse for immunology research?
Prof Stuart Tangye (18:21):
So immunology has always been a hugely successful discipline of
medical research across Australia, and that's been the case probably
since the sixties, because of some pioneers back in the day.
And that's still the case today. So we're very lucky
that there's been a really great collection of individuals and colleagues,
collaborators who have come to Garvan over the last 20
(18:42):
years to work in the immunology space. Garvan immunology has
changed a lot since I've been there, but the constant
has been the collegiality, the collaborations, the brains trust, that
critical mass that you need to have a really creative, innovative,
dynamic research environment that can be done with your colleagues
or in your own lab. But knowing that you're contributing
(19:03):
to something bigger than the individual parts, Garvan has always been
at the forefront of medical research across Australia and internationally,
and the immunology research that's being there is certainly world class.
There's terrific scientists, terrific leaders, but for me, working in
the genomic space, Garvan really is a powerhouse in genomic technologies,
(19:25):
adopting new techniques to study the genome, where we can
combine bioinformatics and genomic biology with what I do, which
is cellular immunology. And it comes together to try to
solve these puzzles that I've always been intrigued about since
I was a kid into how things work, why things
work and why don't they work when things go wrong
and how can we fix it? And then if we
(19:46):
can take that information and then transfer it to the
clinic and see the application of research for improving treatments
or outcomes for a patient, that's just gold.
Dr Viviane Richter (19:57):
Stu, or those listening today, what can we do in
our everyday life to help our immune system out?
Prof Stuart Tangye (20:02):
Well, being an immunologist, I am a huge advocate for vaccination.
So I strongly encourage people to get vaccinated to get
their kids vaccinated, to be up-to-date with their vaccine boosters.
And I think we just need to look back. A
couple of 100 years ago, life expectancy was much shorter
than what it is today. It was, you know, 30
40 50 years of age. If we were having this conversation,
(20:23):
then there's a very good chance that I may not
be alive because there were so many infectious diseases. But
these days, with the ongoing development of vaccines, many of
those infectious diseases are now preventable.
Dr Viviane Richter (20:36):
Stu, when you're thinking back at the boy who wanted
to be a detective, do you think we'll ever completely
solve the puzzle of the immune system?
Prof Stuart Tangye (20:45):
I'd really like to think we will. However, COVID has shown
us that as much as we know, there's a hell
of a lot that we don't. For me, there's just
these stark observations. We could be vaccinated against, say, smallpox,
and you just need one dose of a smallpox vaccine
and you're protected for life. SARS-CoV-2 showed us though, you
(21:07):
can be continually exposed, you can be vaccinated, but we're
still getting sick. The way your immune system responds to
one pathogen can be very different and defective to the way
it responds to another one. COVID has just made that stark.
We know a lot. There's no doubt about it. We
know so much more now than we did even when
I started 30 years ago, but that's a stark reminder
(21:29):
that we don't know everything. The mystery will continue. Hopefully,
we will get resolution around a lot of it. But
there's always gonna be unknowns. And the beauty of research
in one way is that as many questions as it answers,
it often throws up new questions. And for people like
me who love the unknown or those puzzles, it keeps
us going, and it's rewarding because you're solving one problem.
(21:51):
But you're opening a door to another set of questions
which you didn't know was there, and that's the door
you go through next.
Dr Viviane Richter (21:59):
OK, Stu. So this is the part of the podcast
where we get to find out all sorts of things
about you. It's called the Fast Five. Are you up
for it?
Prof Stuart Tangye (22:08):
Sure I am.
Dr Viviane Richter (22:09):
What do you do in your down time?
Prof Stuart Tangye (22:10):
I have, I have three kids aged nearly 12, 14
and 16, so I don't have a lot of down time,
but I spend a lot of my non work time
with my kids.
Dr Viviane Richter (22:19):
Favourite movie?
Prof Stuart Tangye (22:21):
Well, my favourite movie is Flying High. Uh, and that
almost ended my relationship with my current wife.
Dr Viviane Richter (22:29):
You have to tell us why.
Prof Stuart Tangye (22:30):
Well, when we were dating initially, I thought I'd impress
her by saying, oh, let's watch my favourite movie. Let's
just say she didn't think it was the best movie
ever made.
Dr Viviane Richter (22:43):
You're still together. You got over it.
Prof Stuart Tangye (22:45):
Oh, we're still very much together. But she still hasn't seen
all of Flying High.
Dr Viviane Richter (22:50):
Stu, do you have any secret skills?
Prof Stuart Tangye (22:52):
Well, I don't know if you call it a skill,
but when I was a kid, I always wanted to
learn how to play guitar. But one of my sons
started learning guitar himself a number of years ago, so
I thought, why not? So I started learning guitar about
six years ago.
Dr Viviane Richter (23:07):
What do you like to rip out on your guitar?
Prof Stuart Tangye (23:09):
I don't mind playing a few Cure songs, or I really
quite like Neil Young's Rocking in the Free World.
Dr Viviane Richter (23:15):
If you could be a movie character, who would you be?
Prof Stuart Tangye (23:17):
I certainly do like Indiana Jones... some of those characters
from the early Star Wars movies, so I think something
like that would be pretty cool. I think Indiana Jones
would be pretty hard to beat. Or James Bond.
Dr Viviane Richter (23:29):
What's the first concert you ever went to?
Prof Stuart Tangye (23:31):
Midnight Oil in 1993 at the Sydney Entertainment Centre. But
my mum reminds me that she took me to see
Johnny Farnham years before that when I was a kid.
But for some reason, I don't remember that one.
Dr Viviane Richter (23:43):
Love that. Professor Stuart Tangye. Thank you so much for
joining us on Medical Minds.
Prof Stuart Tangye (23:49):
It's been an absolute pleasure, Viv. Thanks very much.
Dr Viviane Richter (23:52):
If you'd like to know more about Professor Stuart Tangye'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
(24:13):
Gadigal people of the Eora nation. We recognise their continuing
connection to land, waters and community. We pay our respect
to Aboriginal and Torres Strait Islander cultures and Elders past,
present and emerging.
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