December 11, 2023 • 33 mins
A few hundred years ago, the idea of cells moving around in your body, protecting you from disease would have seemed like complete fantasy. Today, we don’t just know those remarkable cells exist – but we can visualise them in vivid detail. In this episode we meet Professor Tri Phan, a clinician-researcher who has combined his expertise in medicine and microscopy to unravel how our immune system works and how to stop it from going wrong.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Dr Viviane Richter (00:01):
150 years ago, the idea of cells moving around in
your body protecting you from disease would have seemed like
complete fantasy. Fast forward to today. We don't just know
those remarkable cells exist, but we can visualise them in
vivid detail. In this episode, we meet a clinician researcher
(00:22):
who has combined his expertise in medicine and microscopy to
unravel how our immune system works and how to stop
it from going wrong. 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
(00:43):
Professor Tri Phan, Head of the Intravital Microscopy and Gene
Expression Lab at Garvan and immunologist at St Vincent's Hospital Sydney.
Welcome Tri.
Prof Tri Phan (00:52):
Hi, Viv. Thank you. It's great to be here.
Dr Viviane Richter (00:55):
Tri, I heard your career path started off at the
dinner table when you were a kid.
Prof Tri Phan (01:01):
Yeah. So we were refugees. We were boat people, came
to Australia in the late seventies and Dad had to
learn English and, go back to medical school again. So
a lot of time, I actually would help Dad with
his study and I spent a lot of time surrounded
by his medical textbooks, which really initially sparked my interest
(01:23):
in infectious diseases. But after that, I guess in school
I spent a lot of time in the library. We
had a big collection of Scientific Americans, and I started
reading and became really fascinated by the immune system. And
I think what really, really sparked it off was I
discovered this great Australian immunologist, Macfarlane Burnet, who'd had all these
(01:45):
wonderful theories about how the immune system worked.
Dr Viviane Richter (01:48):
What was it about the immune system that really sparked your interest?
Prof Tri Phan (01:51):
I think one of the things that was really interesting
for me was that unlike a lot of the other
medical specialties where, for example, if you, you know, studied
cardiology you had an organ, the heart, and it pumped
blood around the body, so it was very concrete. The
immune system was really different because it consisted of all
(02:15):
these cells, many of which we hadn't discovered or hadn't
heard of yet. And no one really understood how these
cells got together, how they talked, how they, you know,
sensed what was dangerous, what was not dangerous and how
they could coordinate their activities to make sure that they
were protecting you from the outside world without turning on
themselves and causing autoimmune diseases.
Dr Viviane Richter (02:36):
Was it at that point that you knew you wanted
to be an immunologist?
Prof Tri Phan (02:39):
I became fascinated by one particular molecule that people had discovered.
And there was a lot of interest in because there
was this new area at the time of recombinant DNA technology,
Genentech had just started as a biotech company. And the
idea that you could engineer proteins to make biologics and
(03:04):
then treat immune diseases was really exciting. And it opened
up a lot of possibilities. And I thought, Oh, well,
this could be fun.
Dr Viviane Richter (03:12):
So tell us more about this new technology. How did
this work?
Prof Tri Phan (03:16):
Essentially the the idea was that if you had the
DNA sequence for a protein, then you basically had a
blueprint of how to make it and what recombinant DNA
technology is, it's just essentially using that blueprint and getting cells
to make it in a test tube. And then you
could do it at scale, mass produce those proteins and
(03:39):
purify it, and then make a therapeutic drug out of it,
and of course. Nowadays, recombinant DNA technology is what sits
behind all the blockbuster monoclonal antibodies that we use as
biologics to treat autoimmune diseases, to treat cancers. This is
probably one of the biggest biotech markets.
Dr Viviane Richter (04:00):
You became fascinated by the idea not only of how
the immune system works, but how we can use it
to combat disease.
Prof Tri Phan (04:08):
I think that was probably one of the most interesting
things about the immune system. One of the hallmarks is
this amazing ability of the immune system to have specificity.
Somehow the immune system can discriminate in the finest detail
between different molecules on the surface of a pathogen. You know,
(04:29):
a virus or a bacteria or your own cell, and
so that specificity can be harnessed because that allows you
to target the cell or the the disease and leave
other cells you know, avoid off-target effects. And this is
a huge problem in the treatment, for example, of autoimmune diseases,
because up till now we still have very, very blunt
(04:51):
instruments with which to treat patients that have lots and
lots of side effects because they're broad acting. They are non-specific,
and they have all these off-target effects. So specificity gives
us the first clue of how we might be able
to harness the immune system. The other thing about the
immune system is its extraordinary capacity for memory. So the
immune system encodes the ability to remember a threat that
(05:15):
it's encountered before and then through that be able to
mount very rigorous, really powerful responses the second time around.
So those two elements, specificity and memory are essentially the
key ingredients for making a really powerful weapon. If you
want to call it that, against, you know, infectious diseases
(05:36):
and also against cells, that might be a threat to
your own bodies, like cancer cells. So one example of
how we can take advantage of specificity is that in
many autoimmune diseases, we know what the target antigen is
that the immune system is attacking so we can use
that knowledge to then flip it around and target the
(05:57):
cell that's causing the damage. So in the example of
a blistering skin disease called pemphigus, we know that there
are these B cells that make antibodies that target a
protein called DSG3, and this is a protein that holds
your skin cells together and stops it from falling apart.
So if we use that DSG3 protein to then target
(06:22):
the B cell that's making the antibody, we can then
specifically kill only the B cells that's causing the damage.
That leaves all the other B cells untouched. That means
you can still have an intact immune system. You can
still make responses to vaccines, and if you encounter a virus,
you can still fight that virus. So that's the sort
(06:43):
of approach that we at the Garvan particularly are trying
to develop now with our precision immunology program, which is
to harness these two powerful attributes of the immune system
to develop the next generation of therapeutics.
Dr Viviane Richter (06:56):
That all sounds very complicated. I'd love to go back
to hear about how you came to learn about the
immune system.
Prof Tri Phan (07:05):
I wanted to be an immunologist when I was in school,
and my dad was a doctor. My brother and sister
had gotten into medical school, and I think the school
got in all these professors to give me career advice,
and they all said that if you were really interested
in immunology, then you should first study medicine and then
(07:29):
you can be a medical researcher. So that's how I
started off with medicine. And my parents obviously were ecstatic
that I decided to follow in their footsteps.
Dr Viviane Richter (07:39):
They would have been. What was your expectation going into
medical school, and how did it impact your research going forward?
Prof Tri Phan (07:47):
So I guess I had very low expectations of medical
school because I thought it was just gonna be a
drag that I had to go through before I could
actually do a PhD and really dive deep into the
immune system. It turned out to be really good. I
met Tony Basten, who was the Professor of Immunology at
Sydney University, and we had lots of conversations. The upshot,
(08:10):
of which was that he told me, I mean, you not
only have to go through med school, you actually have
to go and train as a specialist immunologist before you
can do a PhD with me. So six years in
med school became six years in med school, plus another
five years of specialist training before I was allowed to
(08:31):
do a PhD. At this point, it really felt like
one of those kung fu movies where you're sitting in
the rain outside the Shaolin Temple waiting to be allowed
to be admitted.
Dr Viviane Richter (08:43):
But you were admitted!
Prof Tri Phan (08:44):
So eventually Tony said that there was a project and
that I was gonna go and work with this fellow
named Robert Brink. And it was great, because by then
I'd been in clinical practice. I'd been looking after quite
a lot of patients with autoimmune diseases, and it was
really clear that there was an urgent need to actually
understand more about these autoimmune diseases because at the time,
(09:06):
no matter what the patient had, we always ended up
reaching for high dose corticosteroids. These are amazing drugs because
they kill off the cells of the immune system. So,
you know, they can put patients, for example, with an
autoimmune disease like systemic lupus erythematosus or SLE into remission.
But it comes at a huge price because, you know,
(09:28):
steroids have these terrible metabolic complications. You know, patients become diabetic, osteoporotic,
but also because they're so non-specific – and they were very
immunosuppressive – we were, actually, you know, making patients sick because the
immune system then wouldn't be able to fight infections. So
there really had to be a better way. And so
(09:49):
I was really keen to learn more about B cells
and learned more about how we could target them specifically
in a way that was going to not have all
these other side effects.
Dr Viviane Richter (09:59):
A lot of the researchers that we have here on
the podcast have spent times overseas. You went to San Francisco?
Prof Tri Phan (10:06):
Yeah, so San Francisco was really exciting. But I wanna
tell you why I went there. So we had developed
this model with which to track B cells and not
just track any B cell, B cells that were reacting
against a specific antigen. And what was really clear was
that the B cell was making this decision in the
(10:28):
dark to become activated and become a plasma cell. And
for me, it was really important to get into that
dark space and find out what that cell was talking to,
what instructions it was receiving and how that decision was
being made. And to do that, we really needed a
new technology. And at the time, intravital 2-photo microscopy was
(10:51):
bursting onto the scene, and one of the pioneers of
that new technology was Jason Cyster at the University of California
in San Francisco. To me, it was a no brainer.
The next step in my journey was really to learn
this new technology and to really be able to then
put the two together
(11:13):
cells and a microscope that allows us to see how
those B cells were behaving. We packed our bags and
headed off to San Francisco. So California, and particularly San Francisco,
was a really amazing place to be. I think everything
was happening at that time, we had, you know, Silicon
Valley going off with Apple, YouTube, Facebook. But also, there
(11:37):
was an amazing amount of biotech going on, and UCSF
was kind of like at the centre of that. And
so at work, we had all these crazy, smart people with,
you know, even crazy ideas, and I reflect now, 10, 15
years later and they've all turned into amazing discoveries, they've
really transformed not just medical research, but, uh, also the
(12:00):
practice of medicine.
Dr Viviane Richter (12:03):
And you came back to Australia after that?
Prof Tri Phan (12:06):
Yeah. So I came back to Australia to the Garvan Institute,
and I set about finding ways to bring back this
amazing technology that I had learned at UCSF and to
really start building up intravital microscopy at the Garvan Institute.
Dr Viviane Richter (12:25):
What were some of the questions that you were hoping
to answer with this new technology?
Prof Tri Phan (12:29):
One of the things that actually is really exciting about
intravital microscopy, as opposed, I guess, to some of the
other ways of approaching science is that literally we are
shining a light into a dark space that no one
has ever looked at before. So on the one hand, it's
(12:50):
incredibly challenging, the technology, the techniques. We are really, quite
often the only people in the world that can do
what we do, and we are very clearly sometimes the
first people to see what we're seeing, and that's super exciting.
What's even more exciting about that is that we are
seeing things that we never had imagined before, and so
(13:13):
that's completely rewriting and changing the way we're thinking about
the immune system. The problem was that until then, the
way we approached studying the immune system was very static,
even with animal models, the way we would try to
understand how, for example, the spatial organisation of the immune
system would be through destructive imaging. We would harvest tissue
(13:35):
and then cut slices and put it under the microscope.
What we were doing was completely different. We were dealing
with live tissue, live cells inside a live animal, and
these cells were moving around. And so we were seeing
things not only in three dimension but in four dimensions,
because we were able to capture the cell's behaviour over
(13:57):
time and this was coming together and generating a completely
different picture of the immune system as we understood it.
And so that was really exciting because we were starting
to appreciate things that we hadn't really thought were important before.
So to me, I think one of the great things
about intravital microscopy is as a discipline, I guess, is
(14:19):
that it really allows for someone who's really prepared to
accept that everything they'd been told about how the immune
system worked up till then may actually not be as
right as they thought it was.
Dr Viviane Richter (14:32):
What are some of the discoveries that you've made using
this form of imaging?
Prof Tri Phan (14:37):
Recently, we had a really exciting project that was carried
out by a PhD student, Abigail Grootveld and Wunna Kyaw,
and working with collaborators at Oxford University we decided to
look at a cell that had been forgotten entirely in
the immune system, and this was a cell called a
tingible body macrophage, or TBM. So when your immune system
(15:01):
is activated, the B cells need to go into a
structure called a germinal centre, and this is kind of
like school for B cells, right? Inside the germinal centre, the
B cells divide so they multiply and they multiply exponentially.
And during that process of multiplication, they change their receptor
for the B cell receptor for the antigen. And the
(15:23):
education part comes in because by changing the receptor, some
changes will make them react or neutralise the pathogen better.
Others will make it worse so that you can then
select the B cells that are actually going to be
able to neutralise better. So that's a process called affinity maturation.
But what happens to the B cells that aren't able
(15:44):
to bind as well Or worse s till, what happens when
the B cell, by changing its receptor, now suddenly reacts
against the self, becomes self-reactive? Those B cells die. So
inside this germinal centre there's an enormous amount of cell proliferation,
but also then an enormous amount of cell death. What
happens is that these TBMs, that's their function. Their housekeeping function
(16:07):
is to clear up all this dead and dying cell debris.
So you might think if you have teenage kids that
you know, telling your kids to clean up your room
is kind of like annoying... in the immune system, if
you don't clean up the dead and dying debris in
the germinal centre, those can become a source of antigens
(16:28):
that can activate a self-reactive B cell. And we know
in patients with SLE that there's defective apoptotic cell clearance.
So this cell was first described in 1885 and yet
we still know very little about it. And one of
the reasons why we know so little about it is
because it only appears when there's a germinal centre and
then it disappears. There's not many of them, and they're
(16:51):
very hard to isolate. They are incredibly elusive. But that's
exactly what intravital microscopy is designed to do to get
inside a live mouse to capture dynamics over periods of
time so that you don't miss the appearance and disappearance
of these cells. And so we were then able to
track the origin, the function and the fate of these
cells using intravital microscopy. And what's really exciting is that
(17:14):
the things that we're learning about these cells now means
that actually, we can think, if you don't clear away
this debris, you can get an autoimmune disease called systemic
lupus erythematosus or SLE. And one of the problems is
that SLE was the disease that the patients that I
used to have in the clinic that I couldn't treat
except by hitting them hard with steroids and causing all
(17:36):
these side effects. And now there are all these new
drugs new biologics that actually can target the B cells.
But even those drugs don't work very well in OE.
So we need a new way to think about how
we can treat this disease. And so what's exciting about
this research is that it's revealing to us that maybe
we can target not just the B cell, but also
(17:58):
these tingible body macrophages or TBMs. Because if we can
improve the ability of these macrophages to clear the dead
and dying debris, then we can actually stop that B
cell from getting activated in the first place. That cell
fake decision that I was talking about for the B
cell to become the antibody-producing plasma cell. We can stop
that before it happens, and that would be really exciting.
(18:19):
And then, I think, the third example of where we
can use intravital microscopy for biological discovery
for granted vaccination. I mean, it's one of the great
advances in medical science. But of course vaccination was built
on empiricism, which is trial and error. Moving forward, I
guess now there's an opportunity to take that trial and error,
(18:42):
but also take all the things that we've discovered and
learned about how the immune system works. And so if
you take the COVID vaccine, this is a vaccine that
typically you have two shots first priming shot or dose
and then a second booster shot. And so where do
you get those shots? This is not something that people
(19:02):
have asked systematically, because you go to your GP and you
have the shot in one arm, and then the next
time you have the shot in the same arm, the
other arm? Who knows, what's the right answer? So actually
this becomes really important because when we talk about the
immune system, we have to remember that we're talking about very,
very rare cells whizzing around your body. And the key
(19:23):
thing is that there aren't many of these cells, and
yet somehow they have to work out what's the best
strategy to be in the right place at the right time,
so that when you see the antigen again, you get activated.
And so what we showed through intravital microscopy was that
when you immunise, you generate a pool of memory B
cells that stay in the draining lymph node. That's the
(19:46):
gland that drains the skin, uh, or or the tissue
where the first shot was made. And in addition to that,
you generate another pool of memory B cells that can recirculate.
So this is kind of like having a sentry at
the guard post and then having a patrol running around
the body as well. And it turns out that these
(20:07):
different memory B cells do different things when they see
antigen again. So when they get boosted. So if you
come back and boost on the same side, you're activating
those sentries, and those B cells will go back into
the germinal centre, go back to school, and they have
the opportunity to diversify, to broaden the universe of possible
(20:28):
antigens that they can react to. And they also because
they're in the germinal centre. They have the ability to then fine
tune and tweak it so that they can neutralise with
greater and greater affinity that process of affinity maturation, whereas
if you go on the opposite side, those memory B
cells are more likely just to go straight to becoming
a plasma cell. So what we're showing is that the
(20:50):
site of boosting becomes critically important.
Dr Viviane Richter (20:55):
Fascinating. You're saying, if I'm getting my next COVID booster
or I'm getting next year's flu jab, I should have
it in the same arm as before.
Prof Tri Phan (21:03):
Normally, because you can get local side effects, you tend
to use your non-dominant arm, and so it just so happens,
and this is the empiricism that I was talking about.
It just so happens that maybe as much as 90%
of the time people are getting the the booster in
the same arm, which is what we would recommend. But
there's still, you know, 10% who, for whatever reason, are
(21:24):
choosing to get it in the opposite arm. And we
would suggest that by getting your boosters in the same arm,
you're gonna get a much better quality and quantity of
the vaccine response.
Dr Viviane Richter (21:35):
Tri, you're making some incredible discoveries in the lab, but
you have also made some life-changing discoveries in the clinic.
Prof Tri Phan (21:44):
Yeah, so I have a clinic at St Vincent's Hospital
where essentially, it's like the Salon des Refuses because I get sent
patients that many of the other specialists have come to
a dead end in terms of working out
with these patients? To me, that's really exciting, because essentially,
(22:05):
these are patients that are not contained anywhere in those
large volumes of medical textbooks. I think it's a really
important clinic because quite a lot of time we have
patients who fall outside the box. They're clearly very, very sick,
and they have a range of symptoms and signs, quite often,
(22:25):
very debilitating, chronic. But the problem is that they don't
fit into any neat category in any of the large
volumes of medical textbooks, and quite often they've undergone a
diagnostic odyssey. They've seen lots and lots of medical specialists.
One of the things about the clinic, I guess, is
that because they've seen a lot of specialists and doctors before,
(22:49):
then you can be almost sure that all the common
diseases have been excluded and what's left are either the
really rare or things that just haven't been described before.
And so it takes a lot of patience on the
part of the patients themselves, and they obviously have been
through a long journey. But you know, I think I
learn a lot from the patients and listening to them
(23:10):
and use that information to zone in on what part
of the immune system might be sitting underneath all their symptoms.
And we've just really been lucky because we've stumbled upon
a couple of diagnoses along the way. And I think
it's been really gratifying to see the impact of having
a diagnosis for these patients because it's not just the
(23:33):
ability to then have a label for their disease, because
for a lot of these patients, I think that's just
been incredibly frustrating. Many of them feel like they haven't
been heard, so it can be very, very important to
have that diagnosis, but also many of these diagnoses mean
that we can reach for a specific treatment that fixes
the genetic defect that's causing their symptoms, and the impact
(23:58):
of that can be completely life changing. One recent example
that came to mind was about four years ago. I
was referred a young man who was at university. He
had seen a haematologist who thought he had lymphoma because
he had a massively enlarged spleen and had very, very low
blood counts. But it turned out the reason why his
(24:18):
spleen was massively enlarged was because he had very severe
damage to his liver. So this was called hypersplenism, and
the reason why his counts was low was because the
massively enlarged spleen was destroying his blood cells. And when
we looked into it, it turned out that actually there
was this enormous family history of autoimmune diseases, but also
(24:43):
within the family tree, when you looked into it, over four generations
there were all these strange autoimmune diseases that didn't really
quite have a name. Sometimes it would be called systemic
lupus erythematosus. There were family members with lymphoma, but what
was really scary was that two of the male family
members had died at the age of 20 – and he was
(25:05):
19 – from liver disease. And we were really worried that
that was his fate, that if we didn't work out
what was wrong with him and didn't find a way
to treat him, that within a short period of time
he was going to have the same outcome. So it
was kind of like, really lucky that only a year
or two before a new disease had been described, where
(25:27):
they looked at patients with Behcet's and found a mutation
in this gene TNFAIP3 and through our collaborators Dr Andrew
Williams at the Children's Hospital Westmead. And we were able
to sequence that gene in him and show that he
had the same mutation as that had been described in
the original paper. And that was really exciting because knowing
(25:48):
that gene was mutated, we could then offer him a
specific gene targeted therapy, which was a TNF blocker. This
is a drug that's in common everyday use now to
treat patients with rheumatoid arthritis, so we repurposed it to
treat him, and he responded really, really well. At one
point we had actually referred him to the liver service
(26:10):
at Royal Prince Alfred Hospital because we were worried that
he was looking at maybe a liver transplant. But now
you know, he's graduated, three or four years later from uni.
He's got a scholarship at Oxford University, and I actually
think he's gonna change the world. So he's really, really
super bright. The other thing I guess that we were
able to do then was you know, his brother had
(26:31):
been sick all his life and didn't have a diagnosis.
And once we knew what was wrong with him, we
tested his brother. And sure enough, he had the same
genetic mutation, and we also diagnosed his sister with the
mutation as well. And what that means, then, is that
with these rare primary immunodeficiency diseases, what's been shown time
and time again is that the earlier you diagnose and
(26:53):
the earlier you can treat the patients, the better they
do because they don't suffer that long diagnostic odyssey and
they don't suffer the damage to their organs from years
of having no treatment. And I think this is the
power of precision immunology to be able to offer very
specific treatments for the disease.
Dr Viviane Richter (27:12):
Understanding the genetics of the immune system has really transformed
how patients are treated. Is that right?
Prof Tri Phan (27:17):
So I'm kind of like, super optimistic about this because
a long, long time ago, um, Professor Tony Basten told
me that at that time there were many, many diseases.
We don't know the cause or the treatments, and there
were diseases that were called idiopathic. And he said to me,
you know, Tri, in 20 years' time, all the idiopathic
(27:39):
diseases will be immune diseases, and he's actually not far
from the truth, because increasingly, we are seeing the footprint
of the immune system in all sorts of diseases, diseases
that we would not have imagined. Atherosclerosis. You know, people
with heart attacks, Alzheimer's disease, and so the things that
we're learning about the immune system through these studies through
(28:02):
these patients and then also through these animal models. These
are lessons that actually provide instructions on how the immune
system works. And we've already seen that come into effect
with enormous benefits in the cancer space with cancer immunotherapy,
you know, understanding how the immune system regulates itself, how
(28:22):
it puts checkpoints in place to make sure that it
creates the right response, not the wrong response and how
those checkpoints get hijacked by cancer cells to then prevent
immune attack and eradication of the cancer cells meaning that
now we've got an enormously powerful repertoire, which is expanding
of these immune checkpoint inhibitors that we're using to not
(28:45):
only treat but actually in many cases, cure cancers. And
that's super exciting. And I think that's only the tip
of the iceberg, because it won't just be cancers that
I think the immune system's going to revolutionise. I think
we're gonna see increasingly immune therapies for the so called chronic,
complex diseases of ageing. I would say in 20 years' time,
(29:06):
I think we'll be seeing immunotherapies being used to treat
just about every disease.
Dr Viviane Richter (29:12):
Tri the immune system is so overwhelmingly complicated. Do you think
we'll ever truly understand it?
Prof Tri Phan (29:20):
I think we are deluding ourselves if we think we're
ever gonna be in a position to fully understand how
the immune system works. I'm reminded of something I read
of many years ago where people predicted the end of
science because, you know, they thought all the theories are
gonna be proven. Every piece of knowledge is gonna be known.
We're generating so much data these days, right? Surely this
(29:44):
is going to be the end of science, but actually
I think this is the beginning of science because it's
great having an enormous amount of data, and it's great
having tools like AI. But the capacity to hallucinate, particularly
by AI is enormous, and we really need to have
ground truths. And we need to have guiding principles and
(30:06):
ideas sitting behind that. And in fact, you know, a
couple of years ago, Paul Nurse, who won the Nobel Prize,
made a very important point, which was that, actually, we
don't need more data. We need more ideas. And to me,
I think the way we work in our lab is
to actually start with a ground truth. Start with what's
(30:29):
known and more importantly, start with an important clinical problem.
What's bugging our patients? What's stopping us from treating them?
What are the things that's really gonna make a difference?
Dr Viviane Richter (30:41):
Tri, before we let you get back to your research, we
want to find out a little bit more about you.
It's called the Fast Five. What do you do in
your downtime?
Prof Tri Phan (30:49):
My favourite thing to do is the Friday cryptic crossword
by David Astle.
Dr Viviane Richter (30:53):
Favourite movie?
Prof Tri Phan (30:55):
Possibly 2001 A Space Odyssey. I just thought it was
amazing because it left so much for the imagination.
Dr Viviane Richter (31:03):
What's been your best holiday?
Prof Tri Phan (31:04):
Best holiday was last year. We went to the South
Island in New Zealand, the whole family and we started
in Christchurch and made our way to Queenstown. And we,
over a course of a week, did 120 kilometres hiking.
And we would watch Lord of the Rings at night
and go over the landscape and the scenery during the
(31:28):
day and the kids really got into it, so it
was amazing.
Dr Viviane Richter (31:31):
What's the current book you're reading?
Prof Tri Phan (31:33):
So right now I'm reading my Dad's memoir, which has
just been published, tells this really amazing epic story of
his life over 90 years, sort of reflecting the story
of Vietnam, really, you know, from Japanese occupation to French
colonial rule, Vietnam war, his time in the concentration camp,
(31:53):
and then our arrival in Australia as refugees as boat
people and you know all his struggles. It's called From
Vietnam to Australia, Sang's Memoirs.
Do You follow any sport.
Yeah, I love watching sport. I am a Wallabies tragic.
So I watch all the rugby. So But I have
to say that the last couple of years I've been
(32:15):
really excited about watching the Australian women's cricket team and
the Matildas because I think they truly represent what I
think Australian sport is about.
Dr Viviane Richter (32:28):
Professor Tri Phan. Thank you so much for joining us
on Medical Minds.
Prof Tri Phan (32:31):
Thank you, Viv. It's been a great pleasure to be here.
Dr Viviane Richter (32:34):
If you'd like to know more about trees research or
donate to the work we do at Garvan, head to
garvan.org.au and if you've enjoyed this podcast, please leave a
review and share with other podcast lovers. I'm Dr Viviane Richter.
Thanks for listening. This podcast was recorded on the traditional
(32:56):
Country of the 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.
150 years ago, the idea of cells moving around in
your body protecting you from disease would have seemed like
complete fantasy. Fast forward to today. We don't just know
those remarkable cells exist, but we can visualise them in
vivid detail. In this episode, we meet a clinician researcher
(00:22):
who has combined his expertise in medicine and microscopy to
unravel how our immune system works and how to stop
it from going wrong. 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
(00:43):
Professor Tri Phan, Head of the Intravital Microscopy and Gene
Expression Lab at Garvan and immunologist at St Vincent's Hospital Sydney.
Welcome Tri.
Prof Tri Phan (00:52):
Hi, Viv. Thank you. It's great to be here.
Dr Viviane Richter (00:55):
Tri, I heard your career path started off at the
dinner table when you were a kid.
Prof Tri Phan (01:01):
Yeah. So we were refugees. We were boat people, came
to Australia in the late seventies and Dad had to
learn English and, go back to medical school again. So
a lot of time, I actually would help Dad with
his study and I spent a lot of time surrounded
by his medical textbooks, which really initially sparked my interest
(01:23):
in infectious diseases. But after that, I guess in school
I spent a lot of time in the library. We
had a big collection of Scientific Americans, and I started
reading and became really fascinated by the immune system. And
I think what really, really sparked it off was I
discovered this great Australian immunologist, Macfarlane Burnet, who'd had all these
(01:45):
wonderful theories about how the immune system worked.
Dr Viviane Richter (01:48):
What was it about the immune system that really sparked your interest?
Prof Tri Phan (01:51):
I think one of the things that was really interesting
for me was that unlike a lot of the other
medical specialties where, for example, if you, you know, studied
cardiology you had an organ, the heart, and it pumped
blood around the body, so it was very concrete. The
immune system was really different because it consisted of all
(02:15):
these cells, many of which we hadn't discovered or hadn't
heard of yet. And no one really understood how these
cells got together, how they talked, how they, you know,
sensed what was dangerous, what was not dangerous and how
they could coordinate their activities to make sure that they
were protecting you from the outside world without turning on
themselves and causing autoimmune diseases.
Dr Viviane Richter (02:36):
Was it at that point that you knew you wanted
to be an immunologist?
Prof Tri Phan (02:39):
I became fascinated by one particular molecule that people had discovered.
And there was a lot of interest in because there
was this new area at the time of recombinant DNA technology,
Genentech had just started as a biotech company. And the
idea that you could engineer proteins to make biologics and
(03:04):
then treat immune diseases was really exciting. And it opened
up a lot of possibilities. And I thought, Oh, well,
this could be fun.
Dr Viviane Richter (03:12):
So tell us more about this new technology. How did
this work?
Prof Tri Phan (03:16):
Essentially the the idea was that if you had the
DNA sequence for a protein, then you basically had a
blueprint of how to make it and what recombinant DNA
technology is, it's just essentially using that blueprint and getting cells
to make it in a test tube. And then you
could do it at scale, mass produce those proteins and
(03:39):
purify it, and then make a therapeutic drug out of it,
and of course. Nowadays, recombinant DNA technology is what sits
behind all the blockbuster monoclonal antibodies that we use as
biologics to treat autoimmune diseases, to treat cancers. This is
probably one of the biggest biotech markets.
Dr Viviane Richter (04:00):
You became fascinated by the idea not only of how
the immune system works, but how we can use it
to combat disease.
Prof Tri Phan (04:08):
I think that was probably one of the most interesting
things about the immune system. One of the hallmarks is
this amazing ability of the immune system to have specificity.
Somehow the immune system can discriminate in the finest detail
between different molecules on the surface of a pathogen. You know,
(04:29):
a virus or a bacteria or your own cell, and
so that specificity can be harnessed because that allows you
to target the cell or the the disease and leave
other cells you know, avoid off-target effects. And this is
a huge problem in the treatment, for example, of autoimmune diseases,
because up till now we still have very, very blunt
(04:51):
instruments with which to treat patients that have lots and
lots of side effects because they're broad acting. They are non-specific,
and they have all these off-target effects. So specificity gives
us the first clue of how we might be able
to harness the immune system. The other thing about the
immune system is its extraordinary capacity for memory. So the
immune system encodes the ability to remember a threat that
(05:15):
it's encountered before and then through that be able to
mount very rigorous, really powerful responses the second time around.
So those two elements, specificity and memory are essentially the
key ingredients for making a really powerful weapon. If you
want to call it that, against, you know, infectious diseases
(05:36):
and also against cells, that might be a threat to
your own bodies, like cancer cells. So one example of
how we can take advantage of specificity is that in
many autoimmune diseases, we know what the target antigen is
that the immune system is attacking so we can use
that knowledge to then flip it around and target the
(05:57):
cell that's causing the damage. So in the example of
a blistering skin disease called pemphigus, we know that there
are these B cells that make antibodies that target a
protein called DSG3, and this is a protein that holds
your skin cells together and stops it from falling apart.
So if we use that DSG3 protein to then target
(06:22):
the B cell that's making the antibody, we can then
specifically kill only the B cells that's causing the damage.
That leaves all the other B cells untouched. That means
you can still have an intact immune system. You can
still make responses to vaccines, and if you encounter a virus,
you can still fight that virus. So that's the sort
(06:43):
of approach that we at the Garvan particularly are trying
to develop now with our precision immunology program, which is
to harness these two powerful attributes of the immune system
to develop the next generation of therapeutics.
Dr Viviane Richter (06:56):
That all sounds very complicated. I'd love to go back
to hear about how you came to learn about the
immune system.
Prof Tri Phan (07:05):
I wanted to be an immunologist when I was in school,
and my dad was a doctor. My brother and sister
had gotten into medical school, and I think the school
got in all these professors to give me career advice,
and they all said that if you were really interested
in immunology, then you should first study medicine and then
(07:29):
you can be a medical researcher. So that's how I
started off with medicine. And my parents obviously were ecstatic
that I decided to follow in their footsteps.
Dr Viviane Richter (07:39):
They would have been. What was your expectation going into
medical school, and how did it impact your research going forward?
Prof Tri Phan (07:47):
So I guess I had very low expectations of medical
school because I thought it was just gonna be a
drag that I had to go through before I could
actually do a PhD and really dive deep into the
immune system. It turned out to be really good. I
met Tony Basten, who was the Professor of Immunology at
Sydney University, and we had lots of conversations. The upshot,
(08:10):
of which was that he told me, I mean, you not
only have to go through med school, you actually have
to go and train as a specialist immunologist before you
can do a PhD with me. So six years in
med school became six years in med school, plus another
five years of specialist training before I was allowed to
(08:31):
do a PhD. At this point, it really felt like
one of those kung fu movies where you're sitting in
the rain outside the Shaolin Temple waiting to be allowed
to be admitted.
Dr Viviane Richter (08:43):
But you were admitted!
Prof Tri Phan (08:44):
So eventually Tony said that there was a project and
that I was gonna go and work with this fellow
named Robert Brink. And it was great, because by then
I'd been in clinical practice. I'd been looking after quite
a lot of patients with autoimmune diseases, and it was
really clear that there was an urgent need to actually
understand more about these autoimmune diseases because at the time,
(09:06):
no matter what the patient had, we always ended up
reaching for high dose corticosteroids. These are amazing drugs because
they kill off the cells of the immune system. So,
you know, they can put patients, for example, with an
autoimmune disease like systemic lupus erythematosus or SLE into remission.
But it comes at a huge price because, you know,
(09:28):
steroids have these terrible metabolic complications. You know, patients become diabetic, osteoporotic,
but also because they're so non-specific – and they were very
immunosuppressive – we were, actually, you know, making patients sick because the
immune system then wouldn't be able to fight infections. So
there really had to be a better way. And so
(09:49):
I was really keen to learn more about B cells
and learned more about how we could target them specifically
in a way that was going to not have all
these other side effects.
Dr Viviane Richter (09:59):
A lot of the researchers that we have here on
the podcast have spent times overseas. You went to San Francisco?
Prof Tri Phan (10:06):
Yeah, so San Francisco was really exciting. But I wanna
tell you why I went there. So we had developed
this model with which to track B cells and not
just track any B cell, B cells that were reacting
against a specific antigen. And what was really clear was
that the B cell was making this decision in the
(10:28):
dark to become activated and become a plasma cell. And
for me, it was really important to get into that
dark space and find out what that cell was talking to,
what instructions it was receiving and how that decision was
being made. And to do that, we really needed a
new technology. And at the time, intravital 2-photo microscopy was
(10:51):
bursting onto the scene, and one of the pioneers of
that new technology was Jason Cyster at the University of California
in San Francisco. To me, it was a no brainer.
The next step in my journey was really to learn
this new technology and to really be able to then
put the two together
(11:13):
cells and a microscope that allows us to see how
those B cells were behaving. We packed our bags and
headed off to San Francisco. So California, and particularly San Francisco,
was a really amazing place to be. I think everything
was happening at that time, we had, you know, Silicon
Valley going off with Apple, YouTube, Facebook. But also, there
(11:37):
was an amazing amount of biotech going on, and UCSF
was kind of like at the centre of that. And
so at work, we had all these crazy, smart people with,
you know, even crazy ideas, and I reflect now, 10, 15
years later and they've all turned into amazing discoveries, they've
really transformed not just medical research, but, uh, also the
(12:00):
practice of medicine.
Dr Viviane Richter (12:03):
And you came back to Australia after that?
Prof Tri Phan (12:06):
Yeah. So I came back to Australia to the Garvan Institute,
and I set about finding ways to bring back this
amazing technology that I had learned at UCSF and to
really start building up intravital microscopy at the Garvan Institute.
Dr Viviane Richter (12:25):
What were some of the questions that you were hoping
to answer with this new technology?
Prof Tri Phan (12:29):
One of the things that actually is really exciting about
intravital microscopy, as opposed, I guess, to some of the
other ways of approaching science is that literally we are
shining a light into a dark space that no one
has ever looked at before. So on the one hand, it's
(12:50):
incredibly challenging, the technology, the techniques. We are really, quite
often the only people in the world that can do
what we do, and we are very clearly sometimes the
first people to see what we're seeing, and that's super exciting.
What's even more exciting about that is that we are
seeing things that we never had imagined before, and so
(13:13):
that's completely rewriting and changing the way we're thinking about
the immune system. The problem was that until then, the
way we approached studying the immune system was very static,
even with animal models, the way we would try to
understand how, for example, the spatial organisation of the immune
system would be through destructive imaging. We would harvest tissue
(13:35):
and then cut slices and put it under the microscope.
What we were doing was completely different. We were dealing
with live tissue, live cells inside a live animal, and
these cells were moving around. And so we were seeing
things not only in three dimension but in four dimensions,
because we were able to capture the cell's behaviour over
(13:57):
time and this was coming together and generating a completely
different picture of the immune system as we understood it.
And so that was really exciting because we were starting
to appreciate things that we hadn't really thought were important before.
So to me, I think one of the great things
about intravital microscopy is as a discipline, I guess, is
(14:19):
that it really allows for someone who's really prepared to
accept that everything they'd been told about how the immune
system worked up till then may actually not be as
right as they thought it was.
Dr Viviane Richter (14:32):
What are some of the discoveries that you've made using
this form of imaging?
Prof Tri Phan (14:37):
Recently, we had a really exciting project that was carried
out by a PhD student, Abigail Grootveld and Wunna Kyaw,
and working with collaborators at Oxford University we decided to
look at a cell that had been forgotten entirely in
the immune system, and this was a cell called a
tingible body macrophage, or TBM. So when your immune system
(15:01):
is activated, the B cells need to go into a
structure called a germinal centre, and this is kind of
like school for B cells, right? Inside the germinal centre, the
B cells divide so they multiply and they multiply exponentially.
And during that process of multiplication, they change their receptor
for the B cell receptor for the antigen. And the
(15:23):
education part comes in because by changing the receptor, some
changes will make them react or neutralise the pathogen better.
Others will make it worse so that you can then
select the B cells that are actually going to be
able to neutralise better. So that's a process called affinity maturation.
But what happens to the B cells that aren't able
(15:44):
to bind as well Or worse s till, what happens when
the B cell, by changing its receptor, now suddenly reacts
against the self, becomes self-reactive? Those B cells die. So
inside this germinal centre there's an enormous amount of cell proliferation,
but also then an enormous amount of cell death. What
happens is that these TBMs, that's their function. Their housekeeping function
(16:07):
is to clear up all this dead and dying cell debris.
So you might think if you have teenage kids that
you know, telling your kids to clean up your room
is kind of like annoying... in the immune system, if
you don't clean up the dead and dying debris in
the germinal centre, those can become a source of antigens
(16:28):
that can activate a self-reactive B cell. And we know
in patients with SLE that there's defective apoptotic cell clearance.
So this cell was first described in 1885 and yet
we still know very little about it. And one of
the reasons why we know so little about it is
because it only appears when there's a germinal centre and
then it disappears. There's not many of them, and they're
(16:51):
very hard to isolate. They are incredibly elusive. But that's
exactly what intravital microscopy is designed to do to get
inside a live mouse to capture dynamics over periods of
time so that you don't miss the appearance and disappearance
of these cells. And so we were then able to
track the origin, the function and the fate of these
cells using intravital microscopy. And what's really exciting is that
(17:14):
the things that we're learning about these cells now means
that actually, we can think, if you don't clear away
this debris, you can get an autoimmune disease called systemic
lupus erythematosus or SLE. And one of the problems is
that SLE was the disease that the patients that I
used to have in the clinic that I couldn't treat
except by hitting them hard with steroids and causing all
(17:36):
these side effects. And now there are all these new
drugs new biologics that actually can target the B cells.
But even those drugs don't work very well in OE.
So we need a new way to think about how
we can treat this disease. And so what's exciting about
this research is that it's revealing to us that maybe
we can target not just the B cell, but also
(17:58):
these tingible body macrophages or TBMs. Because if we can
improve the ability of these macrophages to clear the dead
and dying debris, then we can actually stop that B
cell from getting activated in the first place. That cell
fake decision that I was talking about for the B
cell to become the antibody-producing plasma cell. We can stop
that before it happens, and that would be really exciting.
(18:19):
And then, I think, the third example of where we
can use intravital microscopy for biological discovery
for granted vaccination. I mean, it's one of the great
advances in medical science. But of course vaccination was built
on empiricism, which is trial and error. Moving forward, I
guess now there's an opportunity to take that trial and error,
(18:42):
but also take all the things that we've discovered and
learned about how the immune system works. And so if
you take the COVID vaccine, this is a vaccine that
typically you have two shots first priming shot or dose
and then a second booster shot. And so where do
you get those shots? This is not something that people
(19:02):
have asked systematically, because you go to your GP and you
have the shot in one arm, and then the next
time you have the shot in the same arm, the
other arm? Who knows, what's the right answer? So actually
this becomes really important because when we talk about the
immune system, we have to remember that we're talking about very,
very rare cells whizzing around your body. And the key
(19:23):
thing is that there aren't many of these cells, and
yet somehow they have to work out what's the best
strategy to be in the right place at the right time,
so that when you see the antigen again, you get activated.
And so what we showed through intravital microscopy was that
when you immunise, you generate a pool of memory B
cells that stay in the draining lymph node. That's the
(19:46):
gland that drains the skin, uh, or or the tissue
where the first shot was made. And in addition to that,
you generate another pool of memory B cells that can recirculate.
So this is kind of like having a sentry at
the guard post and then having a patrol running around
the body as well. And it turns out that these
(20:07):
different memory B cells do different things when they see
antigen again. So when they get boosted. So if you
come back and boost on the same side, you're activating
those sentries, and those B cells will go back into
the germinal centre, go back to school, and they have
the opportunity to diversify, to broaden the universe of possible
(20:28):
antigens that they can react to. And they also because
they're in the germinal centre. They have the ability to then fine
tune and tweak it so that they can neutralise with
greater and greater affinity that process of affinity maturation, whereas
if you go on the opposite side, those memory B
cells are more likely just to go straight to becoming
a plasma cell. So what we're showing is that the
(20:50):
site of boosting becomes critically important.
Dr Viviane Richter (20:55):
Fascinating. You're saying, if I'm getting my next COVID booster
or I'm getting next year's flu jab, I should have
it in the same arm as before.
Prof Tri Phan (21:03):
Normally, because you can get local side effects, you tend
to use your non-dominant arm, and so it just so happens,
and this is the empiricism that I was talking about.
It just so happens that maybe as much as 90%
of the time people are getting the the booster in
the same arm, which is what we would recommend. But
there's still, you know, 10% who, for whatever reason, are
(21:24):
choosing to get it in the opposite arm. And we
would suggest that by getting your boosters in the same arm,
you're gonna get a much better quality and quantity of
the vaccine response.
Dr Viviane Richter (21:35):
Tri, you're making some incredible discoveries in the lab, but
you have also made some life-changing discoveries in the clinic.
Prof Tri Phan (21:44):
Yeah, so I have a clinic at St Vincent's Hospital
where essentially, it's like the Salon des Refuses because I get sent
patients that many of the other specialists have come to
a dead end in terms of working out
with these patients? To me, that's really exciting, because essentially,
(22:05):
these are patients that are not contained anywhere in those
large volumes of medical textbooks. I think it's a really
important clinic because quite a lot of time we have
patients who fall outside the box. They're clearly very, very sick,
and they have a range of symptoms and signs, quite often,
(22:25):
very debilitating, chronic. But the problem is that they don't
fit into any neat category in any of the large
volumes of medical textbooks, and quite often they've undergone a
diagnostic odyssey. They've seen lots and lots of medical specialists.
One of the things about the clinic, I guess, is
that because they've seen a lot of specialists and doctors before,
(22:49):
then you can be almost sure that all the common
diseases have been excluded and what's left are either the
really rare or things that just haven't been described before.
And so it takes a lot of patience on the
part of the patients themselves, and they obviously have been
through a long journey. But you know, I think I
learn a lot from the patients and listening to them
(23:10):
and use that information to zone in on what part
of the immune system might be sitting underneath all their symptoms.
And we've just really been lucky because we've stumbled upon
a couple of diagnoses along the way. And I think
it's been really gratifying to see the impact of having
a diagnosis for these patients because it's not just the
(23:33):
ability to then have a label for their disease, because
for a lot of these patients, I think that's just
been incredibly frustrating. Many of them feel like they haven't
been heard, so it can be very, very important to
have that diagnosis, but also many of these diagnoses mean
that we can reach for a specific treatment that fixes
the genetic defect that's causing their symptoms, and the impact
(23:58):
of that can be completely life changing. One recent example
that came to mind was about four years ago. I
was referred a young man who was at university. He
had seen a haematologist who thought he had lymphoma because
he had a massively enlarged spleen and had very, very low
blood counts. But it turned out the reason why his
(24:18):
spleen was massively enlarged was because he had very severe
damage to his liver. So this was called hypersplenism, and
the reason why his counts was low was because the
massively enlarged spleen was destroying his blood cells. And when
we looked into it, it turned out that actually there
was this enormous family history of autoimmune diseases, but also
(24:43):
within the family tree, when you looked into it, over four generations
there were all these strange autoimmune diseases that didn't really
quite have a name. Sometimes it would be called systemic
lupus erythematosus. There were family members with lymphoma, but what
was really scary was that two of the male family
members had died at the age of 20 – and he was
(25:05):
19 – from liver disease. And we were really worried that
that was his fate, that if we didn't work out
what was wrong with him and didn't find a way
to treat him, that within a short period of time
he was going to have the same outcome. So it
was kind of like, really lucky that only a year
or two before a new disease had been described, where
(25:27):
they looked at patients with Behcet's and found a mutation
in this gene TNFAIP3 and through our collaborators Dr Andrew
Williams at the Children's Hospital Westmead. And we were able
to sequence that gene in him and show that he
had the same mutation as that had been described in
the original paper. And that was really exciting because knowing
(25:48):
that gene was mutated, we could then offer him a
specific gene targeted therapy, which was a TNF blocker. This
is a drug that's in common everyday use now to
treat patients with rheumatoid arthritis, so we repurposed it to
treat him, and he responded really, really well. At one
point we had actually referred him to the liver service
(26:10):
at Royal Prince Alfred Hospital because we were worried that
he was looking at maybe a liver transplant. But now
you know, he's graduated, three or four years later from uni.
He's got a scholarship at Oxford University, and I actually
think he's gonna change the world. So he's really, really
super bright. The other thing I guess that we were
able to do then was you know, his brother had
(26:31):
been sick all his life and didn't have a diagnosis.
And once we knew what was wrong with him, we
tested his brother. And sure enough, he had the same
genetic mutation, and we also diagnosed his sister with the
mutation as well. And what that means, then, is that
with these rare primary immunodeficiency diseases, what's been shown time
and time again is that the earlier you diagnose and
(26:53):
the earlier you can treat the patients, the better they
do because they don't suffer that long diagnostic odyssey and
they don't suffer the damage to their organs from years
of having no treatment. And I think this is the
power of precision immunology to be able to offer very
specific treatments for the disease.
Dr Viviane Richter (27:12):
Understanding the genetics of the immune system has really transformed
how patients are treated. Is that right?
Prof Tri Phan (27:17):
So I'm kind of like, super optimistic about this because
a long, long time ago, um, Professor Tony Basten told
me that at that time there were many, many diseases.
We don't know the cause or the treatments, and there
were diseases that were called idiopathic. And he said to me,
you know, Tri, in 20 years' time, all the idiopathic
(27:39):
diseases will be immune diseases, and he's actually not far
from the truth, because increasingly, we are seeing the footprint
of the immune system in all sorts of diseases, diseases
that we would not have imagined. Atherosclerosis. You know, people
with heart attacks, Alzheimer's disease, and so the things that
we're learning about the immune system through these studies through
(28:02):
these patients and then also through these animal models. These
are lessons that actually provide instructions on how the immune
system works. And we've already seen that come into effect
with enormous benefits in the cancer space with cancer immunotherapy,
you know, understanding how the immune system regulates itself, how
(28:22):
it puts checkpoints in place to make sure that it
creates the right response, not the wrong response and how
those checkpoints get hijacked by cancer cells to then prevent
immune attack and eradication of the cancer cells meaning that
now we've got an enormously powerful repertoire, which is expanding
of these immune checkpoint inhibitors that we're using to not
(28:45):
only treat but actually in many cases, cure cancers. And
that's super exciting. And I think that's only the tip
of the iceberg, because it won't just be cancers that
I think the immune system's going to revolutionise. I think
we're gonna see increasingly immune therapies for the so called chronic,
complex diseases of ageing. I would say in 20 years' time,
(29:06):
I think we'll be seeing immunotherapies being used to treat
just about every disease.
Dr Viviane Richter (29:12):
Tri the immune system is so overwhelmingly complicated. Do you think
we'll ever truly understand it?
Prof Tri Phan (29:20):
I think we are deluding ourselves if we think we're
ever gonna be in a position to fully understand how
the immune system works. I'm reminded of something I read
of many years ago where people predicted the end of
science because, you know, they thought all the theories are
gonna be proven. Every piece of knowledge is gonna be known.
We're generating so much data these days, right? Surely this
(29:44):
is going to be the end of science, but actually
I think this is the beginning of science because it's
great having an enormous amount of data, and it's great
having tools like AI. But the capacity to hallucinate, particularly
by AI is enormous, and we really need to have
ground truths. And we need to have guiding principles and
(30:06):
ideas sitting behind that. And in fact, you know, a
couple of years ago, Paul Nurse, who won the Nobel Prize,
made a very important point, which was that, actually, we
don't need more data. We need more ideas. And to me,
I think the way we work in our lab is
to actually start with a ground truth. Start with what's
(30:29):
known and more importantly, start with an important clinical problem.
What's bugging our patients? What's stopping us from treating them?
What are the things that's really gonna make a difference?
Dr Viviane Richter (30:41):
Tri, before we let you get back to your research, we
want to find out a little bit more about you.
It's called the Fast Five. What do you do in
your downtime?
Prof Tri Phan (30:49):
My favourite thing to do is the Friday cryptic crossword
by David Astle.
Dr Viviane Richter (30:53):
Favourite movie?
Prof Tri Phan (30:55):
Possibly 2001 A Space Odyssey. I just thought it was
amazing because it left so much for the imagination.
Dr Viviane Richter (31:03):
What's been your best holiday?
Prof Tri Phan (31:04):
Best holiday was last year. We went to the South
Island in New Zealand, the whole family and we started
in Christchurch and made our way to Queenstown. And we,
over a course of a week, did 120 kilometres hiking.
And we would watch Lord of the Rings at night
and go over the landscape and the scenery during the
(31:28):
day and the kids really got into it, so it
was amazing.
Dr Viviane Richter (31:31):
What's the current book you're reading?
Prof Tri Phan (31:33):
So right now I'm reading my Dad's memoir, which has
just been published, tells this really amazing epic story of
his life over 90 years, sort of reflecting the story
of Vietnam, really, you know, from Japanese occupation to French
colonial rule, Vietnam war, his time in the concentration camp,
(31:53):
and then our arrival in Australia as refugees as boat
people and you know all his struggles. It's called From
Vietnam to Australia, Sang's Memoirs.
Do You follow any sport.
Yeah, I love watching sport. I am a Wallabies tragic.
So I watch all the rugby. So But I have
to say that the last couple of years I've been
(32:15):
really excited about watching the Australian women's cricket team and
the Matildas because I think they truly represent what I
think Australian sport is about.
Dr Viviane Richter (32:28):
Professor Tri Phan. Thank you so much for joining us
on Medical Minds.
Prof Tri Phan (32:31):
Thank you, Viv. It's been a great pleasure to be here.
Dr Viviane Richter (32:34):
If you'd like to know more about trees research or
donate to the work we do at Garvan, head to
garvan.org.au and if you've enjoyed this podcast, please leave a
review and share with other podcast lovers. I'm Dr Viviane Richter.
Thanks for listening. This podcast was recorded on the traditional
(32:56):
Country of the 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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