February 5, 2024 • 28 mins
If you’ve ever seen an image of fluorescent cancer cells under the microscope, you may agree that it’s hard to understand how something so beautiful could be so deadly. In this episode, we speak to Professor Paul Timpson who is visualising pancreatic cancer in vivid detail to understand what the cancer's weak spots are and how to improve treatments for patients.
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Episode Transcript
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Dr Viviane Richter (00:01):
If you've ever seen an image of fluorescent cancer cells
under the microscope, you may agree that it's hard to
understand how something so beautiful could be so deadly. Today
we speak to a researcher who is visualising one of
the deadliest cancers in vividly beautiful detail to figure out
what the cancer's weak spot are and how patients can
(00:22):
receive the right treatment in the right amount at the
right time. 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 Paul Timpson, Head of the Invasion
and Metastasis Lab at Garvan. Welcome, Paul!
Prof Paul Timpson (00:43):
Hi Viv. Great to be here.
Dr Viviane Richter (00:45):
Paul, you are a world leader in pancreatic cancer research.
You have high profile publications, prestigious awards and significant grants
to back this up. But I heard your career in
science actually started out with you dropping out of uni.
Prof Paul Timpson (01:00):
Yes, that's true. So originally I was good at maths,
and physics. I was very lucky to not have to go
to school on Thursdays and I actually joined quite a geeky
club called the Young Engineers Club. My school friends did
not like the fact I didn't get to go to
school on Thursdays. They were all jealous and I absolutely loved
(01:20):
competing at a very young age. So therefore, engineering was my destiny,
and that's where I was supposed to go. I was
allowed to go to university and already was accepted to
engineering very early. So I did the spare class in biology,
which I loved. Once I went to university, I realised
(01:41):
that actually engineering was not what I loved. And I think
I've never been happier than the day I dropped out of
university and I've never looked back. Not sure my family
were happy about that. But I had a vision. And I
actually had to go to a completely different school to
do advanced maths, advanced biology – because the university didn't think
I could keep up with organic chemistry. I loved going
(02:05):
to different school, but I knew this was where I
wanted to be, and I wanted to do biology not to
mash up plants but to actually attack human diseases. Obviously,
what I do now is cancer, but there was lots of
diseases I could really envisage using the biology, but accidentally, the
(02:25):
math and the physics I was already good at in biology.
And again, you can never really escape all forms of
science if you're really going to make a difference in
the disease.
Dr Viviane Richter (02:34):
What university did you go to?
Prof Paul Timpson (02:36):
Okay, Viv. As you can tell from my accent, I
am very Scottish. I went to university in Glasgow, Strathclyde
University for my undergraduate. Then I studied at the Beatson
Institute or CRUK, and that's in Glasgow University itself. So,
born and bred, educated in Glasgow and then moved to
(02:58):
Australia for some sunshine.
Dr Viviane Richter (03:00):
What was it about biology that really appealed to you?
Prof Paul Timpson (03:04):
I loved the idea that we could actually attack various
human diseases like cancer, for example, but I was very privileged
in the third year of university when I was selected to
go to New York, which you can imagine would be amazing.
I represented Scotland with someone from England, Russia, France, etcetera.
That was three months of a very defining time in
(03:27):
my life, where I hung about with like minded people
all over American over Europe, etcetera. And really did pure
actual science, not pass exams, type science. We don't know
the answer to these questions. Please be part of a
team to work on it, loved that, came back to university
and instantly talked to my lecturers and said I will
(03:49):
be doing a PhD now which they questioned and thought
that was a little bit cocky. But after I actually showed
how I really believed and wanted to do it, they could
see the difference. And I think that sometimes it's not
just how well you can pass an exam. It's actually what
is your passion and how hard will you want to
take that on? Because a PhD is not easy. And a ctually,
(04:11):
any proper PhD doesn't have an answer. It's you that
has to try and find that answer.
Dr Viviane Richter (04:17):
So tell us about what you did during your PhD.
Prof Paul Timpson (04:20):
So my PhD, I really got interested in how cells move.
So the biggest killer in cancer, and we still know that today is:
as soon as it spreads, the game is over, really.
So we need to understand how they spread before we
can attack it. And I think that's what you said
at the beginning of the podcast, which was how can
something so beautiful or something that you actually appreciate work
(04:44):
for you? So you need to understand your enemy. So
you must actually embrace how it co-opts different mechanisms, how
it changes to act in a cytoskeleton, which, like the skeleton of
an individual cell or a cancer. How does it co-opt that?
How does it use this to actually spread throughout the body?
Once we can understand it, we can possibly see its vulnerabilities.
(05:07):
And that's what I did in my PhD, which is to
understand how cancer spreads as a pure, fundamental understanding.
Dr Viviane Richter (05:16):
So, why imaging?
Prof Paul Timpson (05:19):
I think I love imaging because it's unbiased. Seeing is believing.
We've all heard that saying, but actually, quite often you
just have to watch a process. We can read every
textbook under the sun. We can talk to even experts,
and then you can actually image the process. And there's
always a nuance
(05:43):
my PhD I did lots of imaging. I actually left
the imaging field when I came to Garvan to do biochemistry.
While I loved that, it gave me that depth of
understanding of molecular pathways. But I still had to go
back to what I truly loved, because I didn't think
I was achieving enough and also right at that time
(06:04):
there was subcellular imaging and intravital imaging and multi-photon imaging, and
these were really hot topics. But you could only truly
learn them in three or four pockets of the world.
And so, luckily, I got to do that. And not
only that, I got to do that under the guise
and protection of AstraZeneca Blue Sky Laboratory type research, where
(06:28):
they wanted to make new models of cancer rather than, say,
the tumour is big, the tumour is small, let's look at the molecular processes,
including my favourite metastasis and spread, and that's where I
actually started learning this really advanced imaging mode, and it
really just opened my world up.
Dr Viviane Richter (06:46):
So what can imaging tell us about cancer cells?
Prof Paul Timpson (06:50):
So I've worked on multiple different pathways, and I guess
people call them hallmarks of cancer. One was, we could
actually see cancers uncouple, detach from each other before they've
actually spread, so you can imagine from a biotech or
any druggable aspect, targeting something before it occurs, and before that deadly spread occurs,
(07:14):
is a key aspect we're still trying to actually attack in this disease We
work in pancreas, but we work in any cancer that
would spread or actually grow. There's lots of vulnerabilities when
you look inside the cancer as well, where you must
admit that if you test in a Petri dish a drug,
it's wonderful. We actually look inside the real pancreas. You
(07:37):
see hot spots where that cancer doesn't care about that drug.
That cancer has not even received the drug. Or there's things
like low or high oxygen that mean it is resistant to that drug.
Once you can watch these processes, you can actually manipulate
the blood vessels, the oxygen content, the drug delivery and
(07:57):
you can overcome these things. And we can really start
to look at why stuff doesn't work in the real tumour and
it still works in the Petri dish. I'm not against
the Petri dish. We still need to understand things there,
and the fundamentals need to be there. But we need
to go to a higher fidelity model to actually start understanding. Why
(08:18):
are drugs working? Why they don't. I think all models
add up, and that's well, the kind of biochemistry I
did before the imaging I did at AstraZeneca and the current work
that we do now all add up and every single project
involves multiple expertise to actually ask and answer one question.
And quite often you have to ask the commission, because
(08:40):
sometimes no one's even dared to ask the question yet.
Dr Viviane Richter (08:44):
Paul, you specialise in pancreatic cancer. Can you tell us
why it's such a difficult cancer to treat and what
your hope is for turning the dial?
Prof Paul Timpson (08:56):
This disease was ignored around 10–15 years ago. There was
not many people working on it. Gratefully lots of people
now realise this is a major problem. There was unmet
number of researchers working this area. Once people are diagnosed with
pancreatic cancer, they're often already metastatic, and so we need
(09:17):
to not ignore them at this metastasis, which is exactly what
we're trying to do. 80% of those patients have already
got local invasion, and we need to actually stop that spread.
So that's the first difficulty. Maybe the first difficulty before
the first I just discussed is that diagnosis of pancreatic
cancer is very difficult. The symptoms are very generalised. We
(09:41):
actually very often present with that metastatic disease, and so
I think that early detection, something that we don't specialise
in yet, and we should, and we will move to that, and many of the community are
already going there. If we can get earlier detection, we
may actually twist and change that dial. For decades, we
were always thinking about the cancer cell and not actually
(10:03):
the surrounding environment. So the simple and crazy idea that
we said was
attack with a hammer on a nail with chemotherapy. What
can we understand about its environment that is created in? It's
a highly dense fibrotic environment where drugs cannot penetrate, where the
(10:24):
blood vessels are collapsed. So by simply softening the tumour,
we can actually open those blood vessels, change that dense
fibrotic tissue and then prove that chemotherapy. So it's a
kind of one-two punch attack rather than trying the same thing
over and over again and hitting her head against the wall.
(10:45):
Thinking outside the box. But maybe thinking outside the box
means thinking outside the cancer cell, right?
Dr Viviane Richter (10:50):
You just mentioned fibrotic tissue there. Can you tell us
what that is? And I heard that you were actually
involved in discovering its crucial role in pancreatic cancer.
Prof Paul Timpson (11:01):
So fibrotic tissue I guess, in the simplest way is the cancer itself
co-opts the surrounding tissue and creates and lays down lots
of things like collagens, etcetera, to actually make the surrounding
tissue very hard, very dense, closes off the ability for
(11:22):
us to actually even drug the cancer. So if the
cancer can't see the drug, what hope do we have? And many,
many years ago – and it's wonderful work where we looked
in sequenced cancers, including pancreatic cancer – we used to throw away
this fibrotic tissue or "fibroblasts", because they were seen as
(11:43):
a contaminant. But unfortunately what we were doing was throwing
away half of the problem. Now, that was the correct
thing to do then. But now what we've done with
my colleagues at the Garvan is we've actually focused in on
this fibrotic tissue . And we still understand that we need
to attack the cancer, but we need to attack this
other half of the problem. And sometimes it's a simple thing. Like,
(12:07):
what did we throw away was where the new targets are,
and that's exactly where we're focusing now to target key
molecules that are driving that fibrotic tissue, softening that tissue, and
then we will attack the cancer. So now we're attacking
both sides of the problem. So when we take a
(12:27):
patient sample, for example, we will take that sample. We'll
smash it up and we'll put it through a machine
called a FACT sorter. And we will only look for
the epithelial cells, which would be the cancer cells, and
everything else we were throwing away. We actually use that exact
same protocol to identify the cells we were throwing away
(12:49):
to now actually purify that part of the problem. So
it wasn't all lost. It just took us a while
to realise that maybe we've missed this and let's go back,
and that's great. And that's a key thing, to be
a scientist is – and I said this before – real science, there
isn't an answer, there's not correct answer, and you definitely
(13:09):
need to get used to being wrong. Being wrong is
probably the most important thing about being a scientist, because
you will go back. If you're a proper scientist, you
go back, you fix. Or you attack that problem.
Dr Viviane Richter (13:22):
That's what you did and that work has actually led
to clinical trials in pancreatic cancer patients.
Prof Paul Timpson (13:28):
I still don't believe when you say that. We've got
a long way to go with my colleagues Marina Pajic, Tom
Cox and many, many other wonderful scientists that are at the
Garvan, we actually went back and attacked that problem. And so
that's led to multiple different clinical trials to co-target the environment,
(13:49):
or prime, we call it, the environment, before we give that chemotherapy.
And we've done that in various models from the Petri dish to three-dimensional models.
To more advanced models and in patient samples. And it looks
very exciting. And it's now being tested and Australia and
(14:10):
in multiple different countries to see if we can actually
change the dire response rates in this disease.
Dr Viviane Richter (14:19):
Paul, tell us about this clinical trial. What treatment are you investigating specifically?
Prof Paul Timpson (14:24):
So there's multiple trials. They all have a kind of key,
fundamental aspect. We'll test genetically first, whether as a treatment
for a specific patient sample or a patient. Once we
can find that, that's wonderful. We'll try that. But if we don't,
we give anti-fibrotic treatments to soften those tumours, improve drug delivery
(14:48):
and actually improve chemotherapies so that fibrotic tissue is created by
the fibroblasts that surround the cancer contracting, closing in, you
can imagine, a dense kind of fibrotic tissue. If we
can just release that. We do not want to completely
release that. It could cause a problem as well. The
(15:10):
other one is to actually look at the feedback between
the cancer cell and how it tells those fibroblasts to behave.
So there's a hierarchy in cancer, where the cancer cell
tells the fibroblast what to do the fibroblasts obey, and we just
want to uncouple those aspects. That's a very simplified version
of it. But ultimately that's what we're trying to do.
(15:32):
And we'll do this not only with chemotherapies, but we
will in the future try and use this to maybe
improve the ability of immunotherapies to attack this traditionally cold cancer.
So cold meaning – immunological term – the immune system is not seeing that tumour,
so if we can allow the immune system to see it,
(15:54):
that would also be wonderful. That's kind of where we're going.
Maybe in the next 5 to 10 years, and I
think that I started my research group 10 years ago.
It was around 4 to 5% survival rate then, and
that was stagnant. That stayed like that for the previous
30 to 40 years, which was embarrassing. I actually used
(16:14):
to write that as my favourite sentence and a grant.
But I was also embarrassed as a human being and
a scientist, to keep writing that for year after year after year.
We've changed that now. It's now around 11 to 12%. People
listening will think that's pathetic. But if you actually look
(16:35):
where we were 10 years and I do think we
will improve it exponentially now because of so many people
working on so many angles. So that's my hope for
the future. And again, your pancreas is important. It's not
like a heart. We don't associate it with love. But,
you know, if it doesn't work, we're in trouble.
Dr Viviane Richter (16:58):
Take us inside your microscopy lab. Tell us about what
imaging you do.
Prof Paul Timpson (17:05):
Take us inside the mind of a madman, I think
is what you actually asked. Yes. So it was a
big deal for the Garvan to take me on because
they actually had to purchase a multi-photon microscope. So, this
microscope is rare, it's super expensive. 10 years ago it was a
(17:26):
million dollars, and they're now helped purchase much more than that,
and we've had unbelievable funding from people like ACRF, for example, to
expand upon the one microscope, we now have an entire
centre looking at different types of cancers. We can look
really fast. We can look really deep. But what does
(17:48):
that actually mean in terms of a cancer? So I
guess there's two aspects to that. There are these gold standard,
mouse models, which have the exact genetic mutations we typically
would find in a human patient. They take over a
year to create the tumour and a high fidelity model so
(18:09):
it mimics as close as we possibly can what that tumour
looks like. We then look inside a tumour at various
stages of the disease. And again, this fibrotic tissue I was talking
about before, we can individually watch cancer cells at the
single-cell resolution and then even go sub-cellular to actually watch
(18:32):
how we can break away that dense fibrotic tissue, and we
can see when we've gone too far. We actually can
say less is more sometimes, and we can actually finetune –
not to completely ablate or take away that fibrotic tissue,
but to manipulate it such that you can actually see
those collagens. You can actually see that dense kind of
(18:54):
matrix surrounding a tissue that almost looks like a cage
protecting the cancer. We can actually see that at the
single cell level. We can see our drugs working at
this sub-cellular level. We can actually watch the molecules switching
on and off and the pharmaceutical and biotech sector absolutely love to
(19:16):
see this in real time. So what do I mean
by real time? Quite often we used to take photographs,
so we'd have snapshots. It's like watching a movie being
allowed to see four photos from the movie. You have
no chance of knowing what's happening during that movie. We
just watch the entire process. We then give drugs, and
(19:37):
we see that matrix fall apart. We see those cells respond,
but then we see that we've given too much, right and again,
I keep saying hammer on a nail. Less is more sometimes and so we
can actually watch when it's enough, when the cancer responding,
when that matrix is falling apart and when those cells
(19:58):
start to die on an individual level so we can
see areas where they were resistant now becoming responsive. And
then we can actually do this over time, multiple times,
multiple patients, different patients respond to different doses. Again, we
can actually start to watch how much is enough and
(20:19):
start to make signatures of which patient would respond to
this exact drug and which ones wouldn't. Again it comes back
to science of admit which ones you cannot help. Admit the
science that you cannot yet do, yet being the operative word.
But we can actually say this section this 15% we can
(20:40):
treat with this amount of drug. And so, by fine
tuning that or what we call normalising it back to
what it used to be like deep inside a normal pancreas,
not deep inside a pancreatic tumour.
Dr Viviane Richter (20:55):
Paul, when you're doing this imaging, I'm sure you're busy
checking that the right cells are in focus, that you're measuring the
time points correctly that everything is calibrated properly. But do
you ever just feel a sense of wonder when you
look down the microscope.
Prof Paul Timpson (21:11):
Can I tell the truth? I'm not allowed in the
microscope room anymore. And all the scientists in the group are there, but
I still absolutely love those images. I wait with bated
breath to actually see them because they sometimes often come
from your mind about what does that look like? What
would it really look like? And I think the best
(21:34):
way and I think we talked about it before is
you need to take yourself out of your own body
inside that tumour and wonder what it's like in there.
And quite often you see that cancer cell bending, interacting
with that fibroblast, interacting with that surrounding tissue and starting to move.
Then it becomes really alive when it starts to move
(21:56):
because you're making movies and you're watching that entire process.
The even greater aspect is when you actually give the
drug that you thought could change that. More often than not it
doesn't work, but when it works, it's absolute beautiful proof,
and you actually show it off to every person on the
(22:17):
street and anyone that walks past your lab because you
want to show them
this right? I've never said I told you so more
than once or twice in my entire life again, being
wrong is great, but... again, we're still learning what we don't know.
Once we had a movie where we could just see if you imagine
(22:38):
you're on a beach and you take a photo of someone.
There's just a blur in the background, like a bicycle has say gone by.
People used to ask me what's that? And I went:
it ruined my experiment, but it turns out that that
was the immune system. It was just too fast. And
so we have learned what we couldn't see. And we're now
going deeper and faster, and we're now actually able to
(23:00):
see that. But currently what we can see is absolutely amazing.
And I never, ever thought that an image would take
me to a clinical trial. So it's something that I'll
always remember. I'll always remember that image, and it's kinda
ingrained into my brain that that was the image that
(23:21):
created the next stage, which, we're always here as a part
of that jigsaw, but actually to be able to pinpoint
the beautiful image they created. Hopefully, the beautiful trial and again i
t's an iterative process. We need to take that trial
and go back and say, why did it work and
(23:41):
why did it not work for these patients?
Dr Viviane Richter (23:44):
What's next for your research, Paul?
Prof Paul Timpson (23:46):
We've actually moved to become – this is the hardest thing
in science – unbiased. So quite often, if you're thinking about
fibrosis that we've talked about, even still we know molecules
and targets that would be involved in that. So it's
relatively easy to go after those targets or to talk
(24:07):
to various companies to say, can you target this properly?
I think what we've talked about before was, we only thought
about the cancer cell. We've only touched the tip of
the iceberg for what's actually out there, and the what's
called the fibrosis or the matrix, right? I think there's a
reservoir of brand new untapped targets out there, and that's
(24:33):
exactly what we're doing now. And that's where we see
the future, which is to go after those patients with
completely different, what we call, molecular signatures of what is
wrong with their matrix that causes this fibrosis. And while
we've targeted that, I think there is thousands upon thousands
(24:53):
of new targets out there, and it's a lifetime of
work to map them. Create the landscape for my team
and other teams all over the world to attack these individually, sequentially,
at the same time, you can see it could go
on and on. But unbiased targeting of new unfound cancer
(25:17):
research targets is where we want to go. And that's
where I would like to be in the future. And
for many other cancers as well. That's something we haven't
touched upon. Quite often, we will take targets from other diseases,
and I'm not talking just about cancer. Repurpose them to
pancreas cancer but at the same time, it's our duty to find
(25:38):
new targets in this disease and open that up for
other highly fibrotic cancers such as breast cancer, for example,
we need to work as a massive unit.
Dr Viviane Richter (25:50):
Do you think we'll see a cure for pancreatic cancer
one day?
Prof Paul Timpson (25:53):
That's a difficult question. That's the same question that every
taxi driver asks you. And my answer is for some yes,
for others. We want to be able to manage a
disease such that you don't die of it. You may actually
die with it. That sounds like a negative, but right
now that's in the forefront, on the horizon, and I
(26:15):
think that we should aim for that, and then we
will move to the stage where we hope to eradicate it. Otherwise,
I wouldn't go to work every day.
Dr Viviane Richter (26:24):
Paul, it's time to get to know you a little
bit better. It's time for the Fast Five. Favourite movie?
Prof Paul Timpson (26:30):
Back to the Future. I can watch it 10 times
in a row and I still feel like I'm eight years old.
I'm still kind of waiting for the hovercraft to be real.
Dr Viviane Richter (26:42):
What's the most challenging thing you've ever had to do?
Prof Paul Timpson (26:44):
Jump out of an aeroplane on my own with a
parachute and no one attached to me. I'm still scarred from it. I had
to jump out or you were – the parachute was attached to the aeroplane, but you jump
on your own and if the parachute doesn't open you have
seven seconds to get the second one, and even when
it does open, you still have to direct yourself across
(27:06):
fields in Stirling, Scotland. As much as I loved it, I don't
think I should be given that responsibility again.
Dr Viviane Richter (27:15):
What's been your best holiday?
Prof Paul Timpson (27:17):
Japan. Love Japan, I actually gave a talk in Japan and
my high school mates came and met me. We went
to the Rugby World Cup. It was like another world. And again,
you're starting to see a theme, it brought me back
to being young and at school. So Japan.
Dr Viviane Richter (27:37):
Is there anything you're afraid of?
Prof Paul Timpson (27:39):
Being alone. I'm actually far too social. And yeah, I
would hate to be in a room on my own.
Dr Viviane Richter (27:48):
What's your favourite meal?
Prof Paul Timpson (27:49):
My favourite meal is, do you know Hogmanay is in Scotland?
That's New Year's Eve here. My mum makes a stew
with puff pastry and mushy peas. That's my favourite meal.
Plus a can of iron brew from Scotland.
Dr Viviane Richter (28:08):
Sounds perfect. Professor Paul Timpson, thanks for joining us on
Medical Minds.
Prof Paul Timpson (28:14):
It's great to be here and thank you for having me.
Dr Viviane Richter (28:17):
If you'd like to know more about Paul's research or
donate to the work we do at Garvan, head to garvan.org.au.
And if you've enjoyed this podcast, please leave a review
and share with other podcast lovers. I'm Dr Viviane Richter.
Thanks for listening. This podcast was recorded on the traditional
(28:39):
country of the Gadigal People of the Eora N ation. 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.
If you've ever seen an image of fluorescent cancer cells
under the microscope, you may agree that it's hard to
understand how something so beautiful could be so deadly. Today
we speak to a researcher who is visualising one of
the deadliest cancers in vividly beautiful detail to figure out
what the cancer's weak spot are and how patients can
(00:22):
receive the right treatment in the right amount at the
right time. 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 Paul Timpson, Head of the Invasion
and Metastasis Lab at Garvan. Welcome, Paul!
Prof Paul Timpson (00:43):
Hi Viv. Great to be here.
Dr Viviane Richter (00:45):
Paul, you are a world leader in pancreatic cancer research.
You have high profile publications, prestigious awards and significant grants
to back this up. But I heard your career in
science actually started out with you dropping out of uni.
Prof Paul Timpson (01:00):
Yes, that's true. So originally I was good at maths,
and physics. I was very lucky to not have to go
to school on Thursdays and I actually joined quite a geeky
club called the Young Engineers Club. My school friends did
not like the fact I didn't get to go to
school on Thursdays. They were all jealous and I absolutely loved
(01:20):
competing at a very young age. So therefore, engineering was my destiny,
and that's where I was supposed to go. I was
allowed to go to university and already was accepted to
engineering very early. So I did the spare class in biology,
which I loved. Once I went to university, I realised
(01:41):
that actually engineering was not what I loved. And I think
I've never been happier than the day I dropped out of
university and I've never looked back. Not sure my family
were happy about that. But I had a vision. And I
actually had to go to a completely different school to
do advanced maths, advanced biology – because the university didn't think
I could keep up with organic chemistry. I loved going
(02:05):
to different school, but I knew this was where I
wanted to be, and I wanted to do biology not to
mash up plants but to actually attack human diseases. Obviously,
what I do now is cancer, but there was lots of
diseases I could really envisage using the biology, but accidentally, the
(02:25):
math and the physics I was already good at in biology.
And again, you can never really escape all forms of
science if you're really going to make a difference in
the disease.
Dr Viviane Richter (02:34):
What university did you go to?
Prof Paul Timpson (02:36):
Okay, Viv. As you can tell from my accent, I
am very Scottish. I went to university in Glasgow, Strathclyde
University for my undergraduate. Then I studied at the Beatson
Institute or CRUK, and that's in Glasgow University itself. So,
born and bred, educated in Glasgow and then moved to
(02:58):
Australia for some sunshine.
Dr Viviane Richter (03:00):
What was it about biology that really appealed to you?
Prof Paul Timpson (03:04):
I loved the idea that we could actually attack various
human diseases like cancer, for example, but I was very privileged
in the third year of university when I was selected to
go to New York, which you can imagine would be amazing.
I represented Scotland with someone from England, Russia, France, etcetera.
That was three months of a very defining time in
(03:27):
my life, where I hung about with like minded people
all over American over Europe, etcetera. And really did pure
actual science, not pass exams, type science. We don't know
the answer to these questions. Please be part of a
team to work on it, loved that, came back to university
and instantly talked to my lecturers and said I will
(03:49):
be doing a PhD now which they questioned and thought
that was a little bit cocky. But after I actually showed
how I really believed and wanted to do it, they could
see the difference. And I think that sometimes it's not
just how well you can pass an exam. It's actually what
is your passion and how hard will you want to
take that on? Because a PhD is not easy. And a ctually,
(04:11):
any proper PhD doesn't have an answer. It's you that
has to try and find that answer.
Dr Viviane Richter (04:17):
So tell us about what you did during your PhD.
Prof Paul Timpson (04:20):
So my PhD, I really got interested in how cells move.
So the biggest killer in cancer, and we still know that today is:
as soon as it spreads, the game is over, really.
So we need to understand how they spread before we
can attack it. And I think that's what you said
at the beginning of the podcast, which was how can
something so beautiful or something that you actually appreciate work
(04:44):
for you? So you need to understand your enemy. So
you must actually embrace how it co-opts different mechanisms, how
it changes to act in a cytoskeleton, which, like the skeleton of
an individual cell or a cancer. How does it co-opt that?
How does it use this to actually spread throughout the body?
Once we can understand it, we can possibly see its vulnerabilities.
(05:07):
And that's what I did in my PhD, which is to
understand how cancer spreads as a pure, fundamental understanding.
Dr Viviane Richter (05:16):
So, why imaging?
Prof Paul Timpson (05:19):
I think I love imaging because it's unbiased. Seeing is believing.
We've all heard that saying, but actually, quite often you
just have to watch a process. We can read every
textbook under the sun. We can talk to even experts,
and then you can actually image the process. And there's
always a nuance
(05:43):
my PhD I did lots of imaging. I actually left
the imaging field when I came to Garvan to do biochemistry.
While I loved that, it gave me that depth of
understanding of molecular pathways. But I still had to go
back to what I truly loved, because I didn't think
I was achieving enough and also right at that time
(06:04):
there was subcellular imaging and intravital imaging and multi-photon imaging, and
these were really hot topics. But you could only truly
learn them in three or four pockets of the world.
And so, luckily, I got to do that. And not
only that, I got to do that under the guise
and protection of AstraZeneca Blue Sky Laboratory type research, where
(06:28):
they wanted to make new models of cancer rather than, say,
the tumour is big, the tumour is small, let's look at the molecular processes,
including my favourite metastasis and spread, and that's where I
actually started learning this really advanced imaging mode, and it
really just opened my world up.
Dr Viviane Richter (06:46):
So what can imaging tell us about cancer cells?
Prof Paul Timpson (06:50):
So I've worked on multiple different pathways, and I guess
people call them hallmarks of cancer. One was, we could
actually see cancers uncouple, detach from each other before they've
actually spread, so you can imagine from a biotech or
any druggable aspect, targeting something before it occurs, and before that deadly spread occurs,
(07:14):
is a key aspect we're still trying to actually attack in this disease We
work in pancreas, but we work in any cancer that
would spread or actually grow. There's lots of vulnerabilities when
you look inside the cancer as well, where you must
admit that if you test in a Petri dish a drug,
it's wonderful. We actually look inside the real pancreas. You
(07:37):
see hot spots where that cancer doesn't care about that drug.
That cancer has not even received the drug. Or there's things
like low or high oxygen that mean it is resistant to that drug.
Once you can watch these processes, you can actually manipulate
the blood vessels, the oxygen content, the drug delivery and
(07:57):
you can overcome these things. And we can really start
to look at why stuff doesn't work in the real tumour and
it still works in the Petri dish. I'm not against
the Petri dish. We still need to understand things there,
and the fundamentals need to be there. But we need
to go to a higher fidelity model to actually start understanding. Why
(08:18):
are drugs working? Why they don't. I think all models
add up, and that's well, the kind of biochemistry I
did before the imaging I did at AstraZeneca and the current work
that we do now all add up and every single project
involves multiple expertise to actually ask and answer one question.
And quite often you have to ask the commission, because
(08:40):
sometimes no one's even dared to ask the question yet.
Dr Viviane Richter (08:44):
Paul, you specialise in pancreatic cancer. Can you tell us
why it's such a difficult cancer to treat and what
your hope is for turning the dial?
Prof Paul Timpson (08:56):
This disease was ignored around 10–15 years ago. There was
not many people working on it. Gratefully lots of people
now realise this is a major problem. There was unmet
number of researchers working this area. Once people are diagnosed with
pancreatic cancer, they're often already metastatic, and so we need
(09:17):
to not ignore them at this metastasis, which is exactly what
we're trying to do. 80% of those patients have already
got local invasion, and we need to actually stop that spread.
So that's the first difficulty. Maybe the first difficulty before
the first I just discussed is that diagnosis of pancreatic
cancer is very difficult. The symptoms are very generalised. We
(09:41):
actually very often present with that metastatic disease, and so
I think that early detection, something that we don't specialise
in yet, and we should, and we will move to that, and many of the community are
already going there. If we can get earlier detection, we
may actually twist and change that dial. For decades, we
were always thinking about the cancer cell and not actually
(10:03):
the surrounding environment. So the simple and crazy idea that
we said was
attack with a hammer on a nail with chemotherapy. What
can we understand about its environment that is created in? It's
a highly dense fibrotic environment where drugs cannot penetrate, where the
(10:24):
blood vessels are collapsed. So by simply softening the tumour,
we can actually open those blood vessels, change that dense
fibrotic tissue and then prove that chemotherapy. So it's a
kind of one-two punch attack rather than trying the same thing
over and over again and hitting her head against the wall.
(10:45):
Thinking outside the box. But maybe thinking outside the box
means thinking outside the cancer cell, right?
Dr Viviane Richter (10:50):
You just mentioned fibrotic tissue there. Can you tell us
what that is? And I heard that you were actually
involved in discovering its crucial role in pancreatic cancer.
Prof Paul Timpson (11:01):
So fibrotic tissue I guess, in the simplest way is the cancer itself
co-opts the surrounding tissue and creates and lays down lots
of things like collagens, etcetera, to actually make the surrounding
tissue very hard, very dense, closes off the ability for
(11:22):
us to actually even drug the cancer. So if the
cancer can't see the drug, what hope do we have? And many,
many years ago – and it's wonderful work where we looked
in sequenced cancers, including pancreatic cancer – we used to throw away
this fibrotic tissue or "fibroblasts", because they were seen as
(11:43):
a contaminant. But unfortunately what we were doing was throwing
away half of the problem. Now, that was the correct
thing to do then. But now what we've done with
my colleagues at the Garvan is we've actually focused in on
this fibrotic tissue . And we still understand that we need
to attack the cancer, but we need to attack this
other half of the problem. And sometimes it's a simple thing. Like,
(12:07):
what did we throw away was where the new targets are,
and that's exactly where we're focusing now to target key
molecules that are driving that fibrotic tissue, softening that tissue, and
then we will attack the cancer. So now we're attacking
both sides of the problem. So when we take a
(12:27):
patient sample, for example, we will take that sample. We'll
smash it up and we'll put it through a machine
called a FACT sorter. And we will only look for
the epithelial cells, which would be the cancer cells, and
everything else we were throwing away. We actually use that exact
same protocol to identify the cells we were throwing away
(12:49):
to now actually purify that part of the problem. So
it wasn't all lost. It just took us a while
to realise that maybe we've missed this and let's go back,
and that's great. And that's a key thing, to be
a scientist is – and I said this before – real science, there
isn't an answer, there's not correct answer, and you definitely
(13:09):
need to get used to being wrong. Being wrong is
probably the most important thing about being a scientist, because
you will go back. If you're a proper scientist, you
go back, you fix. Or you attack that problem.
Dr Viviane Richter (13:22):
That's what you did and that work has actually led
to clinical trials in pancreatic cancer patients.
Prof Paul Timpson (13:28):
I still don't believe when you say that. We've got
a long way to go with my colleagues Marina Pajic, Tom
Cox and many, many other wonderful scientists that are at the
Garvan, we actually went back and attacked that problem. And so
that's led to multiple different clinical trials to co-target the environment,
(13:49):
or prime, we call it, the environment, before we give that chemotherapy.
And we've done that in various models from the Petri dish to three-dimensional models.
To more advanced models and in patient samples. And it looks
very exciting. And it's now being tested and Australia and
(14:10):
in multiple different countries to see if we can actually
change the dire response rates in this disease.
Dr Viviane Richter (14:19):
Paul, tell us about this clinical trial. What treatment are you investigating specifically?
Prof Paul Timpson (14:24):
So there's multiple trials. They all have a kind of key,
fundamental aspect. We'll test genetically first, whether as a treatment
for a specific patient sample or a patient. Once we
can find that, that's wonderful. We'll try that. But if we don't,
we give anti-fibrotic treatments to soften those tumours, improve drug delivery
(14:48):
and actually improve chemotherapies so that fibrotic tissue is created by
the fibroblasts that surround the cancer contracting, closing in, you
can imagine, a dense kind of fibrotic tissue. If we
can just release that. We do not want to completely
release that. It could cause a problem as well. The
(15:10):
other one is to actually look at the feedback between
the cancer cell and how it tells those fibroblasts to behave.
So there's a hierarchy in cancer, where the cancer cell
tells the fibroblast what to do the fibroblasts obey, and we just
want to uncouple those aspects. That's a very simplified version
of it. But ultimately that's what we're trying to do.
(15:32):
And we'll do this not only with chemotherapies, but we
will in the future try and use this to maybe
improve the ability of immunotherapies to attack this traditionally cold cancer.
So cold meaning – immunological term – the immune system is not seeing that tumour,
so if we can allow the immune system to see it,
(15:54):
that would also be wonderful. That's kind of where we're going.
Maybe in the next 5 to 10 years, and I
think that I started my research group 10 years ago.
It was around 4 to 5% survival rate then, and
that was stagnant. That stayed like that for the previous
30 to 40 years, which was embarrassing. I actually used
(16:14):
to write that as my favourite sentence and a grant.
But I was also embarrassed as a human being and
a scientist, to keep writing that for year after year after year.
We've changed that now. It's now around 11 to 12%. People
listening will think that's pathetic. But if you actually look
(16:35):
where we were 10 years and I do think we
will improve it exponentially now because of so many people
working on so many angles. So that's my hope for
the future. And again, your pancreas is important. It's not
like a heart. We don't associate it with love. But,
you know, if it doesn't work, we're in trouble.
Dr Viviane Richter (16:58):
Take us inside your microscopy lab. Tell us about what
imaging you do.
Prof Paul Timpson (17:05):
Take us inside the mind of a madman, I think
is what you actually asked. Yes. So it was a
big deal for the Garvan to take me on because
they actually had to purchase a multi-photon microscope. So, this
microscope is rare, it's super expensive. 10 years ago it was a
(17:26):
million dollars, and they're now helped purchase much more than that,
and we've had unbelievable funding from people like ACRF, for example, to
expand upon the one microscope, we now have an entire
centre looking at different types of cancers. We can look
really fast. We can look really deep. But what does
(17:48):
that actually mean in terms of a cancer? So I
guess there's two aspects to that. There are these gold standard,
mouse models, which have the exact genetic mutations we typically
would find in a human patient. They take over a
year to create the tumour and a high fidelity model so
(18:09):
it mimics as close as we possibly can what that tumour
looks like. We then look inside a tumour at various
stages of the disease. And again, this fibrotic tissue I was talking
about before, we can individually watch cancer cells at the
single-cell resolution and then even go sub-cellular to actually watch
(18:32):
how we can break away that dense fibrotic tissue, and we
can see when we've gone too far. We actually can
say less is more sometimes, and we can actually finetune –
not to completely ablate or take away that fibrotic tissue,
but to manipulate it such that you can actually see
those collagens. You can actually see that dense kind of
(18:54):
matrix surrounding a tissue that almost looks like a cage
protecting the cancer. We can actually see that at the
single cell level. We can see our drugs working at
this sub-cellular level. We can actually watch the molecules switching
on and off and the pharmaceutical and biotech sector absolutely love to
(19:16):
see this in real time. So what do I mean
by real time? Quite often we used to take photographs,
so we'd have snapshots. It's like watching a movie being
allowed to see four photos from the movie. You have
no chance of knowing what's happening during that movie. We
just watch the entire process. We then give drugs, and
(19:37):
we see that matrix fall apart. We see those cells respond,
but then we see that we've given too much, right and again,
I keep saying hammer on a nail. Less is more sometimes and so we
can actually watch when it's enough, when the cancer responding,
when that matrix is falling apart and when those cells
(19:58):
start to die on an individual level so we can
see areas where they were resistant now becoming responsive. And
then we can actually do this over time, multiple times,
multiple patients, different patients respond to different doses. Again, we
can actually start to watch how much is enough and
(20:19):
start to make signatures of which patient would respond to
this exact drug and which ones wouldn't. Again it comes back
to science of admit which ones you cannot help. Admit the
science that you cannot yet do, yet being the operative word.
But we can actually say this section this 15% we can
(20:40):
treat with this amount of drug. And so, by fine
tuning that or what we call normalising it back to
what it used to be like deep inside a normal pancreas,
not deep inside a pancreatic tumour.
Dr Viviane Richter (20:55):
Paul, when you're doing this imaging, I'm sure you're busy
checking that the right cells are in focus, that you're measuring the
time points correctly that everything is calibrated properly. But do
you ever just feel a sense of wonder when you
look down the microscope.
Prof Paul Timpson (21:11):
Can I tell the truth? I'm not allowed in the
microscope room anymore. And all the scientists in the group are there, but
I still absolutely love those images. I wait with bated
breath to actually see them because they sometimes often come
from your mind about what does that look like? What
would it really look like? And I think the best
(21:34):
way and I think we talked about it before is
you need to take yourself out of your own body
inside that tumour and wonder what it's like in there.
And quite often you see that cancer cell bending, interacting
with that fibroblast, interacting with that surrounding tissue and starting to move.
Then it becomes really alive when it starts to move
(21:56):
because you're making movies and you're watching that entire process.
The even greater aspect is when you actually give the
drug that you thought could change that. More often than not it
doesn't work, but when it works, it's absolute beautiful proof,
and you actually show it off to every person on the
(22:17):
street and anyone that walks past your lab because you
want to show them
this right? I've never said I told you so more
than once or twice in my entire life again, being
wrong is great, but... again, we're still learning what we don't know.
Once we had a movie where we could just see if you imagine
(22:38):
you're on a beach and you take a photo of someone.
There's just a blur in the background, like a bicycle has say gone by.
People used to ask me what's that? And I went:
it ruined my experiment, but it turns out that that
was the immune system. It was just too fast. And
so we have learned what we couldn't see. And we're now
going deeper and faster, and we're now actually able to
(23:00):
see that. But currently what we can see is absolutely amazing.
And I never, ever thought that an image would take
me to a clinical trial. So it's something that I'll
always remember. I'll always remember that image, and it's kinda
ingrained into my brain that that was the image that
(23:21):
created the next stage, which, we're always here as a part
of that jigsaw, but actually to be able to pinpoint
the beautiful image they created. Hopefully, the beautiful trial and again i
t's an iterative process. We need to take that trial
and go back and say, why did it work and
(23:41):
why did it not work for these patients?
Dr Viviane Richter (23:44):
What's next for your research, Paul?
Prof Paul Timpson (23:46):
We've actually moved to become – this is the hardest thing
in science – unbiased. So quite often, if you're thinking about
fibrosis that we've talked about, even still we know molecules
and targets that would be involved in that. So it's
relatively easy to go after those targets or to talk
(24:07):
to various companies to say, can you target this properly?
I think what we've talked about before was, we only thought
about the cancer cell. We've only touched the tip of
the iceberg for what's actually out there, and the what's
called the fibrosis or the matrix, right? I think there's a
reservoir of brand new untapped targets out there, and that's
(24:33):
exactly what we're doing now. And that's where we see
the future, which is to go after those patients with
completely different, what we call, molecular signatures of what is
wrong with their matrix that causes this fibrosis. And while
we've targeted that, I think there is thousands upon thousands
(24:53):
of new targets out there, and it's a lifetime of
work to map them. Create the landscape for my team
and other teams all over the world to attack these individually, sequentially,
at the same time, you can see it could go
on and on. But unbiased targeting of new unfound cancer
(25:17):
research targets is where we want to go. And that's
where I would like to be in the future. And
for many other cancers as well. That's something we haven't
touched upon. Quite often, we will take targets from other diseases,
and I'm not talking just about cancer. Repurpose them to
pancreas cancer but at the same time, it's our duty to find
(25:38):
new targets in this disease and open that up for
other highly fibrotic cancers such as breast cancer, for example,
we need to work as a massive unit.
Dr Viviane Richter (25:50):
Do you think we'll see a cure for pancreatic cancer
one day?
Prof Paul Timpson (25:53):
That's a difficult question. That's the same question that every
taxi driver asks you. And my answer is for some yes,
for others. We want to be able to manage a
disease such that you don't die of it. You may actually
die with it. That sounds like a negative, but right
now that's in the forefront, on the horizon, and I
(26:15):
think that we should aim for that, and then we
will move to the stage where we hope to eradicate it. Otherwise,
I wouldn't go to work every day.
Dr Viviane Richter (26:24):
Paul, it's time to get to know you a little
bit better. It's time for the Fast Five. Favourite movie?
Prof Paul Timpson (26:30):
Back to the Future. I can watch it 10 times
in a row and I still feel like I'm eight years old.
I'm still kind of waiting for the hovercraft to be real.
Dr Viviane Richter (26:42):
What's the most challenging thing you've ever had to do?
Prof Paul Timpson (26:44):
Jump out of an aeroplane on my own with a
parachute and no one attached to me. I'm still scarred from it. I had
to jump out or you were – the parachute was attached to the aeroplane, but you jump
on your own and if the parachute doesn't open you have
seven seconds to get the second one, and even when
it does open, you still have to direct yourself across
(27:06):
fields in Stirling, Scotland. As much as I loved it, I don't
think I should be given that responsibility again.
Dr Viviane Richter (27:15):
What's been your best holiday?
Prof Paul Timpson (27:17):
Japan. Love Japan, I actually gave a talk in Japan and
my high school mates came and met me. We went
to the Rugby World Cup. It was like another world. And again,
you're starting to see a theme, it brought me back
to being young and at school. So Japan.
Dr Viviane Richter (27:37):
Is there anything you're afraid of?
Prof Paul Timpson (27:39):
Being alone. I'm actually far too social. And yeah, I
would hate to be in a room on my own.
Dr Viviane Richter (27:48):
What's your favourite meal?
Prof Paul Timpson (27:49):
My favourite meal is, do you know Hogmanay is in Scotland?
That's New Year's Eve here. My mum makes a stew
with puff pastry and mushy peas. That's my favourite meal.
Plus a can of iron brew from Scotland.
Dr Viviane Richter (28:08):
Sounds perfect. Professor Paul Timpson, thanks for joining us on
Medical Minds.
Prof Paul Timpson (28:14):
It's great to be here and thank you for having me.
Dr Viviane Richter (28:17):
If you'd like to know more about Paul's research or
donate to the work we do at Garvan, head to garvan.org.au.
And if you've enjoyed this podcast, please leave a review
and share with other podcast lovers. I'm Dr Viviane Richter.
Thanks for listening. This podcast was recorded on the traditional
(28:39):
country of the Gadigal People of the Eora N ation. 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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