March 3, 2024 • 25 mins
Genomics is fundamentally changing the way we think about health and disease and driving forward personalised treatment options that would have been pure science fiction just a few years ago. Still, some parts of our genome are more ‘mysterious’ than others. In this episode, we meet Garvan researcher Dr Ira Deveson who is spearheading cutting-edge DNA sequencing methods to future-proof how genomics will integrate into healthcare.
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Episode Transcript
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Dr Viviane Richter (00:01):
Genomics is fundamentally changing the way we think about health
and disease and driving forward personalised treatment options that would have
been pure science fiction just a few years ago. Still,
some parts of our genome are more mysterious than others.
Garvan researcher, Dr Ira Deveson is spearheading cutting-edge DNA sequencing
(00:22):
methods to future-proof how genomics will integrate into healthcare.
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 Dr Ira Deveson, Head of the Genomic Technologies Lab
at Garvan. Welcome Ira!
Dr Ira Deveson (00:42):
A. Hi, Viv, thanks for having me. Really looking forward to
our conversation.
Dr Viviane Richter (00:46):
Ira, what excited you about genomics enough to make it your career?
Dr Ira Deveson (00:50):
Yeah, I guess I've always been interested in the life
sciences and the natural world and I guess just sort
of understanding how things work in the world around you, which,
which really is the goal of science. And I think
I was lucky enough to have a couple of really
excellent high school science teachers towards the latter stages of
my high school who kind of inspired me to take
up biology and chemistry at university.
(01:13):
And I think somewhere along the line there, during those years,
I realised, if you want to understand how the world works,
how living things work, how they came to be and
um how they're changing, you really need to understand the
genome because it is the core program of life that
dictates everything. And I guess once I'd realised that there
was never really gonna be another path for me, I
(01:34):
was always fascinated by it from that point onwards.
Dr Viviane Richter (01:38):
Tell us about the first time you stepped into a
research lab.
Dr Ira Deveson (01:41):
The first time I stepped into a research lab would have
been my honours year at ANU.
So during honours, I studied plant science, doing a plant genetics project.
So I was embedded in a lab where we were
growing little model organisms called arabidopsis and fiddling around with
their genomes to test things about how their genes operate
(02:02):
and switch each other on and off. My project was
actually a bit of a left field one where we
decided we wanted to clone a human gene into this plant.
We were testing the idea that this gene is a
really ancient gene, its function has been around for so long.
That if you take it from a human cell and
(02:23):
put it into a plant, it could still perform its function.
We did that and it kind of worked, it kind
of could still perform its job. But the plant was
a bit messed up. It sort of had weird curly
leaves and was a bit shrunken and imperfect.
But it was a really fun experience about what you can
(02:45):
do in science when you come up with a hypothesis,
even if it's a bit left field and just have
a crack at it. Yeah.
Dr Viviane Richter (02:51):
What did that tell you about genomics?
Dr Ira Deveson (02:53):
I mean, it taught us a lot about this gene. It
taught us that the gene
is so deeply conserved or so ancient that it could
still function in a plant cell. But obviously, there had been in
the intervening hundreds of millions of years, it had changed sufficiently
that its job wasn't perfectly executed in a plant cell.
It wasn't interacting with all of the things that it
would normally interact with in a human cell. So, yeah,
(03:16):
we learned something about the evolution of that gene which
to me was eye-opening and a pretty cool experience as
a undergraduate.
Dr Viviane Richter (03:24):
So you went on to do a PhD. Can you
tell us about what you did?
Dr Ira Deveson (03:28):
Yeah. So my PhD was in genomics in a pretty
broad sense and it was mostly sort of computational stuff.
So I'm a bioinformatician or, or I was a bioinformatician ,
a person who analyses genomics, data sets to learn things about
biology and, I say that because it was a very
broad PhD, I worked on a lot of different projects,
all of them on different subjects, but united by the
(03:51):
fact that they involved genomics.
Actually, the title of my PhD thesis ended up being
'Three largely unrelated experiments in the era of genomics' or
something like this, which my supervisors were not very impressed with.
But I think the main thrust of what I was
doing turned out to be a a biotechnology project where we
(04:11):
developed a new product which was called sequins. These are
sort of synthetic genes. So totally artificial molecules that we
created
that you could actually use as internal controls in your
genomics experiments. So the basic idea is you would get
these synthetic genes, you'd add them to a DNA sample
that you were just about to analyse like maybe a
patient DNA sample. And then you'd do your genomic experiment
(04:35):
as you normally would, but you'd have these synthetic molecules
in there that act as kind of like an internal
truth set or like a a known and
within your experiment and having that in there, lets you
sort of measure how accurate your experiment is because you've
got this truth set, you can see if you're making
any mistakes and that gives you ability to sort of
do quality control, measure your performance over time. And ideally
(04:56):
to optimise your performance, you actually improve the accuracy of
your experiment.
Dr Viviane Richter (05:02):
So rather than investigating a specific biological problem, you're more
focused on developing the technology that sits behind that.
Dr Ira Deveson (05:10):
Yeah, I think that's what sort of came out of
my PhD was this philosophy that you don't necessarily have to
be a expert in one particular disease or one particular
biological system. But you can spend your time building tools and,
and methods and get these sort of capabilities particularly in
the data analysis, which is a huge part of genomic science.
And once you've got this expertise or once you've built
(05:31):
those tools, you can really apply them in many different areas.
And the applications sort of follow naturally, I guess, usually
via collaboration with people who are experts in different disease
areas or different areas of biology.
Dr Viviane Richter (05:44):
What sort of sequencing do you specialise in?
Dr Ira Deveson (05:47):
So my team's called the Genomic Technologies Lab. And we
work on lots of different genomic technologies, but something that
we're really interested in at the moment and over the
last couple of years is called long-read sequencing. So this
is a new class of technologies that are really hitting
their stride over the last couple of years and they're
kind of revolutionary because I guess over the last 10
or 20 years in genomics, we've been pretty reliant on
(06:10):
a technique called next-generation sequencing or shotgun sequencing.
And this is a process where you basically smash the
genome up into tiny little fragments that are about 100
base pairs long or 100 letters of the DNA code long.
The genome is 3 billion letters and we're smashing it
up into these tiny 100 base pair pieces. And then
you have to stitch all those together like a, like
(06:30):
a jigsaw puzzle to sort of understand what the genome
looked like in a given person or a given organism.
But now with these new technologies that are coming along, long-read sequencing -
it's called long read because we don't have to smash
the genome up into these tiny pieces. We can actually
read much longer pieces of the DNA code. So thousands
or tens of thousands or even up to millions of
(06:52):
letters long in a single continuous piece.
So that basically just means that when you're stitching the
genome back together for your patient or for your organism,
you're doing a much less complicated jigsaw puzzle. You don't
have all these tiny little fragments, you have these long
continuous molecules. And so that makes the problem much simpler,
much less chance of making mistakes. And it lets you access
(07:14):
parts of the genome that are too complicated to stitch
together with those small jigsaw pieces.
Dr Viviane Richter (07:20):
You're saying this is giving us the most accurate view
of our genome.
Dr Ira Deveson (07:25):
Yeah, this is giving us the best resolution, I would
say when it comes to reading a genome and
I guess you need to think about the fact that
the genome is not a single homogenous object. It has
lots of areas that have specific contexts that make it
difficult to read. And the thing that's usually most difficult
(07:46):
is a repetitive sequence. And you can imagine if you're
doing a jigsaw
puzzle, if there's a section of the puzzle that has
lots of the same feature being repeated over and over
again without any kind of unique features, that's really hard
for you to interpret and stitch together correctly. And that's
the same in the genome. If we have large sections
of the genome where you just have the same
(08:07):
DNA code repeating itself again and again, you're very likely
to make mistakes when you're trying to piece that together
and read it out. So there's maybe 10 or 20%
of the genome that's like this. It's too repetitive for
us to have properly analysed in the last 10-15 years
of genomics. But now with these new technologies, we can
finally read these sections, these sort of mysterious dark regions
(08:28):
of the genome.
Dr Viviane Richter (08:30):
And why do we need to know about these regions?
Dr Ira Deveson (08:33):
Partly because it's just really interesting, we don't know what's
in there. And that's what drives us as scientists, is
driving our knowledge for just finding out what these regions
look like. But we also know that there's lots of
important genes within these regions and there's lots of important
genes that have roles in disease where we already know
that they have roles in disease. But we haven't been
(08:53):
able to properly analyse them because the technologies have not
been there or we can analyse them maybe to diagnose
a genetic disease, but it's really slow and laborious and
challenging and error-prone . So with these new technologies, we
can eliminate a lot of those difficulties, but we can
also just shed new light on things that we haven't
understood before.
An example that we've been working on a lot in
(09:14):
the last couple of years, a specific group of disorders
called repeat expansion disorders. These are typically neurodegenerative diseases affecting
the nervous system, but they involve lots of different genes.
There's at least 50 genes involved and probably many more
out there that we haven't yet discovered.
But they contain these repetitive sequences that are kind of
(09:36):
like repeating syllables within a word, everybody has these genes.
But in certain people, those repetitive sections of the gene
actually get blown out in size and they become massively expanded.
So you can maybe think about a word like Woolloomooloo,
the suburb in Sydney, everyone has a few repetitive syllables
in that word. But maybe in your patient when you
read it out, there's is Woolloomooloomooloomooloo , right? And so
(09:59):
it's become massively expanded. And
that's the nature of these repetitive sequences that they're quite unstable,
but that actually leads to disease in some cases. And
so some very well known genetic diseases like Huntington's disease
is actually caused by these repetitive expansions in a particular gene.
So those have been difficult to research and difficult to
(10:20):
diagnose until recently. But we're actually now applying these new
long-read sequencing technologies that we have to read these out
very accurately so that we can tell the difference in
the length of these genes between different individuals. And that
we hope is gonna lead to much better, much more streamlined,
much more accurate patient diagnoses
Dr Viviane Richter (10:39):
being able to diagnose these diseases much earlier on would
lead to a transformation in patient outcomes.
Dr Ira Deveson (10:46):
So unfortunately for a lot of these neurodegenerative diseases that
we're looking at, there's no current cure, but there are
cures on the horizon. There are very promising clinical trials
getting underway for things like gene therapies now coming out for
different inherited diseases. It's only a matter of time before
there will
be ways to treat these disorders that are very debilitating,
(11:09):
but we really need to be able to diagnose them
and work out exactly what a particular patient's specific mutation
is or variant is so that they can be accurately
targeted within these trials and when these therapies come online.
Dr Viviane Richter (11:24):
Ira, tell us what else you're using this long-read sequencing for.
Dr Ira Deveson (11:28):
Yeah. So we've spent a lot of time and energy
building up our capabilities in this area, long-read sequencing. We
have a lot of different instruments and we've really become the
leader in Australia in this area. And it means we
actually work on all sorts of different genomics projects. There's
a lot of demand for these instruments and for these capabilities.
(11:48):
But we started offering a sequencing service and we collaborate
with many different researchers around
Australia. So we work on everything from clinical genomics projects
like what I've just described where we're trying to improve
patient diagnoses. We work on cancer research which is obviously
a disease that's driven by genomic events. We work on
(12:09):
immunology because there's a lot of great immunology labs at
the Garvan, who we collaborate with, who you know, require
genomics capabilities for their work.
But we also do some more left field things like
working on non-human biology. So we collaborate with a lot
of researchers in the plant and animal world who want to sequence
a genome for their particular species that they're most interested in.
Maybe for evolution studies or ecology
(12:31):
studies, we help them build the genomics resources that they
need to make their work happen. That's a really interesting
and fun side project that we do. But it often
teaches us a lot about how the human genome works
as well to understand non-human organisms. In addition to that,
we work on different microbes including viruses, which have obviously
been very front and centre over the last couple of years.
(12:54):
And obviously, you know, all of these things involve DNA,
all of them have a genome.
And basically in modern science, you need to understand the
genome to understand whatever organism you're working on. We've found
that there's a huge appetite for these technologies. We obviously
put in the hard work to build these capabilities up.
But then once we've started offering them to the wider
research community in Australia, there's no limit to the people
(13:17):
who are showing up with cool projects to work on
and really taking advantage of the capabilities that we have
at the Garvan Institute.
Dr Viviane Richter (13:23):
Speaking of viruses, in 2020 you were approached about a
project that had quite a significant impact. Can you tell
us about that?
Dr Ira Deveson (13:32):
I started my new role as a lab leader at the
Garvan Institute
in I think it was February 2020 as the COVID pandemic
was just getting underway. And so within about a month
of me taking over that role, the world had descended
into chaos and we were in lockdowns. And scientifically, it
(13:53):
was quite interesting for us because we had these DNA
sequencing technologies that we were working with, that we had
really unique expertise in Australia. And we realised pretty quickly
that these could be applied for sequencing the gene
of the virus, which is a really useful thing to
be able to do because it allows you to tell
what the strain is. And as you know, we all
(14:14):
became super familiar with Delta and Omicron and all these
sorts of things. But you know, that's ultimately a genomic classification.
You need to sequence the virus's genome to know what
strain it is. It also informs contact tracing. So the
genome of the virus acts kind of like a fingerprint
and you can work out who passed it on to who.
So you can connect these clusters or these outbreaks together,
(14:37):
like the Crossroads Hotel and the Thai restaurant in Kings
Cross. To know that they had a common source, you have to
be able to sequence the genome of the virus which
provides that fingerprint that I mentioned. So we knew that
we had the capabilities to be able to do this.
We were generally using these technologies to sequence human genomes,
which are much bigger and more complicated sequencing. The virus
(14:58):
is actually not that
hard. And so we got in touch with some virology
labs and also ended up getting in touch with NSW
Health Pathology very early on in the outbreak in Australia.
And we said, you know, we've got these technologies and
we are available to help if you need it. And
so that kicked off a fairly long and intense and
(15:18):
exciting collaboration with NSW Health
to look at a work flow , to perform this
very rapid DNA sequencing on the virus that we would
then feed back information to them to inform their contact
tracing and, and strain surveillance.
Dr Viviane Richter (15:34):
We are four years on from that time, tell us
about what you're focusing on now.
Dr Ira Deveson (15:40):
So having built up all of these capabilities in these long-read
sequencing technologies that I've mentioned, we've now got the ability
to sequence human genomes at scale quite cheaply. And when
I say sequence human genomes, because we're using this unique technology,
we're fully sequencing them. So we're getting right into these
dark mysterious corners of the genome that I mentioned, these
repetitive genes that haven't been able to be to be
(16:03):
read out. And these are very interesting because they're the
most dynamic parts of the genome, they're the
most diverse parts of the genome. So if you compare
the genome of any two human individuals, the places where
they're going to be most different are in these dark repetitive regions.
And so a disproportionate source of genetic variation or genetic
(16:24):
diversity are in these genes. And so what we now
want to do is actually scale this up, spread it
out
to look at diverse human populations around Australia and potentially
around the world to study these dynamic regions and start
to build up a a much clearer picture of how
they look across populations. Like what are the shared features
between individuals and between different community groups? And what are
(16:47):
the features in these regions that are unique? And ultimately,
the goal is to build reference data and the resources
that we're gonna need to
understand these in a medical context. So that we can
potentially diagnose genetic diseases that involve these genes to do
that you need a really clear picture of what that
normal genetic variation actually looks like because that's just your
(17:07):
normal healthy background level.
Dr Viviane Richter (17:10):
What have you found out through that work so far?
Dr Ira Deveson (17:13):
So it's early days, but we've just been involved in
a very exciting pilot study with the National Center for
Indigenous Genomics in Canberra. It's a long-term study that we're
going to be continuing to work on. But the goal of
this pilot phase was just to look at the genome
sequences of individuals in four indigenous communities in Northern Australia.
(17:33):
So three in the northern territory and one in Queensland
and to start to characterise genetic variation in these groups,
but specifically focused on these complex repetitive areas of the
genome and and what we call structural variants. So these
are large pieces of DNA that are deleted or inserted
or rearranged between different individuals' genome sequences. So big changes
(17:57):
that are really often quite relevant and have a big
effect on people's genetic code. This is kind of the
first time that
indigenous Australian genomes have been studied to this level. And
so we obviously characterise a whole lot of unique genetic diversity,
a lot of new gene variants that have never been
seen before and probably don't occur outside of Australia. So
(18:20):
we discovered a lot of variation that appears to be
unique to indigenous Australians much more than you would find
in a European person who comes from a population that's
been very heavily studied in the past.
In addition to showing that these indigenous communities are genomically
very different to people from other parts of the world.
We also discovered somewhat surprisingly that these communities are very,
(18:44):
very genetically different from one another. So people from two
different communities in the Northern Territory separated by a couple
of 100 kilometres, shared some genetic variation, but had many
many unique genetic variants that were not found in another
community that were
specific to that community. They almost look like people from
totally separate countries in different corners of the globe, even
(19:05):
though they're just separated by a few 100 kilometers in
the northern territory. So that speaks to how long these
people have been living here in this country in largely
isolated pockets of the country and, and how unique their
genetic variation is.
Dr Viviane Richter (19:19):
What does this work mean for indigenous Australians?
Dr Ira Deveson (19:22):
This work tells us a lot about the genetic diversity
of indigenous Australians. They're really rich and unique genetic features.
But what's really more important about this is the first
step towards building the resources. We need to be able
to diagnose and research genetic disease in a manner that's
fit for purpose for these communities. So as I said,
(19:43):
we discovered that each community is very different from one
another and that all of them are genetically very different
from Europeans or East Asians. And so if we're trying
to diagnose any
indigenous person with a potential genetic disease, at the moment,
we'd be comparing their data to a reference data sets
that were built with Europeans. And it's not the right comparison.
(20:05):
So you're gonna find lots of features in that indigenous
patients genome that look different or stand out from the
crowd if you're using a European backdrop, I guess, and
that makes it very hard to diagnose the disease because
those are all gonna look like potential places where a
gene might be broken or something. But it's actually just
a natural feature of the fact that these communities have
(20:25):
been living, you know, separate for hundreds of thousands of
years potentially. So it's really important that we build that
reference data and, and, and build that map of what
normal healthy genetic variation looks like in the appropriate communities in, in,
in Australian indigenous population. And even in the specific communities
that particular patient might come from
genomics is the future of healthcare. And it's gonna become
(20:48):
increasingly intertwined and embedded with, with everything that we do
in medicine that might be five years down the track,
10 years down the track, 20 years down the track.
But if we don't build the resources now for these communities,
they're gonna be left behind. And that's just gonna be
another area in which the health disparities that already exist
in this country become wider.
Dr Viviane Richter (21:10):
And I understand you have a special family connection with
this project.
Dr Ira Deveson (21:14):
Yeah. So it's a bit of a crazy coincidence but
these communities that we're working with um and this, this
center called the, the National Center for Indigenous genomics was
actually started around 10 years ago. Um At the anu,
what prompted this was that a large collection of Indigenous
Australian blood samples were found in a a minus 80
(21:37):
freezer at the John Curtin School of Medical Research that
had been basically collected in sort of the 19 I
think 19 sixties. So,
uh and then how is it the anu indefinitely just
sort of put on ice uh because the the person
looking after them and, and running the project was no
longer around these samples were discovered. And the National Center
(21:57):
for Indigenous genomics was set up to basically repatriate them,
return them to the the communities from where they were collected,
but also to prompt dialogue with those communities so that
we could then start working with them genomic and come
up with projects and engage their leadership for future genomics research.
Some of the samples actually ended up being analyzed some
(22:17):
of these historical samples. You can still get DNA out
of them and you can uh you know, with the
consent of the of the communities involved, you can still
do genomics research on them.
The real crazy coincidence here at these samples were actually
collected by my grandfather in the, you know, who, who
was a, a genetics, genetics researcher back many decades ago.
He died when I was quite young. So I had
(22:38):
no idea who was working on any of this stuff.
My mum was sort of vaguely aware and she was
obviously contacted when they were starting this center
and utilizing his old lab, notebooks and journals and specimens
and things. But then just much later on, I was
just at a conference and my colleague from Anu was
giving a talk about this new center and popping up
(22:58):
photos of like historical photos that my grandfather
taken in the field of him working with, with these communities.
And I was like, oh that's, that's my, that's my
grandfather and he was like, oh, bloody hell. So, uh, we,
we better, we better get you involved in the, in
the research. And so that was, that was kind of
how we struck up the conversation. And, yeah, just a,
a bit of a crazy coincidence.
Dr Viviane Richter (23:18):
I a before we let you get back to your
genomic sequencing.
It's time for the fast five. What do you do
in your downtime? Uh,
Dr Ira Deveson (23:27):
at the moment I'm doing a lot of long distance running.
Most
Dr Viviane Richter (23:30):
challenging thing you've ever done. When
Dr Ira Deveson (23:32):
I finished university, I rode my bicycle across Europe for
about 4000 kilometers over a couple of months, which was
extremely challenging. I wouldn't say it was something I had
to do. I did it voluntarily and it was a
lot of fun. Uh, but yeah, that was pretty difficult.
Any
Dr Viviane Richter (23:48):
secret skills.
Dr Ira Deveson (23:50):
Uh, I'm really good at trivia questions about landlocked countries. So,
if you tell me any country, I can tell you
whether it's landlocked, possibly Kenya, not landlocked. Yeah, 100% sure
about that. There's two countries that are doubly landlocked. So
they're landlocked by other landlocked countries. Uzbekistan and Liechtenstein. You
(24:12):
need to know that one. It, it comes up on the,
on the quiz quite a bit.
Any pets? Uh, yeah, I got a dog called Tony. Uh,
short for rigger. Tony. He's a, uh Maltese terrier cross
with a toy poodle. So a moodle. He's a good
little Boy,
Dr Viviane Richter (24:25):
what's the current book you're reading?
Dr Ira Deveson (24:27):
I'm reading a book called Paradise Estate by an author
called Max Easton. He's a Sydney author. The book's actually
about a moldy sharehouse in Sydney's Inner West, which is
a topic. I'm very familiar with
Dr Viviane Richter (24:39):
Doctor Ira Davison. Thank you so much for joining us
on medical minds.
Dr Ira Deveson (24:43):
Thanks for having me viv It's um been really great
to speak with you if
Dr Viviane Richter (24:46):
you'd like to know more about Ira's research or donate
to the work we do at Garvan head to garvan.org
dot au. And if you've enjoyed this podcast, please leave
a review and share with other podcast lovers. I'm Doctor
Vivian Richter. Thanks for listening.
This podcast was recorded on the traditional country of the Gadigal,
(25:09):
people of the Eora nation. We recognize 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.
Genomics is fundamentally changing the way we think about health
and disease and driving forward personalised treatment options that would have
been pure science fiction just a few years ago. Still,
some parts of our genome are more mysterious than others.
Garvan researcher, Dr Ira Deveson is spearheading cutting-edge DNA sequencing
(00:22):
methods to future-proof how genomics will integrate into healthcare.
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 Dr Ira Deveson, Head of the Genomic Technologies Lab
at Garvan. Welcome Ira!
Dr Ira Deveson (00:42):
A. Hi, Viv, thanks for having me. Really looking forward to
our conversation.
Dr Viviane Richter (00:46):
Ira, what excited you about genomics enough to make it your career?
Dr Ira Deveson (00:50):
Yeah, I guess I've always been interested in the life
sciences and the natural world and I guess just sort
of understanding how things work in the world around you, which,
which really is the goal of science. And I think
I was lucky enough to have a couple of really
excellent high school science teachers towards the latter stages of
my high school who kind of inspired me to take
up biology and chemistry at university.
(01:13):
And I think somewhere along the line there, during those years,
I realised, if you want to understand how the world works,
how living things work, how they came to be and
um how they're changing, you really need to understand the
genome because it is the core program of life that
dictates everything. And I guess once I'd realised that there
was never really gonna be another path for me, I
(01:34):
was always fascinated by it from that point onwards.
Dr Viviane Richter (01:38):
Tell us about the first time you stepped into a
research lab.
Dr Ira Deveson (01:41):
The first time I stepped into a research lab would have
been my honours year at ANU.
So during honours, I studied plant science, doing a plant genetics project.
So I was embedded in a lab where we were
growing little model organisms called arabidopsis and fiddling around with
their genomes to test things about how their genes operate
(02:02):
and switch each other on and off. My project was
actually a bit of a left field one where we
decided we wanted to clone a human gene into this plant.
We were testing the idea that this gene is a
really ancient gene, its function has been around for so long.
That if you take it from a human cell and
(02:23):
put it into a plant, it could still perform its function.
We did that and it kind of worked, it kind
of could still perform its job. But the plant was
a bit messed up. It sort of had weird curly
leaves and was a bit shrunken and imperfect.
But it was a really fun experience about what you can
(02:45):
do in science when you come up with a hypothesis,
even if it's a bit left field and just have
a crack at it. Yeah.
Dr Viviane Richter (02:51):
What did that tell you about genomics?
Dr Ira Deveson (02:53):
I mean, it taught us a lot about this gene. It
taught us that the gene
is so deeply conserved or so ancient that it could
still function in a plant cell. But obviously, there had been in
the intervening hundreds of millions of years, it had changed sufficiently
that its job wasn't perfectly executed in a plant cell.
It wasn't interacting with all of the things that it
would normally interact with in a human cell. So, yeah,
(03:16):
we learned something about the evolution of that gene which
to me was eye-opening and a pretty cool experience as
a undergraduate.
Dr Viviane Richter (03:24):
So you went on to do a PhD. Can you
tell us about what you did?
Dr Ira Deveson (03:28):
Yeah. So my PhD was in genomics in a pretty
broad sense and it was mostly sort of computational stuff.
So I'm a bioinformatician or, or I was a bioinformatician ,
a person who analyses genomics, data sets to learn things about
biology and, I say that because it was a very
broad PhD, I worked on a lot of different projects,
all of them on different subjects, but united by the
(03:51):
fact that they involved genomics.
Actually, the title of my PhD thesis ended up being
'Three largely unrelated experiments in the era of genomics' or
something like this, which my supervisors were not very impressed with.
But I think the main thrust of what I was
doing turned out to be a a biotechnology project where we
(04:11):
developed a new product which was called sequins. These are
sort of synthetic genes. So totally artificial molecules that we
created
that you could actually use as internal controls in your
genomics experiments. So the basic idea is you would get
these synthetic genes, you'd add them to a DNA sample
that you were just about to analyse like maybe a
patient DNA sample. And then you'd do your genomic experiment
(04:35):
as you normally would, but you'd have these synthetic molecules
in there that act as kind of like an internal
truth set or like a a known and
within your experiment and having that in there, lets you
sort of measure how accurate your experiment is because you've
got this truth set, you can see if you're making
any mistakes and that gives you ability to sort of
do quality control, measure your performance over time. And ideally
(04:56):
to optimise your performance, you actually improve the accuracy of
your experiment.
Dr Viviane Richter (05:02):
So rather than investigating a specific biological problem, you're more
focused on developing the technology that sits behind that.
Dr Ira Deveson (05:10):
Yeah, I think that's what sort of came out of
my PhD was this philosophy that you don't necessarily have to
be a expert in one particular disease or one particular
biological system. But you can spend your time building tools and,
and methods and get these sort of capabilities particularly in
the data analysis, which is a huge part of genomic science.
And once you've got this expertise or once you've built
(05:31):
those tools, you can really apply them in many different areas.
And the applications sort of follow naturally, I guess, usually
via collaboration with people who are experts in different disease
areas or different areas of biology.
Dr Viviane Richter (05:44):
What sort of sequencing do you specialise in?
Dr Ira Deveson (05:47):
So my team's called the Genomic Technologies Lab. And we
work on lots of different genomic technologies, but something that
we're really interested in at the moment and over the
last couple of years is called long-read sequencing. So this
is a new class of technologies that are really hitting
their stride over the last couple of years and they're
kind of revolutionary because I guess over the last 10
or 20 years in genomics, we've been pretty reliant on
(06:10):
a technique called next-generation sequencing or shotgun sequencing.
And this is a process where you basically smash the
genome up into tiny little fragments that are about 100
base pairs long or 100 letters of the DNA code long.
The genome is 3 billion letters and we're smashing it
up into these tiny 100 base pair pieces. And then
you have to stitch all those together like a, like
(06:30):
a jigsaw puzzle to sort of understand what the genome
looked like in a given person or a given organism.
But now with these new technologies that are coming along, long-read sequencing -
it's called long read because we don't have to smash
the genome up into these tiny pieces. We can actually
read much longer pieces of the DNA code. So thousands
or tens of thousands or even up to millions of
(06:52):
letters long in a single continuous piece.
So that basically just means that when you're stitching the
genome back together for your patient or for your organism,
you're doing a much less complicated jigsaw puzzle. You don't
have all these tiny little fragments, you have these long
continuous molecules. And so that makes the problem much simpler,
much less chance of making mistakes. And it lets you access
(07:14):
parts of the genome that are too complicated to stitch
together with those small jigsaw pieces.
Dr Viviane Richter (07:20):
You're saying this is giving us the most accurate view
of our genome.
Dr Ira Deveson (07:25):
Yeah, this is giving us the best resolution, I would
say when it comes to reading a genome and
I guess you need to think about the fact that
the genome is not a single homogenous object. It has
lots of areas that have specific contexts that make it
difficult to read. And the thing that's usually most difficult
(07:46):
is a repetitive sequence. And you can imagine if you're
doing a jigsaw
puzzle, if there's a section of the puzzle that has
lots of the same feature being repeated over and over
again without any kind of unique features, that's really hard
for you to interpret and stitch together correctly. And that's
the same in the genome. If we have large sections
of the genome where you just have the same
(08:07):
DNA code repeating itself again and again, you're very likely
to make mistakes when you're trying to piece that together
and read it out. So there's maybe 10 or 20%
of the genome that's like this. It's too repetitive for
us to have properly analysed in the last 10-15 years
of genomics. But now with these new technologies, we can
finally read these sections, these sort of mysterious dark regions
(08:28):
of the genome.
Dr Viviane Richter (08:30):
And why do we need to know about these regions?
Dr Ira Deveson (08:33):
Partly because it's just really interesting, we don't know what's
in there. And that's what drives us as scientists, is
driving our knowledge for just finding out what these regions
look like. But we also know that there's lots of
important genes within these regions and there's lots of important
genes that have roles in disease where we already know
that they have roles in disease. But we haven't been
(08:53):
able to properly analyse them because the technologies have not
been there or we can analyse them maybe to diagnose
a genetic disease, but it's really slow and laborious and
challenging and error-prone . So with these new technologies, we
can eliminate a lot of those difficulties, but we can
also just shed new light on things that we haven't
understood before.
An example that we've been working on a lot in
(09:14):
the last couple of years, a specific group of disorders
called repeat expansion disorders. These are typically neurodegenerative diseases affecting
the nervous system, but they involve lots of different genes.
There's at least 50 genes involved and probably many more
out there that we haven't yet discovered.
But they contain these repetitive sequences that are kind of
(09:36):
like repeating syllables within a word, everybody has these genes.
But in certain people, those repetitive sections of the gene
actually get blown out in size and they become massively expanded.
So you can maybe think about a word like Woolloomooloo,
the suburb in Sydney, everyone has a few repetitive syllables
in that word. But maybe in your patient when you
read it out, there's is Woolloomooloomooloomooloo , right? And so
(09:59):
it's become massively expanded. And
that's the nature of these repetitive sequences that they're quite unstable,
but that actually leads to disease in some cases. And
so some very well known genetic diseases like Huntington's disease
is actually caused by these repetitive expansions in a particular gene.
So those have been difficult to research and difficult to
(10:20):
diagnose until recently. But we're actually now applying these new
long-read sequencing technologies that we have to read these out
very accurately so that we can tell the difference in
the length of these genes between different individuals. And that
we hope is gonna lead to much better, much more streamlined,
much more accurate patient diagnoses
Dr Viviane Richter (10:39):
being able to diagnose these diseases much earlier on would
lead to a transformation in patient outcomes.
Dr Ira Deveson (10:46):
So unfortunately for a lot of these neurodegenerative diseases that
we're looking at, there's no current cure, but there are
cures on the horizon. There are very promising clinical trials
getting underway for things like gene therapies now coming out for
different inherited diseases. It's only a matter of time before
there will
be ways to treat these disorders that are very debilitating,
(11:09):
but we really need to be able to diagnose them
and work out exactly what a particular patient's specific mutation
is or variant is so that they can be accurately
targeted within these trials and when these therapies come online.
Dr Viviane Richter (11:24):
Ira, tell us what else you're using this long-read sequencing for.
Dr Ira Deveson (11:28):
Yeah. So we've spent a lot of time and energy
building up our capabilities in this area, long-read sequencing. We
have a lot of different instruments and we've really become the
leader in Australia in this area. And it means we
actually work on all sorts of different genomics projects. There's
a lot of demand for these instruments and for these capabilities.
(11:48):
But we started offering a sequencing service and we collaborate
with many different researchers around
Australia. So we work on everything from clinical genomics projects
like what I've just described where we're trying to improve
patient diagnoses. We work on cancer research which is obviously
a disease that's driven by genomic events. We work on
(12:09):
immunology because there's a lot of great immunology labs at
the Garvan, who we collaborate with, who you know, require
genomics capabilities for their work.
But we also do some more left field things like
working on non-human biology. So we collaborate with a lot
of researchers in the plant and animal world who want to sequence
a genome for their particular species that they're most interested in.
Maybe for evolution studies or ecology
(12:31):
studies, we help them build the genomics resources that they
need to make their work happen. That's a really interesting
and fun side project that we do. But it often
teaches us a lot about how the human genome works
as well to understand non-human organisms. In addition to that,
we work on different microbes including viruses, which have obviously
been very front and centre over the last couple of years.
(12:54):
And obviously, you know, all of these things involve DNA,
all of them have a genome.
And basically in modern science, you need to understand the
genome to understand whatever organism you're working on. We've found
that there's a huge appetite for these technologies. We obviously
put in the hard work to build these capabilities up.
But then once we've started offering them to the wider
research community in Australia, there's no limit to the people
(13:17):
who are showing up with cool projects to work on
and really taking advantage of the capabilities that we have
at the Garvan Institute.
Dr Viviane Richter (13:23):
Speaking of viruses, in 2020 you were approached about a
project that had quite a significant impact. Can you tell
us about that?
Dr Ira Deveson (13:32):
I started my new role as a lab leader at the
Garvan Institute
in I think it was February 2020 as the COVID pandemic
was just getting underway. And so within about a month
of me taking over that role, the world had descended
into chaos and we were in lockdowns. And scientifically, it
(13:53):
was quite interesting for us because we had these DNA
sequencing technologies that we were working with, that we had
really unique expertise in Australia. And we realised pretty quickly
that these could be applied for sequencing the gene
of the virus, which is a really useful thing to
be able to do because it allows you to tell
what the strain is. And as you know, we all
(14:14):
became super familiar with Delta and Omicron and all these
sorts of things. But you know, that's ultimately a genomic classification.
You need to sequence the virus's genome to know what
strain it is. It also informs contact tracing. So the
genome of the virus acts kind of like a fingerprint
and you can work out who passed it on to who.
So you can connect these clusters or these outbreaks together,
(14:37):
like the Crossroads Hotel and the Thai restaurant in Kings
Cross. To know that they had a common source, you have to
be able to sequence the genome of the virus which
provides that fingerprint that I mentioned. So we knew that
we had the capabilities to be able to do this.
We were generally using these technologies to sequence human genomes,
which are much bigger and more complicated sequencing. The virus
(14:58):
is actually not that
hard. And so we got in touch with some virology
labs and also ended up getting in touch with NSW
Health Pathology very early on in the outbreak in Australia.
And we said, you know, we've got these technologies and
we are available to help if you need it. And
so that kicked off a fairly long and intense and
(15:18):
exciting collaboration with NSW Health
to look at a work flow , to perform this
very rapid DNA sequencing on the virus that we would
then feed back information to them to inform their contact
tracing and, and strain surveillance.
Dr Viviane Richter (15:34):
We are four years on from that time, tell us
about what you're focusing on now.
Dr Ira Deveson (15:40):
So having built up all of these capabilities in these long-read
sequencing technologies that I've mentioned, we've now got the ability
to sequence human genomes at scale quite cheaply. And when
I say sequence human genomes, because we're using this unique technology,
we're fully sequencing them. So we're getting right into these
dark mysterious corners of the genome that I mentioned, these
repetitive genes that haven't been able to be to be
(16:03):
read out. And these are very interesting because they're the
most dynamic parts of the genome, they're the
most diverse parts of the genome. So if you compare
the genome of any two human individuals, the places where
they're going to be most different are in these dark repetitive regions.
And so a disproportionate source of genetic variation or genetic
(16:24):
diversity are in these genes. And so what we now
want to do is actually scale this up, spread it
out
to look at diverse human populations around Australia and potentially
around the world to study these dynamic regions and start
to build up a a much clearer picture of how
they look across populations. Like what are the shared features
between individuals and between different community groups? And what are
(16:47):
the features in these regions that are unique? And ultimately,
the goal is to build reference data and the resources
that we're gonna need to
understand these in a medical context. So that we can
potentially diagnose genetic diseases that involve these genes to do
that you need a really clear picture of what that
normal genetic variation actually looks like because that's just your
(17:07):
normal healthy background level.
Dr Viviane Richter (17:10):
What have you found out through that work so far?
Dr Ira Deveson (17:13):
So it's early days, but we've just been involved in
a very exciting pilot study with the National Center for
Indigenous Genomics in Canberra. It's a long-term study that we're
going to be continuing to work on. But the goal of
this pilot phase was just to look at the genome
sequences of individuals in four indigenous communities in Northern Australia.
(17:33):
So three in the northern territory and one in Queensland
and to start to characterise genetic variation in these groups,
but specifically focused on these complex repetitive areas of the
genome and and what we call structural variants. So these
are large pieces of DNA that are deleted or inserted
or rearranged between different individuals' genome sequences. So big changes
(17:57):
that are really often quite relevant and have a big
effect on people's genetic code. This is kind of the
first time that
indigenous Australian genomes have been studied to this level. And
so we obviously characterise a whole lot of unique genetic diversity,
a lot of new gene variants that have never been
seen before and probably don't occur outside of Australia. So
(18:20):
we discovered a lot of variation that appears to be
unique to indigenous Australians much more than you would find
in a European person who comes from a population that's
been very heavily studied in the past.
In addition to showing that these indigenous communities are genomically
very different to people from other parts of the world.
We also discovered somewhat surprisingly that these communities are very,
(18:44):
very genetically different from one another. So people from two
different communities in the Northern Territory separated by a couple
of 100 kilometres, shared some genetic variation, but had many
many unique genetic variants that were not found in another
community that were
specific to that community. They almost look like people from
totally separate countries in different corners of the globe, even
(19:05):
though they're just separated by a few 100 kilometers in
the northern territory. So that speaks to how long these
people have been living here in this country in largely
isolated pockets of the country and, and how unique their
genetic variation is.
Dr Viviane Richter (19:19):
What does this work mean for indigenous Australians?
Dr Ira Deveson (19:22):
This work tells us a lot about the genetic diversity
of indigenous Australians. They're really rich and unique genetic features.
But what's really more important about this is the first
step towards building the resources. We need to be able
to diagnose and research genetic disease in a manner that's
fit for purpose for these communities. So as I said,
(19:43):
we discovered that each community is very different from one
another and that all of them are genetically very different
from Europeans or East Asians. And so if we're trying
to diagnose any
indigenous person with a potential genetic disease, at the moment,
we'd be comparing their data to a reference data sets
that were built with Europeans. And it's not the right comparison.
(20:05):
So you're gonna find lots of features in that indigenous
patients genome that look different or stand out from the
crowd if you're using a European backdrop, I guess, and
that makes it very hard to diagnose the disease because
those are all gonna look like potential places where a
gene might be broken or something. But it's actually just
a natural feature of the fact that these communities have
(20:25):
been living, you know, separate for hundreds of thousands of
years potentially. So it's really important that we build that
reference data and, and, and build that map of what
normal healthy genetic variation looks like in the appropriate communities in, in,
in Australian indigenous population. And even in the specific communities
that particular patient might come from
genomics is the future of healthcare. And it's gonna become
(20:48):
increasingly intertwined and embedded with, with everything that we do
in medicine that might be five years down the track,
10 years down the track, 20 years down the track.
But if we don't build the resources now for these communities,
they're gonna be left behind. And that's just gonna be
another area in which the health disparities that already exist
in this country become wider.
Dr Viviane Richter (21:10):
And I understand you have a special family connection with
this project.
Dr Ira Deveson (21:14):
Yeah. So it's a bit of a crazy coincidence but
these communities that we're working with um and this, this
center called the, the National Center for Indigenous genomics was
actually started around 10 years ago. Um At the anu,
what prompted this was that a large collection of Indigenous
Australian blood samples were found in a a minus 80
(21:37):
freezer at the John Curtin School of Medical Research that
had been basically collected in sort of the 19 I
think 19 sixties. So,
uh and then how is it the anu indefinitely just
sort of put on ice uh because the the person
looking after them and, and running the project was no
longer around these samples were discovered. And the National Center
(21:57):
for Indigenous genomics was set up to basically repatriate them,
return them to the the communities from where they were collected,
but also to prompt dialogue with those communities so that
we could then start working with them genomic and come
up with projects and engage their leadership for future genomics research.
Some of the samples actually ended up being analyzed some
(22:17):
of these historical samples. You can still get DNA out
of them and you can uh you know, with the
consent of the of the communities involved, you can still
do genomics research on them.
The real crazy coincidence here at these samples were actually
collected by my grandfather in the, you know, who, who
was a, a genetics, genetics researcher back many decades ago.
He died when I was quite young. So I had
(22:38):
no idea who was working on any of this stuff.
My mum was sort of vaguely aware and she was
obviously contacted when they were starting this center
and utilizing his old lab, notebooks and journals and specimens
and things. But then just much later on, I was
just at a conference and my colleague from Anu was
giving a talk about this new center and popping up
(22:58):
photos of like historical photos that my grandfather
taken in the field of him working with, with these communities.
And I was like, oh that's, that's my, that's my
grandfather and he was like, oh, bloody hell. So, uh, we,
we better, we better get you involved in the, in
the research. And so that was, that was kind of
how we struck up the conversation. And, yeah, just a,
a bit of a crazy coincidence.
Dr Viviane Richter (23:18):
I a before we let you get back to your
genomic sequencing.
It's time for the fast five. What do you do
in your downtime? Uh,
Dr Ira Deveson (23:27):
at the moment I'm doing a lot of long distance running.
Most
Dr Viviane Richter (23:30):
challenging thing you've ever done. When
Dr Ira Deveson (23:32):
I finished university, I rode my bicycle across Europe for
about 4000 kilometers over a couple of months, which was
extremely challenging. I wouldn't say it was something I had
to do. I did it voluntarily and it was a
lot of fun. Uh, but yeah, that was pretty difficult.
Any
Dr Viviane Richter (23:48):
secret skills.
Dr Ira Deveson (23:50):
Uh, I'm really good at trivia questions about landlocked countries. So,
if you tell me any country, I can tell you
whether it's landlocked, possibly Kenya, not landlocked. Yeah, 100% sure
about that. There's two countries that are doubly landlocked. So
they're landlocked by other landlocked countries. Uzbekistan and Liechtenstein. You
(24:12):
need to know that one. It, it comes up on the,
on the quiz quite a bit.
Any pets? Uh, yeah, I got a dog called Tony. Uh,
short for rigger. Tony. He's a, uh Maltese terrier cross
with a toy poodle. So a moodle. He's a good
little Boy,
Dr Viviane Richter (24:25):
what's the current book you're reading?
Dr Ira Deveson (24:27):
I'm reading a book called Paradise Estate by an author
called Max Easton. He's a Sydney author. The book's actually
about a moldy sharehouse in Sydney's Inner West, which is
a topic. I'm very familiar with
Dr Viviane Richter (24:39):
Doctor Ira Davison. Thank you so much for joining us
on medical minds.
Dr Ira Deveson (24:43):
Thanks for having me viv It's um been really great
to speak with you if
Dr Viviane Richter (24:46):
you'd like to know more about Ira's research or donate
to the work we do at Garvan head to garvan.org
dot au. And if you've enjoyed this podcast, please leave
a review and share with other podcast lovers. I'm Doctor
Vivian Richter. Thanks for listening.
This podcast was recorded on the traditional country of the Gadigal,
(25:09):
people of the Eora nation. We recognize 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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