Transcriber: Uschi Symmons Reviewer: Ivana Korom
I want to talk today about a very unusual sort of cancer,
but one that has a good chance
of driving an entire species to extinction
within the next 20 years.
I'm sure for most of us everything we know -
or think we know -
about Tasmanian devils, we learned on Saturday morning cartoons.
But what I hope you noticed in the previous slide
was that in fact they're a whole lot cuter than this.
And they're also
considerably smaller and more docile
than you may ever have imagined.
These marsupials
got their name from the European settlers
to the island of Tasmania, off the cost of Australia,
because the Europeans thought of them as very aggressive hunters,
and because they make terrifying noises at night.
In fact these animals are not hunters.
They are solitary nocturnal scavengers.
They do, however, have a pugnacious side to them.
In that they engage in very ferocious fights
with each other, while they're mating,
and also while they're fighting over food.
Nonetheless, these fights very rarely result in mortal wounds.
Until recently, there was no reason
to think that these animals were in any way threatened.
In fact, you might think that they were actually
at the top of their game, evolutionarily speaking.
They are on top of the food chain
in the Tasmanian ecosystem,
they're well-adapted to their environment.
However, since the early 2000s
their numbers have dropped precipitously,
because of this unusual cancer,
and experts predict that unless there is some successful intervention,
they will be extinct by the year 2035.
So the story I want to tell you begins with these fights,
during which these Tasmanian devils bite each other on the face.
And starting fairly recently,
these bites have been observed to result
in the formation of tumours.
These tumors can be disfiguring, even grotesque,
in fact I've spared you the most graphic images,
which you're welcome to look up online yourself.
These tumors are invariably fatal to these animals.
Either because they grow so big that the animals can't eat,
because the animals get secondary infections,
or because the tumors actually metastasize
to other parts of the body,
the lungs or the heart or whatever,
and result in organ failure.
So the first facial tumor was reported in 1996,
and at this point,
70% of the Tasmanian devils in Tasmania are infected.
That's caused great alarm
among conservation biologists.
It's also caused alarm among the government officials in Australia,
because the Tasmanian devil is rather a mascot
for the Tasmanian tourist industry.
But most importantly for this talk,
it's caused intrigue among cancer biologists.
Because if you think about it,
we don't normally think of cancer as being a contagious disease.
You don't worry when you care for someone
or come in contact with someone who has cancer,
that you're going to contract cancer.
So what I want to do,
just as my students and I did
in my infectious disease tutorial class,
is explore how researchers investigate something
as odd as a contagious cancer.
And so we might need to start
by thinking about what do we know about cancer in general?
So, cancer arises
when a cell makes an inappropriate decision to divide.
Normally our cells keep their growth
and division very tightly controlled,
and we understand some - although not all -
of the ways that those cells know to control their cell division.
A tumor occurs,
when a cell has made a bad decision,
to go on dividing, even when it shouldn't.
Those normal brakes on cell division
are encoded in the DNA.
And so, if we want to understand
what's going on in this cancer,
perhaps we should think about the DNA of these cells.
And that is exactly what researchers did.
So, in 2012 researchers took
the DNA from a healthy Tasmanian devil.
And they also took DNA from two different tumor cells.
And they sequenced
the entire genome of those DNA samples.
And that allowed them to compare
the DNA of the normal cells,
with the DNA of the tumor cells.
And they looked for individual differences in the As, Gs, Cs and Ts
that make up the DNA.
And they didn't find a single obvious difference
between these DNA samples.
In fact, they found 17,000 differences.
Now, to put that in perspective,
a normal human cancer might also have 5,000 or more differences,
from a normal, healthy cell.
At the same time,
other researchers looked at the chromosomes in these tumors.
So you may of know of chromosomes as long strings of DNA,
they're the way we package and organise
the DNA in our cells.
You've probably heard
of the X chromosome and the Y chromosome,
you may know that humans have 46 chromosomes,
if you were paying attention just recently on the video.
Marsupials like the Tasmanian devil
have 7 pairs of chromosomes,
and we can paint the individual chromosomes different colours.
And that allows us to ask,
are these chromosomes intact,
or in fact, has there been some change
in the chromosome structure?
And what you can see in this figure
is that in these tumors in fact there has been a lot of whole scale
moving of chromosomal fragments.
So that here: chromosome 2 has bits of chromosome 1 and the X chromosome,
Likewise, chromosome 6 has a bit of the X chromosome.
And then you've got these
totally funky chromosomes over here,
that are just sort of an amalgam of all different bits of genetic information.
It's almost like when you -
at the end of editing a large body of text
you've not only changed words,
you've not only changed individual letters,
you've moved whole paragraphs around.
And that's what's happened in these tumor cells.
Again, this is not atypical for cancer cells.
But it might lead you to question,
how you could possibly begin to understand cancer,
if you're having all these dramatic changes in the DNA.
In fact, these experiments,
along with some other, earlier experiments,
lead to a critical insight
about this cancer in this Tasmanian devil.
And to help you appreciate that insight
let's think again about what we know about cancer typically.
I said that cancer arises, when the DNA changes,
so that the controls on cell division aren't carried out normally.
So we might ask, well how do those changes
normally happen In a normal cancer?
Some changes are hereditary.
So, we think about the breast cancer gene.
We think about someone who has a history of colon cancer in their family.
Other cancers arise because of environmental exposure.
So too much sunlight can lead to skin cancer.
Exposure to tabacco smoke can lead to lung cancer.
Or, to paraphrase Shakespeare,
some cells are born bad,
other cells have badness thrust upon them.
What we might not appreciate as much,
but certainly plays a critical role in cancer as well,
are things like lifestyle and dietary choices.
And finally, certain viral infections
can also cause cancer.
You may have heard of HPV, human papilloma virus,
which causes cervical cancer.
There are certain types of Hepatitis infections,
that can lead to liver cancer.
But what all these cancers have in common,
is that it's your own cell that has made that bad decision.
to start dividing.
In these Tasmanian devils,
something very different is going on.
Because, in fact, these cancers are acquired,
from a donor animal that is infected.
So when one Tasmanian devil has a tumor on its face,
as it bites another animal,
those tumor cells sluff off,
they lodge themselves in those wound sites,
and then they grow to be tumors in a matter of months
in that recipient animal.
And that's almost unheard of,
that you would catch cancer from something else.
In fact, there's only two well-characterised examples,
one of them being this devil facial tumor,
and the other being a venereal tumor in dogs
that's passed through sexual intercourse.
So we might ask,
how are researchers so sure that this is really passed
from animal to animal?
How do we know it's not a virus that's getting passed,
that then causes the tumor secondarily?
Well, again, if we think about a normal cancer -
suppose that I get lung cancer,
the cells in that tumor
in my lung have my DNA.
If Jim ends up getting lung cancer as well
the cells in his tumor have his DNA,
not my DNA.
But in these transmissible cancers, in fact,
the cells in the cancer are not my cells.
They don't have my DNA.
And again, we can see that by looking at the chromosomes
in these tumors.
So, once again we have the normal chromosomes
from a healthy animal up here,
Again, seven pairs of them.
And here we have 4 different tumors.
And again, we've seen that the chromosomes
in these tumors are very different:
there's missing chromosomes,
there's extra chromosomes.
Although these chromosomes aren't all identical to each other
in these four tumor samples,
they are much more similar to each other,
than they are to a healthy animal.
The same is true in the dog venereal cancer.
So we can depict genetic relatedness
as a sort of tree diagram like this.
where the little twigs on the end of the branches
are breeds of dogs
that are very closely related to each other,
and the length of the branch indicates
how distantly related they are.
A longer branch
meaning more distantly related.
So here we have the Shih Tzus and the Pekingese
very close to each other,
but very far away from the Huskies and the Malamutes.
The wolves are down here all by themselves
on a separate branch.
And look where the dog venereal tumors are.
They're way over by themselves.
They're very closely related to each other,
and very distantly related to the dogs that host them.
In fact, in a study of 40 different tumors
from 40 different dogs on 5 continents
researchers found that every one of those tumors
was derived from a single ancestral cell
that made a bad decision to divide.
And that cell made a bad decision to divide
six thousand years ago.
And it made a bad decision
because of a change in its DNA
as shown in this slide.
And since that time, those cancerous cells
have passed through 30,000 different dogs,
being passed from dog to dog to dog to dog.
It's the oldest known living cell line.
So what does this transmissible cancer in dogs
perhaps tell us about the similar case
in the Tasmanian Devils?
Well, at first glance you might think,
actually, based on what I've told you,
not all that much.
Because, first of all, I've told you
that the dog cancer is very ancient,
the devil cancer is very recent.
I've told you that the mode of transmission is different.
And perhaps most strikingly,
the dog cancer is very rarely lethal.
Whereas the Tasmanian devil cancer is invariably lethal.
Again, just to give you a sense of the impact
on these Tasmanian devils:
an average Tasmanian devil in the wild
will live to be five or six years old, typically.
However, these days if you survey populations
of Tasmanian devils in the wild,
you will rarely find an animal
more than three years old.
Because in fact, all those animals have died
after one or two years,
because of this cancer.
So clearly, we have an urgent need
to figure out what's going on with this cancer,
and to eradicate it before it eliminates this entire species.
One avenue of investigation
that has given us some insight
builds on what we know about how bodies normally
try to protect themselves from infected cells,
as well as from cancer.
So, in our immune system
we have something called T cells.
And T cells' jobs
are to recognize and to destroy
infected cells as well as cancer cells.
They do that by binding
to an infected cell,
producing toxins called perforins,
that make holes or perforations in the target cell.
And those perforations result
in those cells bursting and being destroyed.
It's just like taking a balloon
and popping it with a bunch of pins all at once.
Now, how does the T cell know
that this is an infected cell or a cancer cell,
and not a normal cell that should be left alone?
Well, cancer cells make proteins
that normal cells don't make.
We can think of those as markers for a cancer cell.
And every cell makes a protein called MHC.
And the job of the MHC
is to present those markers to the T cell,
so that the T cell knows
this is a cell that I should attack.
So why then,
doesn't the T cells and the immune response
take care of these infected, contagious cancerous cells?
Well, in the case of the dog cancer
we know, that in fact
the progression of the disease is such,
that in the beginning the immune system
doesn't take care of them.
When the dogs are first infected
they form tumors for the first 3-9 months,
and the tumors progress
precisely because the immmune system
is not doing anything about them.
But then, after that time,
the tumors begin to stabilize, or even regress.
And that correlates exactly
with what's happening to the MHCs.
In those first few months
those cancer cells don't make MHC proteins.
Once they start to make the MHC proteins
the immune system cuts in, and gets the upper hand.
So really there's a balance
between the progression of the tumour
and the immune system.
Now what about
in the contagious cancer in the Tasmanian devils?
Well, until recently
researchers had actually focused
on a rather different sort of story.
And that story has to do with MHC diversity.
So, I've mentioned this MHC protein,
it turns out that MHC comes in many many flavors.
That's shown in this slide here.
Different coloured MHC proteins,
and which MHC proteins your cells make
is determined by which MHC genes
you inherited from your mother and your father.
The diversity is rather remarkable.
Incredibly strikingly,
large repertoir of possible MHC proteins.
Just to give you some sense,
in the human - just for this MHC-A gene
there are 2,000 possible
MHC-A genes you could have.
For the B gene 2,500 possible genes,
and for the C gene
another 1,300 possible genes.
The combination of MHCs
that are on your cells
is completely different than the combination of MHC proteins
on the cells
of the person sitting next to you.
This is in fact
the basis for incompatibility
during organ transplantation.
Because your immune system is primed
to see your own MHCs as self,
and to reject any cells
that don't have the same combination of MHCs.
So, why then doesn't the immune system take care of the contagious cancer
when cells are coming in with different MHCs?
Well, it turns out that for the Tasmanian devils
there actually isn't a great diversity of MHCs.
And that actually makes sense
if you think about these animals.
They live on an island
that's very geographically isolated.
They're not found anywhere other than Tasmania,
and they've been very inbred
over all the time they've lived in Tasmania.
And so particularly for the animals
on the Eastern half of this island
they have the same MHC.
There is no diversity.
And so that makes all the sense in the world then,
that a cancer that arose up here in the north-east corner
could be passed on,
and would not be rejected by the other animals
on the Eastern half of the island.
Because in fact the MHCs are identical.
They're not seen as foreign.
There was hope,
that in fact the animals in the north-west corner would be safe
because those animals have a slightly different MHC.
And it was thought that that disease
would not be able to cross that immune barrier.
However, we now know that that's not true.
Recently, the disease has crossed that immune barrier,
and the animals in the northwest corner
have also gotten sick,
despite not having the same MHC profile.
So, what is going on there?
Well, just a few months ago,
researchers discovered
that in the Tasmanian devil cancer cells
the story is actually much more similar
than one might have thought,
to what's going on in the dogs.
That is to say,
the MHC protein fails to move to the surface,
and if it can't move to the surface,
it can't present those cancer markers,
and the T cells don't know to eliminate
those cancerous cells.
These researchers also gave us some hope,
that we might be able to develop a vaccine.
Because they were able to stimulate the MHC proteins,
to move to the surface,
with an immune stumulant.
And so there is hope now,
that they could maybe prime the immune system, with a vaccine,
so that the Tasmanian devils would be protected
from this disease.
Will that happen in time to save them from extinction?
We certainly hope so.
So what I've shown you,
is that this is a highly unusual disease,
in that it's a contagious form of cancer.
That it defies the normal immune barriers,
and that it does so
in a way that was not at all what was hypothesized
even a year ago, when I taught my tutorial
on infectous disease.
I think this story sort of underscores -
for me - how rapidly a field like this is moving,
and how interesting it is,
even though one might have thought initially
that it was a rather esoteric topic.
More generally it shows the ways
that molecular biologists and conservation biologists
can work together,
to try to prevent the extinction
of an entire species.
And finally, I think it's really interesting
to think about the trade-offs
in the competition between a contagious agent,
like this infectous cancer and the host.
If a cancer spreads so lethally and so rapidly,
that it kills off its host,
then it will be gone as well.
In the case of the dog venereal tumor
that cancer has evolved to not be that lethal.
But that's taken thousands of years.
Will the same thing happen
to the devil facial tumor?
Given enough time?
We don't know,
and we may or may not have a chance to find out.
Thank you.
(Applause)