Transcriber: Tanya Cushman Reviewer: Peter van de Ven
Thank you. It's a real pleasure to be here.
I'm here to tell you today that nature has beat cancer 12 times.
Now, I'm at the Biodesign Institute.
I know, gob-stopping, right?
(Laughter)
I'm at the Biodesign Institute,
and the whole idea behind the Biodesign Institute
is to look into the designs that evolved in nature
and use those designs to solve real-world problems.
And this is an example of that.
Now, these guys have solved the cancer problem.
An elephant is 100 times larger than a human,
has 100 times more cells than a human,
and yet gets less cancer than a human.
Now, I want to take you through this problem in cancer biology
called Peto's paradox,
that was mentioned earlier,
by telling you about these fictional creatures called "fwampow," alright?
These little guys, fwampow, they don't get much cancer.
This one right here has got one cell that's about to become cancerous,
so one out of five, approximately.
And it's important to understand that cancer starts in a single cell.
Now the fwampow have a sister species called the mega-fwampow.
The mega-fwampow have ten times more cells than the little guy;
otherwise, their biology is identical.
So the mega-fwampow have a problem.
Because they have 10 times more cells,
they have the same probability per cell of getting cancer,
and so pretty much every individual mega-fwampow is going to get cancer,
in fact, is more likely to get multiple cancer.
It's a big problem for the mega-fwampow.
They've grown big,
and in nature,
we've independently seen the evolution of large organisms 12 times.
So there's been 12 cases where evolution has solved the cancer problem,
because to grow so large,
you have to find some way of suppressing cancer long enough to reproduce.
Now, there's a very good reason to grow large: it gets you more sex.
There's another good reason: you don't get eaten as often.
So this is the reason why organisms tend to grow large,
evolve to be large over time.
But that brings this problem of cancer vulnerability
with all those extra cells,
and so they also have to evolve better ways of suppressing cancer.
So the evolution of large body size and cancer suppression
have gone hand-in-glove.
Now, why should we care about cancer suppression
in large organisms like elephants?
The short answer is because it's so hard to cure cancer.
And to understand that, I need to take you down into the world of a tumor.
It turns out that a tumor is a microcosm of evolution.
Inside a tumor we have billions to trillions of cells
that are mutating like crazy.
If some of those mutations give a cell an advantage over other cells,
if it can divide faster or survive better,
that mutant cell will start spreading in the tumor.
So you get evolution down at that cellular level
that's driving this whole process of getting cancer,
and eventually in some people, in some organisms,
will lead to a malignancy that may kill them.
Now, this evolutionary process that's happening down at that cell level
is also the reason we've had such a hard time curing cancer.
So when a patient goes to the doctor because they're feeling sick,
and they have cancer,
they have these billions to trillions of cells in their tumor,
hundreds of thousands of mutations,
and just by bad luck,
some of those mutations can make a cell resistant to our chemotherapy.
So when we apply the chemotherapy to a cancer patient,
we kill most of the cells.
It's just like spraying a field with pesticide:
you kill most of the pests in the field,
but you leave behind pests that are resistant to your poison,
and then you get an outbreak of pests
that can no longer be controlled by your poison.
The same thing happens in the oncology clinic.
We apply chemotherapy to a tumor,
we kill most of the cells,
but we leave behind some cells that, just by bad luck, have mutations
that make them resistant to our chemotherapy,
and then the tumor regrows from those resistant cells -
the tumor comes back -
and now it no longer responds to that drug.
That's the basic explanation for why we've had such difficulty curing cancer,
and that explanation applies to every single drug
that's been developed for cancer biology, for cancer therapy.
Every drug selects for a resistant.
So cancer is an adaptive enemy;
we're fighting the power of evolution when we fight cancer.
And that's what led to a phone call from these guys.
So, the Naval War College has a strategic studies group
that convenes every year
to try to address and solve the pressing problems of the U.S. Navy.
And one of those pressing problems is that our enemies adapt to whatever we do.
Right? True in general: in warfare and military, our enemies adapt.
So they called me, for some strange reason,
but that reason was because I think about how do we deal with an adaptive enemy,
that is cancer,
and what can we learn from that?
And this led to an embarrassing moment of my life.
So, I'm there; there's a U-shaped table;
the military brass is around the table;
the admiral of the War College starts introducing them.
There's captain, captain, commander,
captain, captain, captain,
and I'm sort of used to thinking about rank in the army
where captain is ranked somewhere below major
and a little bit above lieutenant.
And suddenly I realize, "Wait a minute, these are captains of ships."
They have thousands of people under them that depend on them,
and I'm standing in front of them.
It took me a moment to recover from that, but when I did, I told them three things,
you can do three things with an adaptive enemy.
One, you can change the incentives on that enemy
to make them into a friend or, at least, a neutral party.
Two, you can try to contain them.
That was the whole premise of the Cold War strategy.
Or third, you can try to slow them down
so they can't adapt so quickly to what you do.
And that's a key to cancer.
Because in cancer, in many cases,
the first mutation that starts that cancerous process
happens 50 to 60 years
before you feel sick enough to go to the doctor -
happening throughout our lives, 50 to 60 years.
Well, the implication of that is if we slow the process just by a factor of two,
if we could double the time it takes to get cancer,
then it would take 100 to 120 years to get cancer,
and we wouldn't start feeling sick
until we were well into the second century of our lives.
That's where we're going.
So the way we're trying to address this in my lab is with aspirin.
So, the epidemiologists have told us
that aspirin often seems to help prevent cancer.
Now, aspirin is an anti-inflammatory drug, it reduces inflammation.
We think that's important because often inflammation drives cancer.
But we don't know exactly how,
so we study Barrett's esophagus -
it's one of the tumors we study.
It's a precancerous tumor -
it hasn't yet become malignant or life-threatening;
it doesn't always do so -
and we have a cohort of patients in Seattle that we've been following.
In that cohort are some patients that changed their use of aspirin,
usually for heart disease.
So we're just observing what happens.
And we use these observations of the patients over time
and sample their tumors.
What we found is the people that went on aspirin,
the mutation rate inside their tumor dropped by an order of magnitude:
ten times slower mutation rate in the people that started taking [aspirin].
That's one way that we're trying to approach it -
to try to slow down this process by reducing the mutation rate.
How have elephants done it?
Well, our collaborator in Utah, Josh Schiffman and his lab,
what they found was when you take elephant cells
and apply a little bit of radiation or some chemical mutagen,
those elephant cells,
rather than getting their DNA damaged and causing a mutation,
they just kill the cells like that.
Elephant cells are extremely sensitive to the DNA damage,
and they kill themselves;
it's a cell-suicide process called apoptosis.
So this is another way of reducing the mutation rate -
just kill every new cell that gets a mutation.
Now, a human cell won't kill itself so easily;
it requires more radiation or more DNA damage
for a human cell to commit suicide.
In a mouse cell, they don't care if they get DNA damage;
they're going to get picked off by a predator within a few months.
They better just reproduce as fast as they can.
The mechanism that nature has discovered for preventing cancer in elephants
seems to be through apoptosis, through the cell-suicide mechanism.
Now, how do the elephant cells do this?
Well, they do it through a gene called p53.
p53 is the most important tumor suppressor gene we know of.
In humans, we have two copies of it:
one from your mother and one from your father.
Elephants have 40 copies.
That's only a discovery my student Aleah Caulin made a number of years ago.
So, elephants suppress cancer.
This is the first time we were able to answer Peto's paradox:
elephants suppress cancer by this cell-suicide mechanism.
But there have been 12 independent times a large body size has evolved in mammals.
Rhinoceroses also must have a solution to preventing cancer -
they're huge animals.
So do hippopotamuses.
Giraffes also suppress cancer.
They're very large animals;
they've evolved a large body size completely independently
of those other animals.
Water buffalo,
Indian bison,
Shire horses,
polar bears.
Manatees have also grown large independently;
they must have a solution to cancer suppression.
So have elephant seals;
so have walruses,
and so have whales.
It might be the case that nature
rediscovered the same mechanism every time,
but that's not true, at least in whales.
We're currently studying whales in my lab;
we're sequencing the genome, analyzing it,
and I can tell you already, whales do not have extra copies of p53.
They've only got two: one from mother, one from father.
So there's some new solution that we haven't yet discovered
that's preventing cancer.
What's exciting for me about this
is that the solutions for preventing cancer are out there.
They're down the street in the local zoo; they're across the world in other zoos,
and they're in the wild, right?
Now, I know what you're thinking.
What about dinosaurs?
(Laughter)
And you're absolutely right.
Nature discovered a way of suppressing cancer in dinosaurs,
probably multiple times.
They're a lot harder to study than elephants;
nevertheless, my lab is starting to work on dinosaurs as well.
So, the idea from biodesign is to take these solutions from nature,
take these ways that nature discovered -
viable, fertile organisms that can suppress cancer -
and translate that into human.
And the whole idea here, then,
is to use those ideas from nature
to help us humans have longer, healthier lives.
Thank you.
(Applause)