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)
