Translator: Tanya Cushman Reviewer: Peter van de Ven
What if we could regrow a missing arm, just like a starfish can?
I've been obsessed with that question all my life.
Since I was two years old,
I've been spending my summers
on a remote island off the coast of Mount Desert Island
and literally waiting for the huge tides
that ebb and flow and rule our comings and goings.
High tide's easy:
the water flows over the rocks,
the rowboat goes down the beach easily,
and the ramps on the docks are nice and flat.
But when the tide goes out,
you have 40 to 50 more feet of very special land,
and that land is called the littoral zone,
and it is a magic place.
It comes with problems;
it means that you've got steeper docks, and you have grounded boats,
and as a kid, I waited for that low tide
because that meant I could see the ocean floor,
and I could start to really explore it,
and I used to pick up treasures and take them home and draw them.
Now, they included starfish.
Starfish have it pretty rough in the littoral zone.
They get buffeted about by the ebb and flow
of rocks and pebbles and fishermen's nets and predators.
And so many of them have either missing or damaged arms,
and almost always you see a tiny little arm growing back.
And this arm can take as much as years - if the starfish is big -
but it always grows back,
and it grows back perfectly; it's a perfect replica.
And I wondered, how does that happen?
How do they do that?
And then, obviously, the question is,
why can't we do that?
Why can't a war veteran regrow their arm just as easily as a starfish?
So, here I am.
Half century later, I've come back to these islands
to pursue my fascination with regeneration
and to revisit that littoral zone where I first found the inspiration for my work.
As scientists, we learn how to look below the surface
and to literally wait for that hypothetical low tide
that will reveal all these wonderful secrets,
and we wait there for just the right moment,
with the right buckets and spades,
for that fleeting glimpse of the way things really are.
And our now more, increasingly powerful instruments
allow us to dissect out all sorts of things,
like the way a red blood cell works or to measure the curiosity of a mouse.
It's very long work.
It takes a lot of patience to wait for those low tides of science;
they don't come as easily or as regularly as our daily tides on this island.
Here on Mount Desert Island, we wait during the winters,
all by ourselves,
(Laughter)
rummaging around, looking for patterns and picking up clues.
And then in the summer time,
we have the delight of sharing these beautiful tidal zones of biology
with the visitors that flood in,
attracted by the beauty of this island
and by the extraordinary resources we have at the Jackson Laboratory.
And what we find is astonishing.
We are, right now in history of science,
at a point where the technology is sufficient
that we can dive straight into the zone of our genetic inheritance
to find out what makes us human
and to understand how we as humans
relate to the myriad other life forms on the planet.
It's a huge conceptual leap,
something that the framers of Acadia National Park, in 1916,
couldn't have imagined,
or even in 1929,
when Clarence Cook Little founded the Jackson Laboratory
in order to try to study the genetics of cancer
and he didn't even know what a gene looked like.
So now, as scientists, we look at whole genomes -
that is the entire set of DNA sequences
that make up your genetic inheritance.
And that genome, essentially, contains all the information you need
to build and maintain the organism, yourself.
And the information in there, all 3 billion bits of it,
is contained in every single cell of your body, in these chromosomes,
and we can look at all of this now, all at once,
and we can follow it as it passes along generations.
So, just as our genes are inherited from our parents
so are changes in those genes,
changes in the instruction.
So here you see that the father, in blue,
has passed on a defective gene to two of his kids.
But this isn't the only way that genes work.
There's also spontaneous changes, so you can acquire something.
And in this case, the daughter has acquired a new piece of instruction
that may make her better at playing sports or better at solving equations
than her family,
whereas the son may inherit a deleterious change,
and when it causes disease, we call it a mutation.
So, I've had my genome sequenced,
out of curiosity.
And here it is; you get to see it.
(Laughter)
23 chromosomes of it, and it's all in there.
And what did I find?
I found that I am very boring.
(Laughter)
Thank God.
I don't have any of the genes
that we think are going to put me at an increased risk
of cardiovascular disease, of Alzheimer's, of diabetes.
Now, that doesn't mean I won't get those diseases;
It just means that, as far as we know,
I don't have an increased genetic risk of getting those diseases.
And so, I was happy until I came across this little problem:
A G-to-A change in a gene called ABCA4.
And what happens is that that particular change
produces a defective protein that is encoded by that gene,
so I have a defective ABCA4 protein.
So, of course, I'm running to the web,
what is this gene?
And what I discovered was that people with this particular mutation
tend to develop a disease called Stargardt macular dystrophy,
which manifests as a very rapid decline of your sight and blindness as a child.
Well, obviously, I'd missed that one, thank God,
but I then went and read further
and discovered that, indeed, there is another thing that could happen to me
because people who have this disease
tend to get macular degeneration between 60 and 80 years of age,
and this is when the back of your retina starts to degenerate
and you start seeing things,
like what you see on the right-hand side of that slide -
a big hole in your vision.
So I can see you all clearly, and I'm 63,
so, clearly, I'm okay so far,
but, boy, did I rush to the optometrist, immediately,
and I had my macula looked at,
and I'm very happy to say that they're beautiful and smooth
and they look just like the one on the left.
But I wondered how I got that mutation.
Neither of my parents have any problems:
they read without glasses, and they're in their 80s now.
So maybe I got lucky, and I am going to escape my genetic destiny,
just like my parents did.
Or maybe I acquired this mutation
at the time when my parents' sperm and egg came together 63 years ago
and a little mini me came out,
there was one tiny little mistake that was made in the copying of that DNA,
that G-to-A transition,
and that's going to make me go blind.
And you know what? I can solve that mystery, theoretically,
by simply looking at my parents ABCA4 genes
and seeing if they have the mutation or not.
And indeed, we are beginning to solve mysteries like this,
over and over again,
to the extent that we now have a map of inherited diseases
for muscular dystrophy, cystic fibrosis, Huntington's chorea,
a number of these,
and we're just ready now to look at the really big problems,
because those are the simple ones, believe it or not.
Now we're ready to look at the genomes of a starfish and a human
and ask, what is missing in my genome that that starfish has
that with all my sophistication,
I still can't grow back my arm if it's cut off?
Or what happens when a tiny little change gets made in one cell of the blood,
and then an algal bloom happens in your blood,
and you end up with leukemia?
Or what happens in our superbly wired brains
when a tiny change gets made
that then produces this blotting out of memory and total dysfunction,
cripple - a crippling disease?
We're in a process where we can actually say,
well, what's wrong with my heart
if I am getting heart failure at 50,
and yet my brother is climbing Sargent Mountain at 80 -
before breakfast?
And what's going to happen to me
if that gene actually does start acting up,
and I start losing my sight and can't see this glorious view from the South Bubble?
So, we are in a position to look into the future now;
we are at the centennial of Acadia's founding,
and we can forecast what the littoral tide will show us in the future -
what's it going to turn up next? -
and it's fairly mind-boggling.
First of all, we know how to read and compare our genomes,
but we don't really know how to decipher them.
We're only beginning to understand;
they're written in a code we can't translate,
like the Rosetta Stone.
And so we've got to crack the code.
But if we could crack the code
and figure out a way to pinpoint and target
every one of the mutations we can find that produces these diseases,
we could actually eliminate them,
just like we did polio with vaccines.
So no more inherited diseases.
We could, in fact, also take advantage of -
now scientists have looked through hundreds and hundreds of genes
and have compiled lists of genes that predispose people to cancer.
Just two weeks ago, this article showed up on the front page of the BBC website.
It's essentially a genetic landscape of breast cancer,
and what this will allow us to do is to pinpoint, in a woman's genome,
every potential risk she might have to develop breast cancer,
and then put that same set of mutations into a mouse
so that the mouse has the same susceptibility as the woman,
and then test all the cocktails of drugs we might be able to test on that mouse
until we find the one that will cure the woman.
So this is huge.
Up at the Jackson Labs,
we're looking at the genetic circuitry
that keeps our brains free of those tangles,
and we're now looking for faults in that genetic circuitry,
which, when combined with a Western diet,
produces Alzheimer's.
So, that's going to be an amazing revelation
when we finally figure it out.
Stem-cell therapy has finally hit the news.
Early days, but trials are now using a patient's own stem cells
to reimplant into the eye of a macular-degenerative patient,
where those stem cells help to replace the missing tissue,
and cure the disease.
So there's hope for me yet.
And finally, in my own work,
we're working on ways
to take that heart disease and turn it into a cure,
find a way to coax the heart to reactivate its own regenerative potential
and replace the damaged tissue.
And it's all within reach.
We actually know of a mouse
that has the capacity to naturally cure itself from heart attacks;
it just, essentially, heals up.
And now we're, of course, taking its genome apart
to try to figure out what's so different about this mouse.
And eventually, if we could find that difference and start modelling it,
first in mice and then in man,
we might have a way to actually address a huge number of diseases
which we now do not have a cure for.
We have, for instance, new ways of looking at cancer.
So, you get a cancer cell that is sitting in the blood -
we now have ways of detecting that -
and then we send in these killer cells,
these immune cells that are engineered to seek and destroy out
the very cancer that is threatening your life.
Or, for instance, nanorobots - an incredible concept.
You inject them into the veins of a patient that's had an ischemic stroke.
The nanorobot knows to go and dissolve the blood clot in the brain
or to deliver the drugs just where they're needed.
I mean, this is all very futuristic, but it's within reach.
And then, of course, my favorite is to discover the starfish secret:
how to grow back those limbs.
And imagine,
if you could grow back the limb of one of these Paralympic champions,
wouldn't that be amazing?
So, these huge differences in the way we're going to be looking at medicine
are going to have equally huge effects on the economy,
and they're also going to change our health span and our life span,
but they might also give us a clue
into the myriad talents that we humans show.
So, I may not live long enough to be able to decode out of my own genome
whatever it is that my father, there, passed onto me
that allows me to have perfect pitch,
but my niece, who's actually got the same trait,
will probably know what that gene is and why she has perfect pitch.
Genes won't tell us why we find Acadia National Park so beautiful,
but they might explain to us
how the visual circuitry
distinguishes all these artists that keep coming to this island to paint it,
like here, this gorgeous picture of low tide by Richard Estes.
And in doing so,
we may actually be able to understand our own uniqueness as humans
and our own destiny,
and the way we fit into the rest of this world,
this natural world,
including, of course, the starfish.
Now, we have to face the fact
that this insatiable curiosity to understand our own nature
comes with risks.
So science has always been something that is subject to nefarious exploitation,
and it's not going to stop anytime soon.
Our own genomes are going to be as public as our fingerprints,
very, very soon.
And with much, much more information in there
that can be exploited and abused.
We simply have to imagine what it would be like
to be able to not only choose the color of our child's eyes
but, perhaps, even determine certain physical or even mental capacities
simply by genetic engineering.
Imagine that we might even decide to grow wings
as a sort of fashion statement.
(Laughter)
It's possible.
We're going to be wrestling with much more serious questions.
Who in our society is going to get those treatments,
those life-saving treatments,
that are, nevertheless, very, very expensive?
What is precision medicine going to do for the general public?
It may be very fantastic for a few of us.
What are we going to do about the fact
that our whole community
is going to be over 100 years old?
Half of the workforce is going to, essentially, be centenarians,
and how is that going to affect our society?
Now, we might fight against this progress and wish that it weren't happening,
but it's a fairly useless fight because the research will go on.
We as humans are insatiably curious,
just like mice,
and we are continuously drawn by the tide of our own existence
to study our own nature
and the nature of the organisms that we share this planet with.
So, the bicentennial of the Acadia National Park
is going to be a very interesting and surprising place to be,
and some of you might actually see it,
be there.
Thank you.
(Applause)