Translator: Theresa Ranft Reviewer: Peter van de Ven
So, here's a question for everyone here:
Do you know why you're as tall as you are?
Or, to put it more accurately,
do you know why you're taller than you are wider?
Or at least I hope that's the case for most of you!
(Laughter)
I'm going to tell you that I think I do know the reason why,
or at least I'm going to share with you some of the reasons
why this may be the case.
And it comes back
to one of the most basic questions in all of biology.
And that is, how is the final shape,
how is the final form, of an organism actually made?
So, for example, I can throw this picture of Eric and Trudy,
and you instantly recognize them as being human beings.
They have the characteristic shape,
they have the characteristic form, of a human being.
Or I can put a picture up there of my puppy Toby,
and you instantly recognize that as being a dog
because of that shape, because of that form.
And you can tell that one thing is Toby and the other thing is the plant,
which he's not supposed to be in there with. (Laughter)
He was a pretty bad puppy when he was young.
And it's also clear
that biology is capable of really exquisite detail.
So if I show you a picture of this fox -
this fox sometimes visits near my office in the evenings in the summertimes;
it's one of the nice things about living here in Colorado -
you instantly recognize
that although that fox is pretty close to being a dog,
you instantly recognize that that is a fox.
And it's because every time a fox is made,
there's this intricate shaping
that makes the form of a fox each and every time a fox is made.
And finally, it's clear that biology is capable of an amazing diversity.
You can get something as bizarre in body shape as this oarfish here.
And so, what I'm interested in, what fascinates me
is understanding how this generation of shape,
how this generation of form, actually occurs.
Now, obviously, this is a huge question.
I can't tell you how to make a fox, an oarfish, a dog,
and a human being, all today.
So, what we've chosen to focus on
is something that's common to each and every one of these organisms.
You're probably looking at these different organisms, going,
"Okay, what could possibly be common between all these different organisms?"
There is actually something.
If you look at them,
each and every one of them is elongated along one axis.
And this is something that's true of almost every higher animal.
They are elongated
along usually the head-to-tail or anterior-to-posterior axis.
Now this, actually, poses an interesting question.
Probably everyone here knows you started out as a single cell.
That sperm came in, it fertilized an egg, it made a cell.
Usually, that cell is spherical.
What will often happen is that cell will divide a bunch of times
to basically make a clump of cells.
And so, how does that clump of cells, how does that sphere of cells
get turned into something
that's elongated enough to make that dachshund?
So I'm going to tell you a bit about how we think that that happens.
Here is a fly embryo, and it's going to start elongating here in a minute.
The anterior-posterior axis is the horizontal axis,
and each one of those polygons there is a cell.
So we can see the individual cells there,
and what you're going to see is this flooding of cells
down towards what would actually be the belly of the fly.
As they flood down there, there's a crowding
and you get a resulting extension or elongation of it.
This is incredibly rapid.
Basically, that movie that you just saw was only 45 minutes of real time.
We can take these little embryos, we can look at them,
we can put them under the microscope in the lab,
and we can actually follow these movements, these cells,
and what exactly is driving these elongation events.
And so, we've known for a while that this is a process
that's driven by something called cell intercalation.
What we did at the beginning of this movie is we false-colored rows of cells
that start off touching each other along that anterior-posterior axis.
And what you're seeing, as this movie plays,
is you begin to see cells, from either a row above that given row
or a row below that given row,
beginning to intercalate or interdigitate or interpose themselves between two cells
that started off right next to each other.
And it separates them.
And what that does is it makes each one of those individual rows longer
as that new cell moves in.
What that does at the tissue level
is it crunches it down in this dimension and makes it longer in this dimension.
That's what's taking place at the cellular level.
So what are the real molecules,
what are the real proteins that are driving this?
Well, we got a clue when we began looking even closer at these cells.
So that top panel has those different-colored cells.
We can strip away the surface of those cells
and begin looking inside the cells at individual proteins, and ask,
"Are there proteins
that may tell us something about how this is happening?"
We got a clue when we saw that there's these proteins
that are shown there in green -
they are localizing to only certain sides of the cells.
Looking at that protein in green,
it looks like it's on the horizontal sides of the cells,
it's not in the vertical sides of the cells.
And work by me and other people in the field
have shown there's whole groups of proteins
that are present on certain sides of these cells.
So, for example, there's proteins that are related to adhesion -
they basically cause things to stick together -
that are present on the horizontal interfaces.
These are proteins like ekaterin, beta-catenin, bazooka -
flies have really weird names for the proteins in them.
And on opposite sides of those cells
there's a group of proteins that revolve around actin and myosin.
Deep in the recesses of your head,
you may start having synapses firing at the mention of actin and myosin.
You may be going back to high school biology,
undergraduate biology,
and you may be thinking about muscles for some reason.
And the reason you're thinking about muscles
is actin and myosin are the proteins that actually cause muscles to contract.
So that got us thinking,
okay, if there's actin and myosin specifically on one side of the cell,
maybe that's making not a whole muscle contract,
but a side of a cell contract.
And so we tested that
and that's actually what we're showing you here.
So we've marked the vertical sides
of all the cells in this movie at this beginning,
and as this plays, you see each and every one of the sides of those cells
shrinking down and disappearing.
So where you have actin and myosin, you have contraction;
and where you have those adhesion proteins,
it looks like they actually stay around.
So we've marked the horizontal sides,
and basically, those sides of the cells are staying around.
Now what I've told you, if you think about this,
is this shrinking down can potentially cause this tissue
to narrow in one dimension.
But how do you get that extension or elongation in the other dimension?
Well, we've got a clue to how this may be happening
when we saw these really unusual structures of cells.
Usually, cells don't like doing what you're seeing here.
You're seeing all these cells coming together in this pie shape -
we call them rosettes.
These cells are all meeting together in a common point.
It ends up that cells don't actually like doing this.
And so, we asked, "Okay, why are they doing this?"
And because we're making these movies that I'm showing you,
we can go backwards in time, we can go forwards in time,
and ask how are these structures forming
and then what's happening, once they've formed, to them?
And what we saw
was these arrays of cells, these rosettes of cells
are forming from pairs of cells that are lined up along the vertical axis,
and you can see them beginning to contract the internal sides of those cells
to eventually come together into a rosette.
What's interesting about that is that brings, for example,
the dark green cell that's way at the top
and the white cell that's way at the bottom
into close contact with each other.
Then what happens is those two cells
that were nowhere near each other at the beginning
begin building a specific side of that cell.
And look at what that does to the overall group of the cells.
It takes an array of cells that was elongated like this,
and in the end
it turns it into an array of cells elongated like this.
And I call this the Sesame Street lesson of our work -
that actually cooperation is good.
These single cells on their own couldn't do what I'm showing you here,
but that basically by them cooperating their activities together,
you can see them actually reforming themselves
and driving the change of this tissue and basically making it longer,
basically potentially making that organism taller.
And here's a movie.
We'll show you those rosettes popping up at various points.
You'll see them popping up in different places as they form.
You can see them breaking down certain interfaces,
building up other interfaces,
and occurring basically stochastically on the sheet.
And I'll just finish by making the case for curiosity.
What I'm telling you may seem sort of abstract,
it may seem like I'm just telling you how to make something longer.
Does this have any relevance to human health?
Should the federal government be funding my research as they are?
(Laughter)
And what's interesting
is this process of breaking down certain sides of cells
involves the same proteins that now doctors have shown
is involved in, basically, when cancers get really dangerous.
So in our system,
we're breaking down certain sides of cells to make those rosettes.
If you look at the most dangerous cancers,
what happens is those cells in those cancers
begin breaking down their adhesion
to begin escaping to other points in the body.
As long as the tumor stays in the same place,
a surgeon can treat that pretty easily.
He goes in, he cuts out that tumor, you're okay. Right?
But once those cells begin losing adhesion,
begin moving out of that tissue to other places in your body,
that's when you get a really poor prognosis.
Our studies are actually telling the doctors
how these proteins are functioning in a normally functioning organism.
And I'll end by thanking first the University of Denver
for giving me a lab to do my work in.
I'd like to especially thank Jennifer Zallen and Ori Weitz,
who are at the Sloan Kettering Cancer Center
and were intimately involved in this work.
And finally, thank the National Institutes of Health for giving me money to do this.
Thank you, everyone.
(Applause)