Randomness. Shakespeare referred to it. The Bible talks about it.
People love to bicker about what it really is, or whether it truly
exists. And creationists, especially those of the ID subspecies,
consider it a fighting word. A random process, many would say, is a
process that doesn't involve God, or direction, or intention, or
whatever it is that the culture warriors of the Discovery Institute
are so foolishly fighting for. Ah, but it's not just the
propagandists of design-think who can mistakenly assume that an
ordered process is "directed." Consider this tale of a random
process being put to surprising use during vertebrate embryonic
development.
Our story comes from Nature about a month ago, and I will
present it in four acts.
Act I: The elongation of an embryo
We all know that animal embryos acquire their form through various
morphings and twistings. One interesting example is axis elongation,
which is just what it sounds like: the embryo stretches out until it
clearly has a long axis, then continues to elongate to form something
with a head and a tail and everything in between. But "stretch"
is a poor term for what's really happening: the tail end of the
embryo is growing while the structures closer to the head are
beginning to develop into recognizable structures. Developmental
biologists know that new cells are added near the tail end, and we
know that various directed processes control many similar movements
during early development. It was reasonable to assume that these
mechanisms would account for embryo elongation, but the actual
processes were unknown before the experiments of Bénazéraf and
colleagues ("A random cell motility gradient downstream of FGF
controls elongation of an amniote embryo," Nature 8 July
2010).
The authors employed an old warhorse of developmental biology, the
chick embryo. At stage 11, the embryo looks nothing like the animal it will become; it has a head-like thing at one end (the top in the picture on the right), a weird hole at the bottom (Hensen's node), and some blocky structures called somites in between. Down at the bottom, on either side of the hole, is a tissue called the presomitic mesoderm
(PSM). The anatomical details needn't concern us; what matters is
that we understand that the embryo is elongating toward the bottom,
that cells are being made near the top of that hole and that they are
moving toward the tail, making it grow. Curious about how this works,
Bénazéraf and colleagues started deleting pieces of the tail-end of
the embryo, and they found that the PSM was critical for elongation.
Good to know.
Act II: Cell movements in the elongating embryo
So, what's going on in the PSM that causes elongation? The authors
used a nifty technique called electroporation to label the cells in
that region so they could watch them as the embryo grew. Basically,
they used an electric field to introduce DNA into the cells of
interest the day before; the DNA caused the cells to express the
wonderful and famous green fluorescent protein (GFP) so that
individual cells could be monitored as the embryo continued to
develop in culture outside of the egg. They found something
interesting: near the tail of the embryo, the PSM cells were more
motile than they were near the front of the PSM. But the cells near
the front were more packed together. So try to picture it: in this
region on either side of the center of the tail end of the embryo is
an area (the PSM) of cells that are moving more frantically near the
tail and that are more packed together toward the head. It would seem
as though the cells are busily moving toward the tail, and that they
get less crowded and more mobile as they get there. And when the
authors looked at movement of individual cells, sure enough, there
was a directional bias in the movement, meaning simply that cells in
the PSM tended to move toward the tail. It looks like a simple case
of directed migration of cells toward a target. Interesting, maybe,
but not such big news. But then, a noise from the next room. Exeunt.
Act III: Random cell movements in the elongating embryo
So cells seem to move toward the tail. This could mean they're
being directed toward the tail by some kind of homing mechanism, and
this would be a reasonable expectation. But because the embryo is
elongating, it could be that the directed movement of individual
cells is an illusion: the cells are moving toward the tail because
the space they inhabit is moving toward the tail. The authors
addressed this by cancelling out the effect of elongation of the
cells' environment, and focusing solely on the movement of cells
within that environment. The environment in this case is the
extracellular matrix, or ECM, as indicated by one of its components,
fibronectin. I'm sorry about the jargon, but I included it so I could
quote the authors in full as they describe the results of the
experiment:
Surprisingly, the movements of cells relative to the ECM
did not show any local directional bias. The mean square displacement
of these cells compared to the fibronectin movement scales with time,
indicating that cells exhibit a 'random walk'-like diffusive
behaviour, with the diffusion of cells relative to the fibronectin
following a posterior-to-anterior [back-to-front] gradient.
In other words, the cells are moving randomly, behaving like
molecules diffusing in a liquid. The authors verified this by looking
at cell protrusions, the telltale signs of a cell's migrational
direction. The protrusions all pointed in random directions.
Amazingly, this seemingly ordered march of cells toward the back,
resulting in the growth of the tail end of the embryo, is the product
of random cell movement. And yet it yields an ordered result. How?
Act IV: A gradient of random cell movement controlled by a
conserved developmental signaling system
Recall that cell movement in the PSM is not uniform: cells near
the tail move (randomly) more. The authors knew that an ancient and
well-known signaling system functions in a similarly graded fashion
in that tissue. Known as the FGF/MAPK pathway, it's fairly simple to
manipulate experimentally. Bénazéraf and colleagues found that
whether they turned the signaling up or down, the result was the
same: elongation was stunted. This might seem strange, but it makes
perfect sense: it's the graded nature of the signaling that matters,
so turning it all the way up or all the way down erases the gradient
and leads to the same result. What matters, for elongation, is that
random cell movement is greater in the back than in the front. This
leads to elongation, because the tail end contains cells that move
more and have more freedom of motion due to their being less tightly
packed.
The upshot is that an ancient conserved signaling system causes a
simple gradient of random movement which, in the presence of physical
constraints, leads necessarily to elongation of the embryo in one
direction. It looks for all the world like homing or some other
directed migration, but it's not. And, intriguingly, the authors
conclude by suggesting that the mechanism might be quite common in
the biosphere:
Axis formation by outgrowth is a common morphogenetic
strategy that is widely evident in animals and plants. Thus, the
mechanism described here might apply to other well-characterized,
polarized axes, such as the limb buds, in which a similar FGF/MAPK
gradient is established along the proximo-distal axis.
Randomness. Learn to love it. The End.
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Image credit: "Normal stages of chick embryonic development," poster on Developmental Dynamics site
Bénazéraf, B., Francois, P., Baker, R., Denans, N., Little, C., & Pourquié, O. (2010). A random cell motility gradient downstream of FGF controls elongation of an amniote embryo Nature, 466 (7303), 248-252 DOI: 10.1038/nature09151