午夜福利1000集合

CHECKED your insides recently? They could be the wrong way round. No kidding.
The chances are that at least 75 New Scientist readers are the mirror
image of the rest of us, and they鈥檙e probably none the wiser.

Most of us don鈥檛 give our internal body plans a second thought. You鈥檝e
probably been taught that your heart lies on the left-hand side of your chest,
and if you鈥檝e got a right-sided pain in your belly you start getting paranoid
about your appendix. But for one in 8500 people, the exact opposite is true.
It鈥檚 as though they had stepped through a mirror into looking-glass land: the
handedness and placing of their internal organs are completely reversed. It鈥檚 a
secret that many of them carry to the grave, because the reversal is so perfect
they never even notice.

But these people are the lucky ones. An unlucky few find themselves stuck
halfway through the mirror in a deadly limbo where their body pattern is neither
fully one way nor the other. Their internal organs can get tangled up in a
life-threatening jumble, and many need emergency surgery as soon as they are
born. Even partial forays into looking-glass land can land you in trouble: minor
disruptions of this left-right patterning process could be a leading cause of
congenital heart problems in newborn babies.

Curiouser and curiouser indeed, but how do these problems arise? You might
think that college-educated biologists would have figured out how to tell left
from right by now. But for an embryo it鈥檚 not that simple. How it does this, and
then sets up its internal asymmetry, has puzzled developmental biologists for
decades. At last, though, researchers think they may have found the answer in a
thoroughly unexpected place: a tiny molecular motor that waves things to the
left like a police officer directing traffic.

Packing puzzle

Why should our internal organs be asymmetric in the first place? For two main
reasons, says Joseph Yost, a developmental biologist at the University of Utah.
The first is a straightforward packing problem鈥攈ow to fit everything
together in a restricted space. The lungs, for example, have to share space in
the chest with the heart and its great blood vessels. To make room, your left
lung has two lobes and your right has three, and the major airways, the left and
right bronchi, are tilted at different angles. The upshot is that if you manage
to inhale a peanut in some bizarre drunken accident at a party, it鈥檚 practically
guaranteed to lodge in your right lung. A neat piece of trivia to test the
doctors on when you finally stagger, hacking and spluttering, into your local
casualty department.

The second reason is to do with making organs function efficiently, and
making sure that they link up to each other properly. Nowhere is this more
apparent than in the heart, says Nigel Brown, a heart development expert at St
George鈥檚 Hospital Medical School in London. Researchers in Britain have recently
confirmed that the heart鈥檚 asymmetric design improves blood flow and makes it an
extremely efficient pump. In addition, the right side of the heart is smaller
than the left, because it collects blood from the body and only has to pump it
across to the lungs, while the left side has to pump oxygenated blood all the
way round the body. So not only does the heart have to be asymmetric itself, it
must also be plumbed into the lungs and the body the correct way.

If your left-right pattern is completely reversed, a condition called situs
inversus, there鈥檚 no problem, because all the organs are reversed with respect
to each other (see Diagram).
(Curiously, such people have no more chance
of being left-handed than the rest of the population.) But between there and
normality lies dangerous ground. 鈥淎nything in between and you鈥檙e in various
degrees of trouble, depending on exactly what鈥檚 wrong,鈥� says Brown.

The most extreme problem is called isomerism. In this condition, the organs
are entirely symmetrical, as if you鈥檙e standing with a mirror placed down the
midline of your body. The way your organs are affected depends on which side of
your body is being reflected in the mirror. If it鈥檚 the right side, your spleen
will be missing and both your lungs will have three lobes. Worst of all, your
heart will be symmetrical, too.

Too right

A heart with two right sides is a double whammy of bad news. First, the
chambers won鈥檛 be strong enough to pump blood around the body. And even if they
could manage, you run into a second problem, which is that the blood vessels
that connect other organs to the heart don鈥檛 know where to attach. So they just
plug themselves in randomly to the nearest blood vessels, such as the hepatic
vein, which carries blood from the liver. It鈥檚 as if someone鈥檚 done a cowboy job
on the body鈥檚 plumbing. Babies born with a double-right heart need urgent
surgery to have any hope of surviving.

But you don鈥檛 have to go to anything like this extreme to be affected. A mix
of organs, some the right way and others inverted鈥攁 condition called
heterotaxia鈥攁lso lands you with plumbing problems. More subtle problems
with left-right patterning could affect many of the 8 per 1000 British children
born with congenital heart defects, says Brown.

As well as being important clinically, understanding left-right patterning is
a challenging intellectual problem that has puzzled developmental biologists for
years. When an embryo starts to develop, it needs to find its bearings so that
it knows where different parts such as legs and guts should grow. So it
establishes reference lines or 鈥渁xes鈥� that run from head to tail and belly to
back, marking which end is the head and which side is the front. Biologists have
a fair idea of how the embryo does this, but the left-right decision is
trickier. To establish left-right asymmetry, an embryo must break its bilateral
symmetry in a consistently handed fashion, and set up a new axis exactly
perpendicular to the other two.

So what immortal hand or eye could break bilateral symmetry? In the early
1990s, Brown and Lewis Wolpert, a developmental biologist now at University
College London, suggested a mechanism. Imagine a molecule in the shape of the
letter F, they said. No matter how hard you try, you can never superimpose this
F molecule on a mirror image of itself with the same side facing upward鈥攊n
other words, it鈥檚 鈥渃hiral鈥�. This intrinsic handedness means that embryos could
use the F molecule to reliably tell their left hand from their right
(see Diagram).

That鈥檚 fine and dandy in theory, but finding this hypothetical molecule has
been another matter. For a start, nobody knew what it was, or even what it
looked like. Biologists have built up a fairly good picture of the genes and
biochemical pathways that act once the symmetry is broken. But it鈥檚 only now
that the F molecule鈥檚 identity may have been unmasked.

The first clue came in 1976 from studies on a group of people with a rare
condition called Kartagener鈥檚 syndrome. These people show a range of left-right
problems, and intriguingly, the men are infertile. When Bj枚rn Afzelius of
Stockholm University took a closer look he found that the sperm tails, or
flagella, of these men are paralysed, as are similar hair-like structures called
cilia on other cells. What was the link between cilia and left-right asymmetry?
Afzelius suggested a connection. When cilia beat, he said, they might force
developing organs to bend in a particular direction. Nobody paid much attention
to this idea at the time, but 22 years later, a chance discovery by researchers
in Japan pushed cilia back into the limelight.

Nobutaka Hirokawa and his colleagues at Tokyo University were studying a
group of proteins called kinesins. These are the packhorses of the cell, large
protein complexes that shoulder packages called vesicles that contain anything
from chemical messengers that cells use to talk to each other to the bricks and
mortar needed to build cellular structures. Kinesins tramp up or down the cell鈥檚
scaffolding, the cytoskeleton, to deliver their load to its required
destination. Hirokawa鈥檚 group had identified a new kinesin complex in mice, and
to find out exactly what it was doing they genetically engineered mice that
lacked part of the complex.

All these mice died as young embryos 鈥攁nd about half turned out to have
reversed left-right patterning. Intrigued by this result, the researchers took a
closer look at very young embryos, specifically at a structure called the node
that was known to be important for dictating left-right asymmetry. The node is a
triangular patch of cells that forms a pit at the head end of the developing
embryo before marching down the embryo laying down cells that establish the
head-tail axis. It鈥檚 the embryo鈥檚 Mission Control, telling cells where to go and
what to do. The node is normally covered in cilia, but those of Hirokawa鈥檚 mice
were bare. Without the special kinesin, the cells couldn鈥檛 build any.

However, this still didn鈥檛 explain why half the mice had situs inversus.
Studying the nodal cilia under an electron microscope only deepened the mystery,
as they turned out to have an unusual structure. Cilia are usually made up of
nine pairs or 鈥渄oublets鈥� of tubes called microtubules arrayed around two central
singlets: this is the classical 鈥�9+2鈥� arrangement. Large protein motors called
dyneins form arms which link the outer tubule of one doublet with the inner
tubule of the next. The action of these motors forces the doublets to slide past
each other lengthways, driving the lashing motion of the cilia in the process,
although nobody knows exactly how.

The nodal cilia have a slightly different structure that lacks the central
pair, and scientists have generally assumed that these sorts of structures,
called monocilia, don鈥檛 beat. Biologists have largely thought of them as sensory
structures: the light-detecting rods and cones in our retinas, for example, are
monocilia. Just to be sure, though, Hirokawa鈥檚 group watched these cilia in
normal living mouse embryos, using a sophisticated wide-angled microscope to
provide maximum depth of field. To their astonishment, they found that the cilia
were moving. But instead of following the whip-like motion of 9+2 cilia, they
were whizzing around clockwise like tiny propellers. 鈥淭his was a very big
surprise,鈥� says Hirokawa. When the researchers added tiny fluorescent beads to
the fluid around the embryos, the beads were consistently wafted from right to
left. Suddenly, the penny dropped. What if, instead of beads, this 鈥渘odal flow鈥�
wafted a chemical signal over to mark the left side of the embryo?

It鈥檚 an intriguing possibility, but Hirokawa鈥檚 mutant mice alone don鈥檛 prove
that cilia hold the smoking gun. After all, kinesins could influence a number of
cellular processes, and it鈥檚 not just asymmetry that鈥檚 affected in the mutant
embryos. So how do we know that nodal cilia are anything more than gyrating red
herrings?

Well, we don鈥檛 know for sure yet. Nodal cilia are tiny, and hardly anyone has
actually witnessed them moving because they are so hard to see, so many
researchers remain sceptical. One of the doubters was Martina Brueckner, a
cardiologist at Yale University, who wanted to see the cilia for herself. 鈥淚
spent most of last winter struggling with this using every microscope on this
campus,鈥� she recalls. 鈥淚 couldn鈥檛 see it.鈥� Finally, she managed to borrow a
microscope with a very wide-angle lens like Hirokawa鈥檚鈥攁nd there the cilia
were, twirling away. 鈥淭hey鈥檙e there,鈥� she says now. 鈥淚t鈥檚 real.鈥�

Brueckner had a special interest in the outcome because she had been studying
mice with a mutated gene called inversus viscerum, or iv,
which causes various forms of left-right reversal similar to those seen in
people. When she and her colleagues isolated the gene, it turned out to encode a
dynein鈥攖hey called it left-right dynein鈥攖hat was similar to the
dyneins found in the outer arms of cilia. The team then genetically engineered a
mouse strain that lacked only the head-end of the dynein, which is crucial for
its motor function. Under the borrowed microscope, the nodal cilia on her
engineered mice stood stock-still like a battalion of tin soldiers, their dynein
motors jammed. And sure enough, the mice had situs inversus. 鈥淭his supports our
hypothesis very well,鈥� says Hirokawa. The case for nodal flow was starting to
look stronger.

So are cilia truly the movers and shakers of symmetry breaking? To find out
when the cilia and nodal flow were active, Hirokawa and his team looked at the
expression pattern of a gene involved in left-right asymmetry. It is the
earliest-acting gene known so far, and is normally expressed only on the
left-hand side of the developing embryo. In the mutant mice, however, it was
expressed either on both sides or not at all. So whatever process is going wrong
in Hirokawa鈥檚 mutants, it acts earlier than any other known step, possibly
forming the initial symmetry-breaking mechanism that biologists are searching
for.

Moreover, cilia themselves have all the qualities that researchers were
looking for in the elusive F molecule. Imagine you鈥檝e clambered up a nodal
cell鈥檚 cytoskeleton, and are peering up a cilium as it towers out of the
cell鈥攁 beautifully intricate molecular machine. Look at the way it鈥檚
constructed, and you鈥檒l notice that the cilium itself is asymmetric
(see Diagram).
The dynein arms that link the nine outer doublets are all angled to
the right, like spokes on a pinwheel. Cut a slice across the cilium, and you
will find that it cannot be superimposed on a mirror-image of itself: the
structure is chiral. Could this whole massive structure fulfil the role of the
handed molecule postulated by Brown and Wolpert? 鈥淚f you broaden the concept at
that level,鈥� says Brueckner, 鈥渢hen the cilium is a perfectly beautiful F
molecule.鈥� Combined with the shape of the node, the clockwise twirling of the
cilia generates the leftward flow.

It鈥檚 an elegant solution to a complex problem, but the jury is still out, and
the response to Hirokawa鈥檚 nodal flow model has been mixed. Most developmental
biologists are intrigued, but cautious. Intellectually, it鈥檚 a very appealing
model, says Brown, but he questions whether the subtle wafting currents would be
robust enough to do the trick reliably. Another problem with the theory is that
researchers have yet to pinpoint an equivalent population of cilia in other
species. Finding them in other animals鈥攅specially in standard lab
creatures such as chicks and frogs鈥攚ould add more weight to the idea, says
Yost. 鈥淢y general sense is that the cilia [model] is a very exciting
possibility, but there are still a few issues that need to be resolved鈥攁s
far as knowing that they are the instigators of left-right patterning,鈥� he
adds.

Wolpert is also hesitant to hail the unmasking of his elusive F molecule just
yet. 鈥淚 think it鈥檚 a remarkable observation, but you鈥檝e got to be a little
careful,鈥� he says. 鈥淗ow does one know that it is the cilia that are doing it,
and not just a mutation that affects something else and the cilia?鈥� His
reservations are echoed by Denys Wheatley, a cell biologist at the University of
Aberdeen. We need more robust evidence that the twirling motion of cilia
actually causes left-right patterning, he says.

What would convince the doubting Thomases? If someone were to use a jet of
water to interfere with the nodal flow, says Wolpert, then he鈥檇 be impressed.
鈥淚t鈥檚 a trivial experiment,鈥� he laments. 鈥淚 can鈥檛 understand why they don鈥檛 do
it.鈥� But Kyle Vogan, a researcher at Harvard Medical School who studies chick
development, is enthusiastic about the theory. 鈥淚t does have the power to
explain some of the most challenging issues related to left-right patterning,鈥�
he says. The problem of finding similar cilia in other animals could all be down
to timing, he says. They may be active at different stages in different
species.

If Hirokawa鈥檚 theory turns out to be right, it opens up a whole new
understanding of how embryos tell left from right and how this critical
asymmetry goes wrong. The irony is that the human race has always knocked
asymmetry, seeing it as a sign of imperfection. Your symmetrical outside might
make you a beauty, but it鈥檚 your asymmetrical insides that keep you alive. It鈥檚
something to ponder as you inspect yourself in the mirror in the morning. The
next time you claim your heart鈥檚 in the right place, you may want to think
again.